The Opioid Crisis: Prevalence and Markets of Opioids.

The US opioid crisis came in three waves - prescription opioids, heroin, and illicitly manufactured fentanyls - Centers for Disease Control and Prevention Centers for Disease Control and Prevention resulting in the deaths of nearly 500,000 people from 1996 to 2019. In 2009, drug overdose deaths exceeded those involving automobiles. Opioid overdose deaths contributed to the decrease in life expectancy for Americans from 78.8 to 78.5 during 2014 to 2017. The overprescribing of a schedule II prescription opioid was escalated by pharmaceutical companies promoting a growing belief that pain was an undertreated condition. In 2012, the number of opioid prescriptions peaked at 255 million and deaths exceeded 11,000 per year. The typical prescription opioid abuser was white, male, and 45-55 years of age. The hardest-hit states were in Appalachia and the Northeast. When an abuse-resistant formulation was introduced for OxyContin, the most prevalent prescription opioid, users turned to heroin. From the early 1980s, a new pizza delivery style of Mexican trafficking in black tar heroin infiltrated many of the same states hit hardest by prescription opioids. Heroin overdose deaths reached 14,495 in 2017. As heroin abuse increased in states supplied with black tar heroin, fentanyl-contaminated white powder heroin began to appear in the Northeast. Fentanyl was quickly followed by fentanyl analogs. While heroin deaths continued to escalate through 2017, they were soon overshadowed by fentanyl overdose deaths. Finally, prescription opioid and heroin overdose deaths started to decline in 2017, though fentanyl deaths continued to increase. In late 2019, it appeared that restrictions on transportation and travel due to the COVID-19 pandemic had resulted in decreased availability of illicit drugs, but by 2020 drug abuse had escalated in many countries. Globally, heroin was the primary opioid of abuse and only a few countries - including Canada, Germany, Austria, and Belgium - have experienced a significant increase in prescription opioids. However, illicitly manufactured fentanyls are a growing problem in North America, Europe, Australia, and Asia.

Forensic science educational programs (VI) - Programs in the US.

Historically, academic forensic science (FS) programs in the US tended to be relatively small and were embedded in a criminal justice, chemistry, or biology department. Then, in the early 2000s, interest in FS surged, many colleges and universities responded to student demand by adding FS degrees to their curriculums. The search for forensic science programs in the US was done online, using the American Academy of Forensic Sciences' Forensic Science Education Program Accreditation Commission (FEPAC) list of accredited programs, the CollegeSource® Online Google search, Universities.com, and forensicscolleges.com as primary sources. Once a college or university with one or more FS programs was identified, the university's web pages were accessed to confirm that the program was active. The site was searched to find the location, home department, program URL, contract information, degree name, degrees offered, and accrediting body for the institution. For universities and colleges with multiple programs in different departments, each department and its associated degrees is listed separately under the institutions entry. All levels from PhD to certificate programs have been included. However, degrees that offer forensic courses as electives are not included. Only FEPAC is listed for accredited FS programs. Part of FEPAC accreditation is documenting that the institution is accredited by a regional accreditation organization. No attempt has been made to evaluate the quality of the FS programs listed. With the proliferation of FS programs since 2001, it is important for potential students to evaluate a degree program carefully before deciding to enroll.

Predicting population responses to environmental change from individual-level mechanisms: towards a standardized mechanistic approach.

Animal populations will mediate the response of global biodiversity to environmental changes. Population models are thus important tools for both understanding and predicting animal responses to uncertain future conditions. Most approaches, however, are correlative and ignore the individual-level mechanisms that give rise to population dynamics. Here, we assess several existing population modelling approaches and find limitations to both 'correlative' and 'mechanistic' models. We advocate the need for a standardized mechanistic approach for linking individual mechanisms (physiology, behaviour, and evolution) to population dynamics in spatially explicit landscapes. Such an approach is potentially more flexible and informative than current population models. Key to realizing this goal, however, is overcoming current data limitations, the development and testing of eco-evolutionary theory to represent interactions between individual mechanisms, and standardized multi-dimensional environmental change scenarios which incorporate multiple stressors. Such progress is essential in supporting environmental decisions in uncertain future conditions.

