Opioid Addiction what's Going on and what Might Stop it - Juniper Publishers

 Addiction & Rehabilitation Medicine - Juniper Publishers

Abstract

Though opiates are the most effective form of painkillers, they are highly addictive and many of these opiate addictions lead to heroin addictions or death. The medical community has worsened this problem by over prescribing and prescribing strong painkillers for routine surgeries in which patients do not need high-strength medication. Because opiates are expensive, many abusers sum to heroin instead which is cheaper and does not require a prescription, and heroin usage often results in overdose and fatality. However, research being conducted in the medical research field shows signs of optimism in the development of alternative, Jess addictive painkillers. In confronting the issue at hand, lives will be saved and addiction rates will be significantly lowered by maintaining strict prescribing parameters to patients who actually need the opiates.

Keywords: Addiction; Opioids; Heroin; Painkillers

Mini Review

Opioid addiction in the United States is becoming increasingly prevalent as higher numbers of people are killed as a result of long-term opioid usage. Doctors continue over prescribing medications and issuing refills for people who do not need such high-strength painkillers or have no reason to continue usage. Opioid addiction leads to terrible withdrawals that consist of anxiety, agitation, muscle aches, headaches, and insomnia which make it easier to continue the use of opiates than to discontinue usage. However, new breakthroughs in addiction research are yielding promising results for opioid abusers.

The Bayer Co. began commercializing heroin, an opioid, in 1898, though morphine was used to treat pain during the Civil War. Heroin and other opioids were used as anything from cough suppressants to painkillers because no one had yet discovered the harmful side effects of "these poppy derivatives" [1]. However, the Harrison Narcotics Tax Act of 1914 "imposed a tax on those making, importing or selling any derivative of opium or coca leaves" and heroin was then illegalized in 1924. Percocet and Vicodin were introduced in the 70's, though a paragraph published into the New England Journal of Medicine in 1980 by Jane Porter and Dr. Hershel Jick stated, "there were 882 patients who received at least one narcotic we conclude that the development of addiction is rare in patients with no history of addiction" [2]. This paragraph paved the way for opioid addiction because it was assumed that for pepie with no history of addiction, that there was no risk of addiction to opioids, and thus, doctors used no discretion when prescribing painkillers to patients without a history. The analysis included in the study was omitted from the medical journal which stated that the patients only received a controlled amount of opioid for a short amount of time, which is very different from prescription that patients are free to use (or abuse) how they wish.

Purdue Pharma's 1996 release of Oxy Contin triggered an increase in the number of prescriptions by eight million from 1995 to 1996, and in 1998, the company released a video starring patients who took Oxy Contin for their chronic pain called "I Got My Life Back". Following the advertisement, prescription numbers increased by another eleven million. Now, most people have moved on from Oxy Contin after the awareness new studies have brought on and the lack of prescriptions of painkillers available, though heroin has become their new drug of choice because of its accessibility and also because it's cheaper than painkillers. Opioid addiction, with an addiction rate of almost 26%, is a significant problem in the United States and hopefully, these new studies (completed at least within the last two years) will help decrease the addiction and fatality rate of opioids in the country.

The opioid epidemic, which is attributed to both prescription and street drugs, is a topic that requires delicate attention and a serious change in policy. One of the largest issues is doctors prescribing opioid painkillers for unnecessary circumstances, such as low-risk surgeries. In a recent study, it was concluded that four out of every five patients-155,297 in total-filled an opioid prescription within a week of their surgery for: "carpal tunnel repair, laparoscopic gallbladder removal minimally invasive knee surgeries, and knee repair" [3]. These surgeries are usually day surgeries and then the patients are brought back in for follow-ups to ensure the operation was successful, and many patients heal quicker and return to work or school a few days after their operation. So why are doctors prescribing highly addictive opioid for such low-risk surgeries? While it might be necessary for some patients to have access to a few painkillers in case they are sore as a result of the surgery, it should not be an automatic pass for an opioid prescription, especially with such a high addiction rate. If a patient goes home from surgery and faces soreness or excessive pain as they are healing, it might be necessary to provide a limited supply of medicine to assist them in their healing; however, many opioids slow the healing process and therefore are working against the procedure itself.

For "patients undergoing knee arthroscopy investigators estimated a greater than 18 percent increase in the total amount of opioid dispensed" which means people are receiving more medication and thus increasing their chance of developing an addiction. It is a necessity that doctors fix the current prescription requirements- just about anyone who says they have pain can land a prescription with a few refills-and ensure that people who do actually need the opiates are able to do so in small doses that do not allow for abuse. Medical professionals should provide individuals with chronic pain a different form of relief because it has been found that opiates can actually increase pain by affecting a person's pain tolerance.

In a June 2016 study by the Johns Hopkins Bloomberg School of Public Health, it was discovered that six out of ten adults who were prescribed opioid painkillers end up with leftover pills from their prescription that they said they chose to save for a later date. "Fewer than seven percent of people with extra pills reported taking advantage of 'take back' programs" which allow a person to dispose of their extra pills by returning them to pharmacies, police departments, or the DEA without penalty ("Six in Ten Adults Prescribed Opioid Painkillers Have Leftover Pills", 2016). By over prescribing medication, adults are given the opportunity to use the pills later or to share them with friends who have not been given their own prescription and therefore might not respond well to the opiates.

Many people are not given information on how to properly dispose of extra medication, so they keep it in case their pain comes back in the future. However, the larger factor at work here is why doctors continue to prescribe more medication than needed for a patient. In 2014, the foremost cause of injury death in the 25 to 64 age group was drug overdose most of which are accredited to opiates ("Six in Ten Adults Prescribed Opioid painkillers have Leftover Pills", 2016). Saving pills increases the likelihood of heroin abuse, also; the longer a person consumes opiates, and the more likely they are to develop an addiction that turns into heroin abuse. Among 592 participants, 60.6% of them reported having excess pain pills from a prior prescription, 61.3% of whom decided to keep the painkillers for later use instead of properly disposing of them. This, in turn, keeps the opioids around the house (less than 10% said they secured a location for their excess medicine) for anyone to grab and ingest, including children who swallow them accidentally, or anyone else looking for a quick high because no one will notice they are missing.

In response to this problem, doctors should fight the issue by prescribing smaller quantities of opiate painkillers and tell their patients to make an appointment if and when they need more painkillers. By reducing the quantities significantly, it would not allow for spare medicine to sit around their house waiting to be taken later, though people who take all of their pills could still be prescribed more if necessary. This way the doctors are aware of how long their patients are actively consuming the medication and there are no pills left to be shared with friends or taken later to contribute to the development of an addiction. Addiction has only recently had light shed on it as a public issue, so fixing the system which created it is going to take time. But, if doctors are made aware of the life-threatening addictions that their patients might develop because of lackadaisical prescribing, it can be solved and they can work with patients more close y in eliminating the epidemic.

For children ten to twelve years old who begin taking opioids for nonmedical purposes, it is more likely that their fate will lead to heroin usage as an adolescent or young adult than other age groups. "Prior use of nonmedical use of prescription opioids is a strong predictor of heroin use onset" because opiate prescriptions become hard to obtain, and therefore individuals turn to heroin to feed their addiction. Heroin is cheaper and more widely accessible than prescription opioids, and for children who begin abusing them early on, it is likely they will progress to heroin in the future. Users "can obtain the equivalent amount of heroin for about one-tenth the price" making it easier to jump to heroin from painkillers and many adolescents develop connections to heroin dealers through their opioid addictions [4].