Force of infection of Middle East respiratory syndrome in dromedary camels in Kenya.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic disease transmitted from dromedary camels to people, which can result in outbreaks with human-to-human transmission. Because it is a subclinical infection in camels, epidemiological measures other than prevalence are challenging to assess. This study estimated the force of infection (FOI) of MERS-CoV in camel populations from age-stratified serological data. A cross-sectional study of MERS-CoV was conducted in Kenya from July 2016 to July 2017. Seroprevalence was stratified into four age groups: <1, 1-2, 2-3 and >3 years old. Age-independent and age-dependent linear and quadratic generalised linear models were used to estimate FOI in pastoral and ranching camel herds. Models were compared based on computed AIC values. Among pastoral herds, the age-dependent quadratic FOI was the best fit model, while the age-independent FOI was the best fit for the ranching herd data. FOI provides an indirect estimate of infection risk, which is especially valuable where direct estimates of incidence and other measures of infection are challenging to obtain. The FOIs estimated in this study provide important insight about MERS-CoV dynamics in the reservoir species, and contribute to our understanding of the zoonotic risks of this important public health threat.

Development and initial characterization of a novel ghrelin receptor CRISPR/Cas9 knockout wistar rat model.

BACKGROUND/OBJECTIVES: Ghrelin, a stomach-derived hormone implicated in numerous behaviors including feeding, reward, stress, and addictive behaviors, acts by binding to the growth hormone secretagogue receptor (GHSR). Here, we present the development, verification, and initial characterization of a novel GHSR knockout (KO) Wistar rat model created with CRISPR genome editing. METHODS: Using CRISPR/Cas9, we developed a GHSR KO in a Wistar background. Loss of GHSR mRNA expression was histologically verified using RNAscope in wild-type (WT; n = 2) and KO (n = 2) rats. We tested the effects of intraperitoneal acyl-ghrelin administration on food consumption and plasma growth hormone (GH) concentrations in WT (n = 8) and KO (n = 8) rats. We also analyzed locomotion, food consumption, and body fat composition in these animals. Body weight was monitored from early development to adulthood. RESULTS: The RNAscope analysis revealed an abundance of GHSR mRNA expression in the hypothalamus, midbrain, and hippocampus in WTs, and no observed probe binding in KOs. Ghrelin administration increased plasma GH levels (p = 0.0067) and food consumption (p = 0.0448) in WT rats but not KOs. KO rats consumed less food overall at basal conditions and weighed significantly less compared with WTs throughout development (p = 0.0001). Compared with WTs, KOs presented higher concentrations of brown adipose tissue (BAT; p = 0.0322). CONCLUSIONS: We have verified GHSR deletion in our KO model using histological, physiological, neuroendocrinological, and behavioral measures. Our findings indicate that GHSR deletion in rats is not only associated with a lack of response to ghrelin, but also associated with decreases in daily food consumption and body growth, and increases in BAT. This GHSR KO Wistar rat model provides a novel tool for studying the role of the ghrelin system in obesity and in a wide range of medical and neuropsychiatric disorders.

Antisepsis of the skin before spinal surgery with povidone iodine-alcohol followed by chlorhexidine gluconate-alcohol versus povidone iodine-alcohol applied twice for the prevention of contamination of the wound by bacteria: a randomised controlled trial.