Heroin users are more likely to die of HIV transmitted through unclean needles, and children should not be at risk for developing HIV later in their life because of an opiate addiction beginning at age ten. Through efforts aforementioned, such as getting rid of extra medication around the house to prevent it falling into the hands of children, children would fail to develop addictions that lead to heroin abuse. Because children's brains are most susceptible in the early years of their life, children ten to twelve are most likely to feel long terms effects of opiate usage and be unable to combat the addiction successfully because their brains developed on the substance. Suggestions to pediatricians about testing their patients ten years of age or older for drug usage have been useless as many doctors feel like there is no need to test such young children for use; by remedying this, however, early interventions could help children cure their substance use and prevent opiate addiction and heroin usage altogether.

In a study led by Michael Yokell of the Stanford School of Medicine, it was identified that 67.8% overdoses at U.S. hospitals in 2010 were the result of prescription opioids, followed by heroin which was responsible for 16.1% of overdoses out of a total of 135,971 opiate-induced overdose cases [5]. Included in the prescription opioid percentage of overdoses is methadone, a drug which is commonly used to combat opioid addiction. However, methadone itself is addictive and comes with its own set of withdrawal symptoms, similar to the withdrawal effect of sedatives (neuroleptics and benzodiazepines) and "the withdrawal with methadone lasts longer [6]. Treating one withdrawal with a medication that results in another withdrawal is ineffective and brings the attention to a need for an alternative solution for opioid addiction.

A new substance, made from scratch by researchers at the University of California-San Francisco, is said to be the key to the future of treating addiction. The substance, tested only in mice for now, inhibited pain receptors without triggering side effects like trouble breathing or constipation, the two most commonly associated with opiate usage ("Safer opioid painkiller made from scratch" 2016). With a computer program, the researchers ran simulations on "candidate drugs" to figure out all the possibilities for substances, and then tested their resulting substance in mice who responded positively to the new chemical. The dopamine inhibitors were not activated, through the pain receptors were targeted in a specific fashion and the mice's receptors did not respond negatively to the new drug. Instead of treating patients after they have already developed an addiction to opiate painkillers, this new substance would treat pain and therefore eliminate the need for opiates to be prescribed. Targeting pain at the source and eliminating the pain without adding the possibility of addiction is ideal for the future of the United States' opioid epidemic, and alternatives to painkillers are the only way to eradicate the repercussions later [7,8].

Instead of fixing the problem, policies have made it easier to transition from prescription painkillers to heroin and many people struggling with addiction are thrown in jail for their illicit drug use-which many times results in relapse-or are unable to seek treatment because of the overwhelming cost of rehab. Overall, opioid addiction in the United States is a widespread problem, though science continues to take steps in the right direction to eliminate the potential of addiction. In addition to the users, society must hold doctors accountable in only prescribing opiates when medically necessary and limiting the number of pills patients can receive at one time.

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Systematic Review and Meta-Analysis of the Possible Concerns of 5G Radiation and Radiation Emitting Materials - Juniper Publishers

 Juniper Online Journal Material Science - Juniper Publishers

Abstract

This mini review provides a brief introduction on the controversy surrounding the advent of 5G technology. Furthermore, it attempts provide general knowledge on antenna radiation to extend to laymen the possible effects of 5G cell towers by explaining the how a microwave radiation works and the mechanics of 5G radiation. Finally, it explores the honesty of the uncertainty surrounding the latest generation of wireless technology. It also discusses concerns about materials potentially capable to produce 5G radiation.

Keywords: 5G Radiation; 5G Emitting materials; Safety & concerns

Introduction

Cell phone radiation has been a controversial topic for some time now with the new advent and planning for 5G cell towers [1-5]. The American Cancer Society states that since radiation is relatively low compared to gamma rays and ultraviolet light, it is not strong enough to break chemical bonds in DNA and thus is not a threat of cancer [3-6]. They also contend that the waves are too long to be concentrated within the body thus there would likely be no effect on the cellular level since cells are many times smaller than the wave [7-11]. Lastly, they contend that the towers are at a safe distance, so even if you were exposed to such radiation, it would be like being exposed to background radiation [9-14]. It is well understood that this new 5G technology promises faster connections and download speeds however, it can also give great enhancements with developing technologies such as autonomous cars, smart cities, and virtual reality. From an economic perspective it would make sense to further investigate 5G to strengthen the potential of these hot commodities and lucrative avenues. The caveat is, there is a knowledge gap regarding the health effects of 5G radiation. The predecessors of 5G, such as 3G and 4G have been extensively studied. These studies seem to suggest that cell phone radiation can lead to adverse effects [10-16]. Thus, the public concern is that increasing the frequency of the radiation will also increase the effects of the radiation [14-16].

This review does not try to dispute the idea that radiation related to cell phones and cell towers will not have adverse effects. However, the purpose of this paper is to explain the basics of radiation within the radiofrequency spectrum and to exploit possible concerns and byproducts that should be taking into consideration if 5G radiation is to be implemented into the cell phone industry.

Working Mechanism

To understand possible effects of 5G radiation, it is important to know the basics of radio frequencies to thereby apply the mechanics in different situations. Looking at microwave ovens is a good place to derive how radio frequencies are created. The general idea of the workings of the microwave is that the electromagnetic waves administered at radio frequencies are constantly oscillating. When these oscillating electromagnetic waves interact with dipolar molecules such as water (which are molecules that are positively charged at one end and negatively charged at the other end) the oscillating field of the electromagnetic wave causes the molecule to rotate in an increasing manner [16-18]. This oscillating rotation causes proximal molecules to bump against each other thereby causing friction while also increases the kinetic energy within the system, which ultimately increases the thermal energy of the target substance in the microwave. While the surface of the target substance heats up the slightly quicker due to the fact it is the outer layer that is first exposed to incident radiation, the electromagnetic waves are penetrating at the given radio frequencies, thus given enough time one can expect a near uniform distribution of thermal energy inside the subject, though it is not uncommon to see various cold and hot spots in the target substance due to various peaks and nodes of the electromagnetic wave effecting the target. The focal point of microwave production lies within the magnetron. The magnetron contains cooling fins which are thinly sliced plates used to dissipate the acquired heat. The other component of the magnetron are two magnets and a vacuum tube.

To harness the electromagnetic wave at a specific frequency you must send a voltage through the filament in the center. The filament is made out tungsten being it has a high thermal tolerance and thorium because it is rich with electrons. The filament heats up which causes electrons to escape where they proceed to head towards the outer copper anode. The magnetic field causes the path of the electron to bend back from which it came. The strength of the magnetic must maintain the optimum field so the electrons proceed with their optimal orbits which thus allows for radio frequencies to seep through the cavities.

5G Mechanics

When discussing the mechanics of 5G it is important to understand the innovations through each generation. The first generation was the first cell phone. 2G gave us the opportunity to send text messages. 3G gave us the freedom to use the internet. 4G increased the overall speed of the previous applications. And 5G as cited earlier comes with better connections and download speeds. These features are accomplished with 5 components of 5G which include millimeter waves, small cells, massive MIMO, beamforming, and full duplex. The first component of millimeter waves is indictive of the specific part of the electromagnetic spectrum used. Radio frequencies is the part of the spectrum that ranges from 3kHz to 300GHz. Typically, 4G operates from 2-6 GHz. The issue is that as more cell phones come online, there will be less space available and more crowded lines [15-19]. This problem has pushed scientists to study possible ways of increasing the spectrum to reach beyond the standard 4G level of 6 GHz. This leads us to the second component of small cell networks because the higher frequencies tend to get absorbed easily by things like trees and buildings which are common in cities and rural areas. These small cell towers will be a lot smaller and use a lot less power than the predecessor 4G tower which was larger and operating at a much higher wattage. The third component is massive MIMO which means multiple input multiple output and is understood as the device to hold on the ongoing and incoming traffic signals.

All those signals will have overlaps once redistributed; thus the fourth component is needed, the beam former, which filter the signals to the specified device. The beam former uses timing and algorithms to accomplish effective redistribution of incoming and outgoing cell signals [17-20]. The full duplex is the part of the system that allows for multiple people to talk at the same time because of the route it gives the given incoming signals.

Possible Effects

Antennas are the focal point of wireless communications. Cell phone companies have managed to engineer ways of constructing the antenna to release desirable wave formations. Thus, different antennas will create electromagnetic waves of different forms. Thereby when calculating the potential risk of cell tower radiation, it is important to note that if a group of people were standing in a circle equidistant from the source antenna, they might not necessarily revive the same amount of radiation depending on the shape of the wave [14-16, 18-21] (Figures 1-3). 5G towers are going to emit electromagnetic waves at a higher frequency. Higher frequency waves do not travel as far, and they are less penetrating. Thus, there will be many 5G cell towers implemented in close proximity with one another so you can have a constant strong connection. The caveat to this that since the cell towers will be in close proximity with one another there is a chance for the electromagnetic waves to overlap with one another. This overlap could cause destructive interference where at certain spots there will not be a strong connection due to the emergent collapse of the signal [22-26]. Another effect could be that the electromagnetic waves will overlap and cause constructive interference. This could cause people to be exposed to excess radiation and thus pose as health risk to people working near such an environment. Thereby electromagnetic wave overlap should be taken into consideration before the advent of releasing 5G cell towers in close proximity to one another (Figure 4). Photons tend to scatter. Thus, there might be a convulsion effect where certain spots are exceeding the expected radiation concentration. This could result in a hot spot or signaling issues due to the unexpected decibel gains

Another possible effect is that being so close to cell towers can cause one to receive constant doses of radiation. This has been shown to have adverse effects for example people who live near cell towers had reported to have higher rates of headaches as compared to people who do not live close to cell towers. Studies also show that long term exposure at frequencies within 900-1800MHz influenced DNA integrity and even induced hippocampal damage. Moreover, studies displayed that in human neuroblastoma cells there was a higher chance of susceptibility to oxidative stress even after only being exposed to electromagnetic waves at 1800MHz for approximately 10 minutes [24-27]. If these potential effects are ignored there should be at least a stronger push in safety warning regarding the amount of radiation you receive from your cell phone. iPhone have made a push to where you can go into your settings and read a warning about the specific absorption rate limits and how to limit your exposure by simply using the hands-free mode or talking on the phone with speaker mode. However, the common user will not think twice to review these statements [26-29].

Conclusion

i. In conclusion, rather or not the public concern of 5G radiation is legitimate can be argued either way. However, if we agree that health is the primary factor in determining the viability of new technology, then the fact remains that there are many considerations that need to be addressed before the implementation of 5G cell towers. The uncertainty of the putting up the towers could be detrimental being there are so many towers they would affect populations on a large scale. Moreover, it would make more sense from a economical standpoint to 5G cell towers in close proximity to one another. out the effects of 5G towers before we spend money putting them up.

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Cytarabine Syndrome Complicating Induction Therapy of Acute Myelogenous Leukaemia in Ibadan, Nigeria - Juniper Publishers

 Cell Science & Molecular Biology - Juniper Publishers

Abstract

Cytosine arabinoside syndrome is a rare clinical complication of cytosar administration characterized by a constellation of symptoms of fever, myalgia, arthalgia, conjuctival suffusion, non-pruritic maculopapular rash, respiratory distress and non-cardiogenic pulmonary oedema. The clinical manifestation of the syndrome ranges in severity from being mild to fatal. We described a 68-year old man with acute myelogenous leukaemia who developed cytarabine syndrome during subcutaneous cytosar administration. The pathogenesis of this syndrome is still not well understood but it is believed to be an immune mediated cytokine response to cytarabine apoptotic effect on the blasts. Although there is no definite treatment, corticosteroid use has proven efficacious as a prophylactic and treatment agent because of its anti-inflammatory properties. Haematologist should therefore look out for this adverse event in patients with Acute leukaemia who are being treated with Cytosine arabinoside.

Keywords: Cytarabine syndrome; Acute myelogenous leukaemia; Corticosteroids

Introduction

Cytosine arabinoside (Ara-C) is an important component of induction chemotherapy in combination with other agents for acute myeloid leukaemia and other haematological malignancies [1]. Ara-C belongs to the antimetabolites group of cytotoxic drug whose mechanism of action is to block metabolic pathways used in DNA synthesis. Ara-C is an analogue of 2’-deoxycytidine (a pyrimidine), a form it is metabolized to in vivo and incorporated into developing DNA where it acts to inhibit DNA polymerase and blocks replication. It is given at a standard daily dose ranging from low (20mg/m2), standard (100-200mg/m2) and high (3g/m2) through intravenous or subcutaneous routes [2].The commonest side effects of Ara-C are nausea, vomiting, diarrhoea, loss of appetite and fever. In addition, a rare and distinct clinical constellation of fever, arthralgia, myalgia, bone pain, occasional chest pain, maculo -papular rash, conjunctivitis and malaise called Cytarabine syndrome was first described by Castleberry in 1981 and later by other investigators [3,4]. It usually occurs within 12 hours following cytarabine administration [3,5]. A literature search of report of cytarabine syndrome in Africa did not yield any results and hence we concluded that physicians in Africa may be less aware of this complication of Ara-C. This report is therefore aimed at increasing physicians’ awareness to this rare complication of commonly used Ara-C.

Case Report

A 68-year old male who first presented to the Haematology Day Care Unit (HDCU) with a referral letter from another Tertiary health Centre in the country on request of the patient for a second opinion having been previously diagnosed of acute myeloid leukaemia. He had earlier presented to the referral centre with high grade fever and abnormal complete blood count (CBC) ordered by his family physician. He had been on treatment for systemic hypertension, type II DM and benign prostatic hyperplasia. Examination findings at presentation were significant for moderate pallor, shotty left cervical lymph node enlargement and bilateral non-tender pitting pedal oedema. A repeat CBC at our facility shows leucocytosis, severe anaemia and thrombocytopaenia (white blood cell (WBC) 54.5 X 109 Cells/L haemoglobin 7.3g/dl, and platelets 5.0 X 109 Cells/L). Peripheral blood smear review showed leukocytosis with 90% monoblasts and bone marrow revealed a severe hypercellular marrow with maturation arrest and 75% of the nucleated cellular marrow elements being monoblasts.