AIMS: The aim of this study was to determine whether the sequential application of povidone iodine-alcohol (PVI) followed by chlorhexidine gluconate-alcohol (CHG) would reduce surgical wound contamination to a greater extent than PVI applied twice in patients undergoing spinal surgery. PATIENTS AND METHODS: A single-centre, interventional, two arm, parallel group randomised controlled trial was undertaken, involving 407 patients who underwent elective spinal surgery. For 203 patients, the skin was disinfected before surgery using PVI (10% [w/w (1% w/w available iodine)] in 95% industrial denatured alcohol, povidone iodine; Videne Alcoholic Tincture) twice, and for 204 patients using PVI once followed by CHG (2% [w/v] chlorhexidine gluconate in 70% [v/v] isopropyl alcohol; Chloraprep with tint). The primary outcome measure was contamination of the wound determined by aerobic and anaerobic bacterial growth from samples taken after disinfection. RESULTS: The detection of viable bacteria in any one of the samples taken after disinfection (culture-positive) was significantly lower in the group treated with both PVI and CHG than in the group treated with PVI alone (59 (29.1%) versus 85 (41.7%), p = 0.009; odds ratio 0.574; 95% confidence interval, 0.380 to 0.866). CONCLUSIONS: Antisepsis of the skin with the sequential application of PVI and CHG more effectively reduces the contamination of a surgical wound than PVI alone. Cite this article: Bone Joint J 2017;99-B:1354-65.

Ultrasonic bone aspirator use in endoscopic ear surgery: feasibility and safety assessed using cadaveric temporal bones.

OBJECTIVES: To describe the feasibility and assess the safety of using an ultrasonic bone aspirator in endoscopic ear surgery. METHODS: Five temporal bones were dissected via endoscopic ear surgery using a Sonopet ultrasonic bone aspirator. Atticoantrostomy was undertaken. Another four bones were dissected using routine endoscopic equipment and standard bone curettes in a similar manner. Feasibility and safety were assessed in terms of: dissection time, atticoantrostomy adequacy, tympanomeatal flap damage, chorda tympani nerve injury, ossicular injury, ossicular chain disruption, facial nerve exposure and dural injury. RESULTS: The time taken to perform atticoantrostomy was significantly less with the use of the ultrasonic bone aspirator as compared to conventional bone curettes. CONCLUSION: The ultrasonic bone aspirator is a feasible option in endoscopic ear surgery. It enables easy bone removal, with no additional complications and greater efficacy than traditional bone curettes. It should be a part of the armamentarium for transcanal endoscopic ear surgery.

A simple self-reported adherence tool as a predictor of viral rebound in people with viral suppression on antiretroviral therapy.

OBJECTIVES: The aim of the study was to investigate the relationship between self-reported antiretroviral therapy (ART) adherence and virological outcomes in the multinational Strategies for Management of Antiretroviral Therapy (SMART) study. METHODS: Eligible participants were from the continuous ART arm and had at least one viral load (VL) ≤ 50 HIV-1 RNA copies/mL and a subsequent VL value (VL pair). Self-reported adherence was measured at each visit using a five-point Likert scale which employed a 7-day recall. High adherence was defined as taking 'all pills every day' (level 1) for every regimen component; all others had suboptimal adherence (levels 2 - 5). In individuals with VL suppression (≤ 50 copies/mL), the association between adherence (at the time of VL suppression) and VL rebound (> 200 copies/mL at next visit) was assessed using multivariable logistic regression with generalized estimating equations. RESULTS: A total of 10 761 sets of VL pairs from 1986 participants were included in the study. For 1220 (11%) VL pairs, adherence was suboptimal. For 507 VL pairs (5%), VL rebound occurred. The risk of rebound generally increased as adherence decreased: 4.2% for level 1, 7.7% for level 2, 16.3% for level 3, 9.4% for level 4 and 12.9% for level 5. In multivariable analysis, suboptimal adherence at the time of suppression was associated with a 50% increased odds of experiencing subsequent VL rebound [odds ratio (OR) 1.51; 95% confidence interval (CI) 1.19-1.92; P = 0.0023], compared with high adherence. CONCLUSIONS: Self-reported suboptimal adherence in people with VL suppression is associated with an increased risk of VL rebound. Our findings highlight the importance of continued adherence counselling, even in people with VL suppression, and to ensure that people with HIV infection maintain excellent adherence in order to minimize the risk of VL rebound.

DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2.

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth.

Quality of life assessment among HIV-positive persons entering the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: With HIV treatment prolonging survival and HIV infection now managed as a chronic illness, quality of life (QOL) is important to evaluate in persons living with HIV (PLWH). We assessed at study entry the QOL of antiretroviral-naïve PLWH with CD4 counts > 500 cells/µL in the Strategic Timing of AntiRetroviral Treatment (START) clinical trial. METHODS: QOL was assessed with: (1) a visual analogue scale (VAS) for self-assessment of overall current health; (2) the Short-Form 12-Item Version 2 Health Survey(®) (SF-12V2), for which responses are summarized into eight individual QOL domains plus component summary scores for physical health [the Physical Health Component Summary (PCS)] and mental health [the Mental Health Component Summary (MCS)]. The VAS and eight domain scores were scaled from 0 to 100. Mean QOL measures were calculated overall and by demographic, clinical and behavioural factors. RESULTS: A total of 4631 participants completed the VAS and 4119 the SF-12. The mean VAS score (with standard deviation) was 80.9 ± 15.7. Mean SF-12 domain scores were lowest for vitality (66.3 ± 26.4) and mental health (68.6 ± 21.4), and highest for physical functioning (89.3 ± 23.0) and bodily pain (88.0 ± 21.4). Using multiple linear regression, PCS scores were lower (P < 0.001) for Asians, North Americans, female participants, older participants, and those with less education, longer duration of known HIV infection, alcoholism/substance dependence and body mass index ≥ 30 kg/m(2) . MCS scores were highest (P < 0.001) for Africans, South Americans and older participants, and lowest for female participants, current smokers and those with alcoholism/substance dependence. CONCLUSIONS: In this primarily healthy population, QOL was mostly favourable, emphasizing that it is important that HIV treatments do not negatively impact QOL. Self-assessed physical health summary scores were higher than mental health scores. Factors such as older age and geographical region had different effects on perceived physical and mental health.

Hypoglycaemia risk among a hospitalised stroke patient cohort: a case for increased vigilance in glucose monitoring.

We conducted a retrospective cohort study involving a review of the records of 112 patients consecutively admitted with acute stroke or transient ischaemic attack (TIA) to all three district general hospitals in one Health and Social Care Trust in Northern Ireland from 1 January to 15 April 2008. Glucose results for each of the first 5 days of hospital admission were ascertained. We compared interventions and clinical outcome between patients who experienced hypoglycaemia (glucose<4.0 mmol/l) in the first 5 days, and patients with higher glucose results. Our results indicated that 11 (10%) patients experienced incidents of hypoglycaemia ranging from 1.8 to 3.9 mmol/l. None of the individuals affected had received intravenous or subcutaneous insulin. Only two of the hypoglycaemic episodes involved patients with a history of diabetes mellitus. Two patients experienced episodes of hypoglycaemia on 2 or more days. Six patients experienced hypoglycaemia at the lower threshold of glucose<3.5 mmol/l and this was not associated with a history of diabetes. A history of diabetes mellitus prompted near patient glucose testing, but among patients without diagnosed diabetes, glycaemia was under-monitored. The test that most frequently indicated hypoglycaemia was a routine electrolyte profile tested in the hospital laboratory. Patients in the first 5 days after stroke have a small risk of hypoglycaemia. There is a need for greater vigilance in the monitoring of glucose among patients admitted to hospital with stroke or TIA.

Effect of hydrogen peroxide on human tendon allograft.