The patient was thus diagnosed of AML-M5a and commenced on supportive treatment with packed cells and platelets transfusions. He was later commenced on DA 3+7 chemotherapy with intravenous (IV) Daunurobucin 50mg/m 2 on days 1, 3, 5 and subcutaneous Ara-C 100mg/m2/day in 2 divided doses for 7 days. Ondasetron and Allopurinol were added as per protocol. On review on day 4 of commencement of Ara-C, he reported fever (temperature 380C), tachypnoea and tachycardia, palpitation, shortness of breath, myalgia, chills and rigor a few minutes after the 7th dose of Ara-C. These symptoms all resolved following administration of iv paracetamol 1g stat and hydrocortisone 100mg start. He also had 2 similar experiences following 8th and 9th doses of Ara-C and at this time there was associated respiratory distress with SpO2 ranging between 90- 93%. These symptoms resolved following oxygen therapy, iv paracetamol 1g stat and hydrocortisone 100mg. A probable diagnosis of Cytarabine syndrome was made and subsequently premedication with iv paracetamol and hydrocortisone were instituted for every other doses of Ara-C with significant improvement in symptoms. On the 6th day following the administration of 11th dose of Ara-C, high grade fever, rigors, myalgia and respiratory distress re-occurred despite premedication and therefore subsequent doses of Ara-C were withheld and fever subsequently resolved. However, in the third week of admission he developed high grade fever (temp up to 39.50c) and lethargy. Blood and urine samples were taken and sent for microbiological culture and sensitivity and he was commenced on empirical iv ceftriaxone and metronidazole, as well as prophylactic oral fluconazole and acyclovir. Blood culture yielded Klebsiella pneumonea while urine culture was sterile. He died 7days post DA 3+7 chemotherapy of features suggestive of septic shock before culture reports were returned. Figure I below shows the temperature pattern of the patients during the chemotherapy.

Discussion

Our patient developed a new onset of fever about four days (80hours) after initiation of standard dose of Ara-c which is within the reported range of timeline of 9-90 hours of onset of Ara-c fever [6]. Fever is the commonest presentation of Ara-C syndrome in combination with other symptoms [6]. Ara-c fever has been defined as a single axillary temperature of 38.30 c (1040F)………….38.00C (1010 F) and above or a temperature of 38.00 c (1010 F) for ≥ 1hour in a patient with absolute neutrophil count above 500 x 109 cells/L and without an apparent source of fever except Ara-c [7].The neutrophil count of our patient at this time was 750 x 109 cells /L and the patient has no identifiable focus of infection although he was on prophylactic antibiotics and had been empirically treated for malarial because of the possibility of transfusion associated malarial. In addition to fever, this patient also had arthalgia, myalgia and a non-pruritic rash but no conjunctivitis. The association of fever with the above symptoms provided a strong evidence for the diagnosis of Ara-C syndrome. The finding of fever which is the only constant symptom in addition to any of the other symptoms described earlier established the diagnosis [3,6,8]. Furthermore, the fact that these symptoms were abated by administration of paracetamol and hydrocortisone, the efficacy of which has been documented [9,10] laid more credence to our diagnosis. The exact pathogenesis of Cytarabine syndrome is not fully understood. The manifestations of Cytarabine syndrome were initially attributed to hypersensitivity or vasculitis [11]. However, recent evidence supports an immune-mediated response following cytarabine induced apoptosis that results in a rapid increase in proinflammatory cytokines as the critical initiating factor [12,13]. Activation of NFkB, by many pathways in response to Ara-C is central to the production of pro-inflammtory cytokines; tumour necrosis factor-alpha (TNFα), interleukin-6 (IL-6), and interferon gamma (IFNγ) which mediates this syndrome [12]. 

The successes attributable to use of corticosteroids in preventing and treating this syndrome is predicated on its ability to suppress NFkB [10,14]. Our patient also had pulmonary involvement as evidenced by a low spo2 90-93% despite oxygen therapy. Pulmonary adverse effects have been reported to occur in 20-40% of patients exposed to Ara-C12 which may present as mild difficulty with breathing, nonproductive cough, pleural effusion, to severe and fatal respiratory distress syndrome and non-cardiogenic pulmonary oedema [15- 17]. We therefore inferred that the low oxygen saturation in this patient was related to cytarabine although the patient was unable to do a chest x-ray to confirm the pattern of lung affectation due to on non-availability of a functional mobile x-ray machine in our facility at that moment. The clinical severity in our patient can be described as moderate because of the reversible lung involvement. 

The clinical severity of Cytarabine syndrome is dependent on a number of factors including the dose of Ara-C and the tumour burden. [3,4,9,10,18] Matthew et al [12] reported persistent respiratory symptoms in a 41-year old with AML despite steroid prophylaxis and concluded that the poor response in that patient was due to high tumour burden. This finding is similar to that of the index patient who continued to have fever and hypoxaemia despite steroid necessitating discontinuation of Ara-C treatment on day 6 of a 7-day cycle. The recommended treatment protocol for Cytarabine syndrome is per oral (PO)steroid prophylaxis with Prednisolone 10mg daily which may be increased to 10mg tds or changed to PO Dexamethasone 8 mg daily, this may also be increased to twice daily. [12] Hall et al suggested intravenous methylprednisolone, 1mg/kg every 6hours, diphenhydramine, 1mg/kg every 6 hours, and ranitidine, 1mg/kg every 12 hours, given for 2 days before the administration, continued throughout the 5-day treatment course and for 1 day after completion of highdose cytarabine [9].

Conclusion

This case report highlights the clinical presentation, diagnosis and treatment of cytarabine syndrome in patients with AML. It is important to recognize this syndrome which may be common but missed in patients receiving Cytarabine therapy so that appropriate therapy may be instituted to prevent potential fatal complications which may arose from misdiagnosis. 

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The Determination of Bile Acids in Women Upon Suspicion of Intrahepatic Cholestasis of Pregnancy - Juniper Publishers

 Global Journal of Reproductive Medicine - Juniper Publishers

Abstract

Background: Bile acids are used in testing of women with suspicion of intrahepatic cholestasis of pregnancy, but the influence of their levels on diagnoses, week of delivery and response to treatment remains unclear.

Methods: We retrospectively evaluated the serum levels of total bile acids in 217 singleton pregnant women measured by photometric enzymatic method from Dialab.

Results: Medians of bile acids in serum of women with intrahepatic cholestasis of pregnancy increased compared to normal pregnancies (23.4 (19.5-28.2) versus 3.7 (3.0-4.2); P<0.0001). ROC analysis for bile acids showed AUC of 0.942 (95% CI, 0.902-0.969), P<0.0001, a sensitivity of 85,9% and a specificity of 94,9% for intrahepatic cholestasis of pregnancy. The statistically significant correlation between levels of bile acids and ALT, AST and ALP was proved. The difference in week of delivery between group with bile acid < 40µmol/L and > 40µmol/L was about 1 week (P=0.01). The dynamics of concentration of bile acids after treatment by hepatoprotectives was monitored as well. We observed mostly either decreased or unchanged concentration of bile acids, but in almost 24% of cases, there was a rapid and significant increase of bile acids concentration, despite the treatment.

Conclusion: The presented results show that bile acids represent useful parameter, which can detect intrahepatic cholestasis of pregnancy.

Keywords: Intrahepatic cholestasis of pregnancy; Bile acids; Hepatoprotectives; Stillbirth; Pruritus

Introduction

The determination of bile acids in women upon suspicion on intrahepatic cholestasis of pregnancy (ICP) is substantially important and it is gaining on significance these days [1]. ICP is a reverse form of cholestasis occurring in pregnancy with symptoms of dysfunction of liver [2]. It is the most common primary liver disorder in pregnant women, affecting about 0.5-1% of pregnancies [3-5] and associated with numerous adverse perinatal outcomes [6]. The fetus is threatened by arrhythmia or cardiac arrest and is endangered by the aspiration of meconium-stained amniotic fluid. This fetal distress may lead to premature birth [7,8]. Stillbirth complicates 0.83% of ICP. While the risk of stillbirth is increased in women with ICP, it is significantly greater than general population rates only when the concentration of serum bile acids exceeds 100μmol/L [6]. ICP is characterized by pruritus without any skin lesion that occurs in the late second to third trimester of pregnancy [9-11] and raised concentrations of maternal bile acid [2,3,9]. Usually, elevated liver transaminases are present [1,3,12]; 2-10 times higher levels were observed in about 60% of patients with increased bile acids [12]. Hyperbilirubinemia is not present [11]. ICP has a multifactorial etiology [3,5]. The genetic influence is supported by increased rate of ICP found in some families and by difference in prevalence between ethnic groups. The main genes responsible are linked to bile acid excretion. Endocrine factors are involved as well because of increased serum levels of sulphonated progesterone metabolites found in women with ICP mainly in the third trimester and are linked to disease severity [13]. Also, women with a history of allergic reactions were more likely to develop intrahepatic cholestasis of pregnancy [4]. Population-based studies have highlighted environmental factors contributing to the disease, including reduced dietary selenium, low vitamin D and winter months [3,13]. This is supported by higher incidence of ICP (2.7%) in Iceland compared to the rest of the Europe (0.5%) [3].Upon suspicion of ICP, it is necessary to exclude viral and autoimmune causes of raised bile acids andamino transaminases [5,14]. However, it was showed that elevated hepatitis C viral load does not influence bile acids level and the fetal left ventricular Tei index [15]. Increased transport of bile acids from mother with ICP to fetus is proved by elevated level of bile acids in amniotic fluid, umbilical vein, and meconium. Cholic and chenodeoxycholic acids pass through placenta and have toxic influence on the fetus and placenta as well [9]. There is a positive correlation between the concentration of bile acids in the umbilical vein [16,17] and the damage of placenta in ICP [16]. According to the literature, ICP could be divided into an early-onset (< 33-34 gestational week) and a late-onset (≥ 33-34 gestational week) [18,19]. Adverse pregnancy or fetal outcomes and preterm birth affect significantly more patients with the early-onset ICP [18]. 

Another criterion of how to divide women with ICP is into mild, moderate, and severe groups (bile acids concentration 10-39, 40-99 and >100µmol/L resp.). It has been published that the gestational age at diagnosis and at delivery were significantly lower in the severe ICP group, as compared with the mild one.Also, meconium-stained fluid (47.6%), and perinatal death (9.5%) occurred significantly more often in cases with severe ICP [17]. Contemporarily, the common treatment of ICP is a dosage of a naturally hydrophilic bile acid - ursodeoxycholic acid (UDCA), which leads to a decreased amount of bile acids and a reduction in total preterm births [20,21]. The possible effect of UDCA includes improved bile acids transportation and detoxification, cyto protection, and antiapoptotic effect [22]. It was also reported that UDCA stimulates hepatobiliary secretion of bile acids and prevents cholestasis induced by hydrophobic bile acids [23]. The bile acids concentration had been quickly lowered under 10μmol/l in treated women, but their liver function and bile acid profiles were still not back to normal [20]. Not all pregnant women with pruritus are diagnosed with ICP. Part of them has no liver damage and no elevated bile acids till the delivery. The pruritus in these cases is a benign condition without complications for the mother and fetus, called benign pruritus gravidarum [4,24,25]. As the level of bile acids changes during pregnancy, it must be considered, that part of those women later develop abnormal bile acids results, and their diagnosis is changed to ICP [4]. On the other hand, even with increased serum bile acid levels, the pruritus is not sometimes present. Feng´s study recorded that asymptomatic pregnant women with increased serum bile acid levels at least two times during pregnancy were at similar or higher risk of stillbirth than patients with typical ICP [26].

The most appropriate biologic material for the determination of bile acids is fasting serum as was found in a study comparing results after fasting and glucose load with an approximate 2µmol/L difference [27].A frequent method for the analysis of total bile acids is enzymatic photometry with thio-NAD or nitro tetrazolium blue chromophore. POCT bile acids biosensors are also developed and described in the literature. To gain the profile of individual bile acids, HPLC, HPLC-MS, GC-MS [1] or capillary electrophoresis [28] was used. By HPLC MS/MS spectroscopy, it was discovered that the unconjugated bile acids were decreased in women with ICP and taurin conjugates and glycin conjugate bile acids were increased (taurocholic acid, tauro- -muricholic acid and tauro- -muricholic acid) [20]. Similar results have been reached and described in other study [29]. It was also published that lithocholic acid and ursodeoxycholic acid/ lithocholic acid ratio could provide better and more accurate information for the diagnosis of ICP than total bile acids levels [28]. The aim of this retrospective study was to statistically evaluate the influence of bile acids concentrations on diagnoses and week of delivery. Response to treatment in a group of pregnant women with suspected ICP was described.

Materials and Methods

In this retrospective study, serum levels of bile acids in a group of 217 singleton pregnant women with suspicion to ICP were analyzed. The samples were collected at the Department of Gynecology and Obstetrics from July 2016 to April 2019 and measured at the Department of Clinical Biochemistry. For illustration, in the same period, the total of 18370 deliveries were performed in the hospital. The diagnosis of the ICP was confirmed by a gynecologist according to the typical clinical symptoms and pathology in biochemical parameters (increased bile acids, AST, ALT, ALP).The bile acids analyses were performed repeatedly over the course of patient’s treatment, so only the sample with the highest bile acids concentration was selected for the first part of statistical evaluation. The second part of statistical evaluation studying the hepatoprotective treatment effect utilized data from all patient’s samples.Out of the 217 observed pregnant women, there were 99 cases of women with ICP, while the group with other diagnosis counted 118 cases. This second group included women with benign pruritus gravidarum (PG), women with ICP or other problems in previous gravidity, individuals with preeclampsia or abnormal hepatic function test results due to other causes. The bile acids determination in serum samples was carried out on clinical chemistry module c502 of cobas 8000 (F.Hoffman-La Roche Ltd., Basel, Switzerland; further as Roche) by enzymatic photometric assay Bile Acids from Dialab (Dialab Produkten und Laborinstrumenten Gesellshaft m.b.H, Wiener Neudorf, Austria).

The principle of the method is based on photometric cyclic enzymatic reaction of bile acids with Thio-NAD in presence of enzyme 3-α-hydroxysteroid dehydrogenase (3- -HSD) [30]. Reference range according to the reagent’s manufacturer is 0 - 10 [µmol/L]. Further details about methodologies are given in Dialab insert for the test [30]. Statistical analysis were performed with a statistical software Medcalc (MedCalc Software, Ostend, Belgium), version 9.3.2.0. The data in groups of pregnant women with and without ICP were compared by Mann-Whitney tests and a receiver operating characteristic (ROC). The correlation among bile acids and ALT, AST respectively ALP were calculated by Spearman's coefficients (202 women), as normality of the values distribution was rejected by D’Agostino-Pearson test. The Spearman’s coefficients were calculated only for the group of 202 women as in some of the cases the ALT, AST and ALP concentrations were not known (patients from other health care facilities who were measured for bile acids only in our hospital). 

All P values were two-tailed. An independent t-test was used to inspect a possible difference in week of delivery in dependence on bile acid concentration. A total of 87 women (as 13 women did not give birth in our hospital, so their data could not be used) were divided into two groups, first with bile acids ≤ 40 µmol/L and second with bile acids > 40µmol/L [31].Normality of data was verified by a D’Agostino-Pearson test and arithmetic means and medians of both groups were established. The course and effect of treatment by hepatoprotectives such as Essentiale, Urosan and Transmetyl, in different combinations, was monitored on a group of 35 pregnant women in which the bile acids were measured repeatedly during pregnancy. The level of bile acids was analyzed 2-11x within this group and results were divided into four groups according to reaction to the treatment. The study was performed in accordance with the Declaration of Helsinki, institutional policies and has been approved by the local Ethical Committee – No. 02-090119/EK.

Result

Medians and confidence intervals of bile acids for group of pregnant women with and without ICP are given in (Table 1).The median of serum concentration of women with ICP were significantly higher than that of the women with other diagnosis. In the (Figure 1&2), there can be seen different effect of hepatoprotectives as Essentiale, Urosan and Transmetyl on individuals with ICP. The total of 35 monitored individuals was divided into 4 groups. In group A the decrease of bile acids concentration was observed since the treatment started. In some cases, bile acid concentration increased in a few weeks again despite the treatment. In group B patients got hepatoprotectives due to increased values of ALT and AST or/and pruritus only. At this moment bile acids were in reference range and slightly increased later. In group C we have seen an increase of bile acids concentration, often dramatic in course of 1-3 weeks of therapy. Group D had individuals whose concentration stayed even (with pathologic values) for few weeks, in some cases followed by a rather small increase. Out of 35 women, only 27 had pruritus at least in some week of pregnancy. Three of them had meconium-stained amniotic fluid (one of groups A, B and C).

Discussion

Whereas the determination of bile acids for pregnant women with suspicion to ICP (individuals with pruritus or pathological transaminases) is relatively commonly used in practice, the statistical evaluation as presented in this article was not, according to our knowledge, yet presented.The Mann-Whitney test points to a great difference of means of bile acids concentration between the group of women with ICP (23.4 µmol/L) and the group of women with other diagnosis (3.7µmol/L) showing statistical significance with P<0.0001. The ROC analysis showed steep curve with excellent value of AUC (0.942). The counted ideal associated criterion (limit value between negative and positive outcome of the test) of 9.2µmol/L is quite close to reference range mentioned in the method insert (0-10µmol/L) [30]. We suspect that the results could be even better as some patients were already getting hepatoprotectives from their gynecologists right after reaching increased transaminases values and/or pruritus, before they arrived at our hospital. In these cases, the bile acids were measured at the hospital at a time when they could already be decreased. In group of pregnant women with other diagnosis, the individuals with pruritus but no liver damage and no elevated bile acids were observed till the delivery. In one case the pruritus was caused by dermatitis, other cases fill the described condition called benign pruritus gravidarum [4,24].A fair correlation between bile acids concentrations and ALT, AST and ALP levels was found – see (Table 2 & 3).

The best correlation of bile acids was with AST - Spearman’s coefficient of 0.696. Results show that the bile acids are better than ALT, AST, and ALP for the diagnosis of ICP.The disadvantage of using ALT and AST for diagnosis determination of ICP is that the transaminases can be elevated also by other reasons than ICP as preeclampsia, chronic hepatitis, autoimmune hepatopathy. According to literature [12], 2-10 times higher levels of ALT, AST were observed in about 60% of patients with increased bile acids. In our study, all women with ICP had increased transaminases; only 10% of them less than twice the upper value of their respective reference ranges.The ALP values are physiologically elevated in II. and III. trimester due to the production of placental isoenzyme and it is generally considered to be of no great diagnostic importance to ICP [12]. On the other hand, compared to normal pregnancy, the ALP values are even more elevated in the case of ICP according to guideline of national gynecological and obstetric society (CGOS) and our observations. 

The difference in the week of delivery between group with bile acid to 40µmol/L and group with bile acids > 40µmol/L, which is about 1 week, is relatively small, but significant. Results are influenced by ICP treatment and by the fact that, in accordance with CGOS guideline, most deliveries are induced after the end of 37 week of gestation in women with ICP even if the treatment is successful. It corresponds to UK practice, as most cases there undergo induction of labor at week 37-38 as this is considered to balance the effects of prematurity against risk of fetal demise, which is greatest between 37 and 39 weeks of gestation [9]. It is generally known that after a beginning of hepatoprotective treatment, in some cases bile acids levels continue to increase. In this study we observed mostly either decreased or unchanged concentration of bile acids, but in almost 24% of cases, there was a rapid and significant increase of bile acids concentration at the next measurement, despite the treatment. Among others, in this group there was one case of meconium-stained amniotic fluid and one case of silent fetus outcome (this was the only case in all tested pathologic group of 217 with an outcome of silent fetus despite treatment, monitoring and decrease of bile acids value to 22µmol/L).

Individual groups are too small to make a conclusion, but the described possible reactions to treatment should be considered. Responses to the treatment may be affected by the severity of ICP, a week of pregnancy when the disease occurs and by the combination of hepatoprotectives. This implies that monitoring of bile acids levels is very important even after a treatment is applied. In some cases, the considerable decrease of bile acids and even transaminases values were observed in 1-3 weeks of the treatment, where the concentration could reach normal values. But a decrease of ALT and AST values usually steadied at values of 1-2µkat/L. Although the hepatoprotectives has a great significance, the decrease or even return of bile acids values to normal does not mean that the women are without risk, based on both literature [20] and our observations. Values of bile acids are also not 100% specific, as they are increased in patients with cholecystolithiasis or cholestasis, but in the observed group of 227 individuals was only 1 with increase bile acids from other reason than ICP. 

The cause was cholecystolithiasis, a rare diagnosis in pregnant women. Within the group with other diagnosis than ICP, individuals with only preeclampsia had normal bile acids. We found 4 cases within the ICP group, where preeclampsia and ICP was combined. As mentioned in the chapter Materials and methods, twin pregnancy were not included to the study, although according to our observation, in healthy pregnancy the levels of bile acids stay in normal values, independently on the number of fetuses. Unfortunately, we had not enough cases to prove this claim which can be a subject for further study.Another topic that would be interesting to further investigate in the future are normal values of bile acids in umbilical cord. In the literature, there is only information about positive correlation between levels of bile acids in serum and the umbilical vein and finding that values in umbilical cord blood are significantly lower [15].Exact reference ranges for umbilical cord blood are not published according to our knowledge yet. In conclusion bile acids are very good and useful diagnostic parameters for ICP. They are superior to the less specific ALT, AST, and pruritus presence as well. Although results of analysis of individual bile acids in literature [26,28,29] clarify the mechanism of ICP in the important and interesting way, according to our experiences, total bile acids measurement is sufficient in routine practice and correlates well with the patient’s condition. Our results supported bile acids importance and uniqueness.

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RORleans: MMR Vaccination Coverage Among Young Women, Working for OrleansCity Hall : A Cross Sectional Study - Juniper Publishers

Pharmacology & Clinical Research - Juniper Publishers

Abstract

Background: A measles outbreak has been going on in France since 2017, where 2 779 cases were declared, of which 89% were not or poorly vaccinated. Facing the poor immunization among the cases, we carried out this study following the request from French General Direction of Health to “verify the immunization status and promote vaccination or catch-up if necessary”.

Objectives: Principal objective: To assess the vaccination coverage among the women workers in Orleans City Hall. i. Secondary objective: To compare the prevalence vaccination coverage with job activities.

Materials and method: A cross sectional study, based on medical files added to a questionnaire, in the preventive medicine service of Orleans city hall was performed.

i. Participants: including women born from 1980 to 1990 and working for the city at the time of the study. We compared our results by employment category (administrative, childhood and maintenance).

ii. Primary outcome: vaccination rate about women workers in Orleans City Hall

iii. Secondary outcome: prevalence rate and job vaccination coverage rate in Orleans City Hall.

Results: Among the 186 participants, the prevalence of measles vaccination coverage was 57.5% [50.4% - 64.6%] for two doses and 91.9% [88.0% - 95.9%] for one dose. Women working with children were generally less immunized (39.84% [31.52% - 48.17%] for two doses and 59.89% [51.05% 67.74%] for one dose). Moreover, women under 30 were more likely to be immunized (84.6% [74.8% - 94.4%] for two doses and 100% for a single injection).

Conclusion: Our results confirmed our hypothesis. Measles vaccination coverage in working women in the city hall of Orleans is poor compared to national recommendations.

Keywords: Vaccination coverage; Measles; Women’s health; Prevention health

Introduction

A vaccine catch-up is recommended, if measles vaccination of a young woman is not up to date. If they were born after 1980, they must have received a total of two doses of measles-mumps-rubella vaccine spaced a minimum of one month apart, whether or not they had one of these 3 diseases. If they were born before 1980 and have never been vaccinated, vaccination is recommended, especially if they have been exposed in their profession (health professions, early childhood professions). One injection is enough. If the young woman has received a vaccination, she must have effective contraception within 2 months after vaccination. Vaccinations in the workplace have two objectives: To protect employees against occupational risk by assuring them, by this act of prevention primary, individual protection; break the transmission chain and thus avoid, by immunizing them, that they do not contaminate their surroundings (colleagues, patients in the middle care, close). They are governed by: the Code of Public Health (art. L. 3111-4 a , L. 3112-1, R. 3112-1 and R. 3112-2) making certain vaccinations mandatory for some exposed professionals (or exposing the people they have been responsible for Law No. 2016-41 of 21 January 2016) to a risk of contamination; the Labor Code (article R. 4426-6) which provides that an employer, on proposal of the occupational doctor, can recommend a vaccination. For health professionals, is added the recommendation of ensure immunization also of the oldest, born before 1980, unvaccinated, with no history of measles or rubella (or the story is doubtful): a dose trivalent vaccine is recommended for training, hiring or in post, in priority in services hosting subjects at risk of severe measles. It is the same for professionals in contact with children [1].

Why we chosen in our study to follow adults from 28 to 38 years old? These young adults were born during a period of implementation of the vaccination recommendation against measles. The vaccine made its appearance on the calendar in 1983 precisely. But in the following years, the recommendation is followed very gradually. Thus in 1987, only 50% of children were vaccinated, barely 60% in 1988. Result: a wobbly group immunity, which allowed many people born in the 1980s to grow up without encountering the disease in their childhood because less circulation of the virus, while not being vaccinated, since the recommendation was relatively poorly followed. For the record, the highly contagious nature of measles requires about 95% vaccination coverage to prevent the circulation of the virus in the population (principle of group immunity). By contrast, before 1983, only 20% of children were vaccinated. The virus circulated so much, and almost all the children ended up catching it. “In the age groups over 40 years, we have more than 99% of people who are immunized, usually because they had measles as a child [2].

Highly contagious, a person infected by measles can infect 15 to 20 people in a non-immune population [3]. Late complications of measles are well known, such as sclerosing pan encephalitis (mortality rate: 0.5 to 1/1,000) [4]. In France, measles is considered to be harmless, sometimes among the healthcare professionals [5]. Since the vaccination campaigns of the 1980s, measles outbreaks have decreased with the increase in immunization coverage [6]. Consequently, the youngest generations are not familiar with this disease. Since November 2017, in France, a measles epidemic is spreading from Aquitaine to other regions including Centre-Val de Loire (2779 mandatorily reported cases, including 2702 cases in 2018, with a peak in April 2018). Among the cases of measles, 23% were hospitalized. Moreover, 89% of the cases were not or poorly vaccinated [7]. In the Centre-Val de Loire, cases have appeared since mid-January 2018. As of 25 May 2018, 90 cases had been reported in 4 months, indicating that the virus actively spread within the region [8]. To reduce the number of measles cases and their complications, Vaccination is an emergency. Thus, the objective is to reach 95% measles and rubella vaccination coverage (VC) in France [9]. No department achieved this goal until now. For example, in Centre-Val de Loire, in 2015, MMR vaccination coverage among 2-year old children was 76.2% IDC [nc] for two doses of the vaccine.

MMR vaccination has become mandatory for all children born since January 2018 [10]. Based on the High Council of Public Health recommendations, we carried out this study following the request from French General Direction of Health) to “verify the immunization status and promote vaccination or catch-up if necessary”. Following the French cross survey study conducted by Denise ANTONA and colleagues [2], the main objective of our study was to assess the vaccination coverage of women born from 1980 to 1990, working at the Orleans city hall and identify the factors associated with a correct VC. Our hypothesis was inadequate vaccination coverage for this population. The secondary objectives were the influence of job categories and age on vaccination status.

Objectives

i. Principal objective: To assess the vaccination coverage among the women workers in Orleans City Hall.

ii. Secondary objective: To compare the prevalence vaccination coverage with job activities

Materials & Methods

Study Design

A descriptive, cross sectional study based on medical records and a questionnaire were carried out.

Setting: This investigation took place at the Department of Preventive Medicine (SMP) of Orleans city hall.

Eligibility criteria: The population was selected in the local medical monitoring software of the agents: Horizon (version n° 4.95.02A, date of conception 1995 in Nimes). Women born from 1980 to 1990 and working for the city of Orleans were included. We excluded agents no longer working at City Hall, women in long term Medical leave, and refusal to participate. The Department of Preventive Medicine (SMP) is in charge of 5 400 agents for the local authority. 1308 were women born from 1980 to 1990. For our investigation, we selected only the women working in Orleans, so we had 308 subjects. The survey involved 308 agents (Figure 1). 295 women answered to the questionnaire, 3 women refused to participate, 10 women were excluded endly 186 women were analyzed. At first, to inform the most people about our action, we carried out an initial communication strategy for the 5,400 agents of the metropolitan area. This strategy consisted of the dissemination of national documents about measles and measles epidemic. So, we would raise awareness about measles for all agents working for Orleans city hall.

Outcomes: From May to June 2018, all the information contained in the agent’s medical files was collected, aged, immunization status against measles, and profession. In July 2018, a questionnaire for the 308 agents was sent to the services. Including: demographic characteristics (age, employment) and measles vaccination status (dose number and date). Agents could return their responses by service mail or email. A phone call has been made for agents who did not have an e-mail address at the city hall. Three reminders by e-mail were sent on 21/08/2018, 04/09/2018 and 13/09/2018. The responses were collected from August to the end of September 2018.Women reporting two doses of vaccine were considered as complete vaccinated. Women who received a single dose or had childhood measles were considered partially vaccinated. Indeed, this choice had been made because one unique dose didn’t protect. For the secondary objectives, we classified women into three main job categories: administrative officers, childcare officers and maintenance officers. To see the influence of age, we grouped women into two groups, the under 30s and the over 30s. The age classes were chosen as the reference class of a German study [11].

Statistical Methods

Data sources: We estimated the necessary number of subjects. For an observational survey, the number of subjects to be included depends on the expected percentage of subjects for the desired trait (p), its difference from 100%, the desired precision, and the “alpha” risk of 5% of the first kind consented.

Statistical significance: It was considered when P was ≤0.05, Results are presented as means and medians, with 95% confidence intervals (95% CI) or Interquartile Ranges (IQR).

Study size: We estimated a necessary number of 280 subjects for an expected percentage of 76.2% (MMR CV rate among children observed in the region Centre-Val de Loire).

Measurement: The analyses were performed with Excel. Immunization coverage was calculated using as denominator: the sum of the information collected from medical records and the number of responses to the survey.

Quantitative and qualitative variables: The questionnaire was administrated by mail and e-mail and included the following socio-demographic variables: age, sex, socio-professional category and place of residence. Data on history of past measles infection and vaccination status were collected on recall. We did an exact Fisher test between the different use categories and immunization status. We did a chi2 independence test, grouping the age into two classes, under 30s and the over 30s.

Ethical review: The investigation was declared to the CNIL, in category MR-003, research in the field with consent. The declaration number, received on July 18, 2018, was the 2202567 v 0. The data from the questionnaires were anonymous for analysis. Express, free and informed consent was signed by the women during the inclusion.

Results

Participants

Among the study targeted population of 308 women, 186 women were included (60.4%) after exclusion of 10 long term leave and work quitting, 3 refusals to participate, and 109 without information in the medical records, and no response to the questionnaire (figure 1: Flow chart).

Descriptive data

The 186 women were divided into three categories, 97 administrative officers, 80 officers working with children, and 9 maintenance officers. The average age was 33.3 years old [32.9 – 33.7].

Outcome data

The results were 107 complete vaccinated women, 64 partially vaccinated women and 9 who had measles during the childhood. 6 women were not vaccinated (4 administrative officers, 1 childcare officer, 1 maintenance officer).

Main results

The vaccination coverage rate was 57.5% [50.42%-64.63%] for women aged 28 to 38 years for 2 doses of the vaccine. The rate was 91.9% [88.02% - 95.85%] for one dose of the vaccine; this percentage included fully vaccinated women who have at least one dose, and those who received only one injection. Combining women with only one dose and those having had childhood measles, 39.2% [32.2% - 46. 36%] were partially vaccinated. Finally, only 3.2% [0.69% - 5.77%] of women were not vaccinated (Table 1).

Other Analyses

Vaccination against measles was not associated with the profession. We find 51.55% [41.60% - 61.49%] for two dose of vaccine and 86.60% [79.82% - 93.28%] for one dose among administrative officers, (39.84% [31.52% - 48.17%] for two doses and 59.89% [51.05% 67.74%] for one dose) in women working with children, as well as 44.44% [11.98% - 76.91%] for two doses and for one dose in maintenance officers, without any significant difference (p=0.955). Figure 2: Vaccination status by employment category. Taking into account the class-of-age, for the group aged 28 to 30-year old we found a complete immunization coverage of 84.6% [74.8% - 94.2%], and 100% for a single injection. For 31 to 38 years old, the VC is 47.0% [33.5% - 60.6%] for two doses of vaccine and 88.8% [80.2% - 97.4%] for a single dose. With a significant difference according to the age class, women aged 28- 30 years are significantly better covered than those aged 30-38 years (p<0.001) (figure 3: Vaccination coverage by age). There is a significant difference between these two classes (p=3.22.10-6).

Discussion

Between 2000 and 2016, it was estimated that measles immunization prevented 20.4 million deaths, making it the best public health investment. The number of deaths globally decreased by 84%, from 550,100 in 2001 to 89,780 in 2016 [12].

Key Results

Our study estimated vaccination coverage for MMR at 57.5% [50.42% - 64.63%] for two doses for women aged 28 to 38 working in the Orléans metropolitan territorial community. However, the vaccination rate among children in the Centre-Val de Loire is 76% for two doses. Another study conducted in Poitou- Charente [13] shows a CV at 93% for one dose and 76% for two doses in 17 years old adolescents. These results, for children and adolescents, suggest that there has been an increase in vaccination for these new generations. With the obligation since January 2018, it is hoped that immunization coverage will increase. It is important to focus on immunization coverage for both injections. Indeed, the measles vaccination scheme includes two injections. The second dose does not constitute a reminder. This is a catch up for people who have not seroconverted for one or more antigens. Indeed, this decision was taken in view of the vaccine insufficiency and the effectiveness of the vaccine (90-95%) in order to eliminate the risk of having measles. The Vaxisoin study [14] shows that caregivers have insufficient vaccination coverage for recommended vaccines, including vaccination against measles and especially for its the second injection. The vaccination coverage rate for all occupations combined in 49.7% [30.8% - 68.8%]. Our CV rate is close to these results. Yet, the women answering our questionnaire are generally vaccinated women. Non-responders may be unvaccinated. These women may have hesitations about vaccination, or fear of having to be vaccinated. Thus, there is a response bias in our survey. 57% of vaccination coverage is not only a weak result, but it could be overestimated by this way.

Concerning the population of the study, one argument justifying the choice of age, is the importance of injecting the second dose of the vaccine for all persons born since 1980. We based ourselves on the opinion of the High Council of Public Health (HCSP), concerning the MMR, which states that there are no recommendations for people born before 1980. A seroprevalence study shows that these people are much less receptive to the vaccine. In addition, it is assumed that the majority of this population had measles in childhood. A crosssurvey study about measle seroprevalence was conducted on blood donors in France. It showed that the proportion of people 18-32 years old susceptible to measles infections remained high in France in 2013. The rate was estimated 9.2%, in metropolitan France, even after the promotion campaigns about vaccination catch-up during and following the major measles epidemic in 2009-2011 [2]. Moreover, we have taken an interest in women because we know that many works with young children (ATSEM, maintenance officers, childcare assistants, etc.,) and can also be in touch with children in their family life. We may think that some of them show a strong resistance against vaccinations. Indeed, while it is difficult to quantify the number of people hesitant or resistant to vaccinations, the experts acknowledge an increase of these resistances. Vaccination may be perceived as dangerous or unnecessary [15]. Some physicians themselves may have hesitations [16]. The vaccination campaign against influenza / H1N1 has probably had deleterious effects on confidence in vaccines. In the years following this pandemic influenza 2009- 2020, there was a significant decrease in vaccination coverage, suggesting this loss of confidence due to the controversies raised by the vaccination campaign [17-19].

Strengths and Limitations

Our population selection method did not use a random sampling technique. We made a selection of “comfort”, filtered on the city of Orléans for feasibility reasons. In fact, metropolis has been constituted recently. We did not have access to the medical records of the 1308 targeted women, but only to 308 in Orleans. The data were obtained from occupational medicine. The analysis by socio-occupational category, in particular for professions subject to a vaccination obligation, is an innovation approach compared to other methods of measuring immunization coverage [20]. More staff in administrative jobs are not vaccinated, although the difference is not significant, we can hypothesize that they feel less concerned about this vaccination than their colleagues working with children.

Interpretations

Finally, we show that the youngest women aged 28 to 30 are significantly better vaccinated than those aged 31 and over. This result makes it possible to better target priority populations for vaccination catch-up.

Conclusion

This study, the first to be carried out in local authorities at the Orléans City hall, provides very information on the MMR’s vaccination coverage. The MMR coverage rate found in women aged 28 to 38 is well below the 95% required to eradicate the disease. In addition, to providing epidemiological results, this study also aimed to promote vaccination. We believe we have informed many of the city’s agents. We were able to inform women in the study who were only partially vaccinated, to redirect them to appropriate management. In the context of occupational health, this survey could be extended to other vaccines, mandatory or recommended for certain professions.

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