Bacterial contamination of tendon allografts at the completion of processing has historically been about 2 %, with tendons that are found to be culture positive being discarded. Treatment of tendon allograft with hydrogen peroxide at the beginning of tissue processing may reduce bacterial contamination, however, the potential side effects of hydrogen peroxide treatment include hydrolysis of the collagen and this may alter the mechanical properties of the graft. Pairs of human tendons were used. One was washed in 3 % hydrogen peroxide for 5 min and the untreated tendon was used as a control. The ultimate tensile strength of the tendons was determined using a material testing machine. A freeze clamp technique was used to hold the tendons securely at the high loads required to cause tendon failure. There was no statistical difference in the ultimate tensile strength between the treated and untreated tendons. Mean strength ranged from Extensor Hallucis Longus at 588 Newtons to Tibialis Posterior at 2,366 Newtons. Hydrogen peroxide washing may reduce bacterial contamination of tendon allograft and does not affect the strength of the tendon.

Hyperglycaemia monitoring and management in stroke care: policy vs. practice.

AIM: To evaluate the extent to which hyperglycaemia was monitored and managed among patients admitted to hospital with acute stroke and transient ischaemic attack. METHODS: We conducted a retrospective cohort study involving a review of the records of 112 patients consecutively admitted with acute stroke or transient ischaemic attack to all three district general hospitals in one Health and Social Care Trust in Northern Ireland from 1 January to 15 April 2008. Glucose results for each of the first 5 days of hospital admission were ascertained. We compared interventions, clinical outcome and discharge planning between patients who experienced glucose ≥ 7.8 mmol/l in the first 5 days, and patients with lower glucose results. RESULTS: The daily prevalence rate of hyperglycaemia > 7.8 mmol/l across the first 5 days ranged from 24 to 34%. A total of 41 (37%) patients experienced hyperglycaemia on at least one occasion during the first 5 days. A history of diabetes mellitus prompted near patient glucose testing, but, among patients without diagnosed diabetes, glycaemia was under-monitored. Hyperglycaemia was a persisting trend, was under-treated and under-reported to general practitioners. Elevated glucose results failed to influence higher rates of fasting plasma glucose tests and BMI assessment. CONCLUSIONS: There is a need for greater vigilance in the detection of hyperglycaemia and undiagnosed diabetes mellitus among patients admitted to hospital with stroke or transient ischaemic attack.

A randomised controlled trial testing the feasibility and efficacy of a physical activity behavioural change intervention in managing fatigue with gynaecological cancer survivors.

OBJECTIVE: To determine the feasibility and efficacy of a physical activity behavioural change intervention in managing cancer-related fatigue among gynaecological cancer survivors during and post anti-cancer treatments. METHODS: A two arm, single blind, randomised controlled trial was conducted within the Northern Ireland regional Cancer Centre. Thirty three sedentary gynaecological cancer survivors (stage I-III; ≤3 years post diagnosis), experiencing cancer-related fatigue (mild-severe) took part. Participants were randomly assigned to a behavioural change, moderate intensity physical activity intervention (n=16) or a Contact Control group (n=17). The primary outcome was fatigue (Multidimensional Fatigue Symptom Inventory-Short Form and Functional Assessment in Chronic Illness Therapy-Fatigue subscale). Secondary outcomes included quality of life, physical functioning, positive and negative affect, depression, body composition, sleep dysfunction and self-reported physical activity. Feasibility was assessed based on the recruitment rate, programme and physical activity adherence and participants' programme evaluation, including optional focus groups (n=16). RESULTS: Twenty five percent of eligible women took part (33/134). Participants were 8.7 (SD=9.1) months post diagnosis, with a mean age of 53 (SD=10.3) years. The majority of the sample had a diagnosis of ovarian (n=12) or endometrial cancer (n=11). Significant differences favouring the intervention group were observed for fatigue at 12 weeks and 6 months follow-up (12 week: mean difference=-11.06; 95% confidence interval (CI)=-21.89 to -0.23; effect size (d)=0.13; p=0.046; 6 month: mean difference=-19.48; 95% CI=-19.67 to -19.15; effect size (d)=0.20; p=0.01). A mean of 10 calls (SD=1.2 calls) were delivered to the Physical Activity Group, and 10 (SD=1.6 calls) to the CC group. The intervention was positively perceived based on exit questionnaire and focus group findings. CONCLUSIONS: A physical activity behavioural change intervention for gynaecological cancer survivors is feasible in terms of participants' programme adherence and evaluation, and the intervention demonstrates improvements in fatigue. However, confirmation in the form of a larger fully powered RCT is warranted.

Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.

Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.

Tuberculosis testing in correctional officers: a national random survey of jails in the United States.

SETTING: The correctional system in the United States is large and growing. The Centers for Disease Control and Prevention recommend baseline and annual testing of employees in correctional facilities for latent tuberculosis infection (LTBI). OBJECTIVE: To describe the extent of and factors associated with LTBI testing practices for jail correctional officers. DESIGN: A national survey of 1760 randomly selected jails was conducted. We used multivariable logistic regression models to examine factors associated with testing officers in a guideline-concordant manner and having a written policy. RESULTS: A total of 1174 (67%) surveys were returned. Only 52% of jails had a written policy on LTBI testing of officers, and 51% screened officers at least annually (guideline concordance). Large jails (OR 2.41, 95%CI 1.67-3.49) and jails in states with a high tuberculosis incidence (OR 1.67, 95%CI 1.17-2.38) and in the Midwest (OR 1.58, 95%CI 1.07-2.33) were more likely to screen in a guideline-concordant manner. CONCLUSION: Screening for LTBI among correctional officers in the United States was inconsistent. Strategies to improve LTBI testing among correctional officers are needed.

Intact T cell receptor signaling by CD4(+) T cells cultured in the rotating wall-vessel bioreactor.

T lymphocytes fail to proliferate or secrete cytokines in response to T cell receptor (TCR) agonists during culture in spaceflight or ground-based microgravity analogs such as rotating wall-vessel (RWV) bioreactors. In RWVs, these responses can be rescued by co-stimulation with sub-mitogenic doses of the diacyl glycerol (DAG) mimetic phorbol myristate acetate. Based on this result we hypothesized that TCR activation is abrogated in the RWV due to impaired DAG signaling downstream of the TCR. To test this hypothesis we compared TCR-induced signal transduction by primary, human, CD4(+) T cells in RWV, and static culture. Surprisingly, we found little evidence of impaired DAG signaling in the RWV. Upstream of DAG, the tyrosine phosphorylation of several key components of the TCR-proximal signal was not affected by culture in the RWV. Similarly, the phosphorylation and compartmentalization of ERK and the degradation of IkappaB were unchanged by culture in the RWV indicating that RAS- and PKC-mediated signaling downstream of DAG are also unaffected by simulated microgravity. We conclude from these data that TCR signaling through DAG remains intact during culture in the RWV, and that the loss of functional T cell activation in this venue derives from the affect of simulated microgravity on cellular processes that are independent of the canonical TCR pathway.

Is sugar consumption detrimental to health? A review of the evidence 1995-2006.

Many countries set quantitative targets for added sugars, justifying this by expressing concern about the likely impact of sugar on weight control, dental health, diet quality, or metabolic syndrome. This review considers whether current intakes of sugar are harmful to health, and analyses recent literature using a systematic approach to collate, rank, and evaluate published studies from 1995-2006. Results from high quality obesity studies did not suggest a positive association between body mass index and sugar intake. Some studies, specifically on sweetened beverages, highlighted a potential concern in relation to obesity risk, although these were limited by important methodological issues. Diet adequacy appeared to be achieved across sugar intakes of 6 to 20% energy, depending on subject age. Studies on metabolic syndrome reported no adverse effects of sugar in the long-term, even at intakes of 40-50% energy. The evidence for colorectal cancer suggested an association with sugar, but this appeared to have been confounded by energy intake and glycemic load. There was no credible evidence linking sugar with attention-deficit, dementia, or depression. Regarding dental caries, combinations of sugar amount/frequency, fluoride exposure, and food adhesiveness were more reliable predictors of caries risk than the amount of sugar alone. Overall, the available evidence did not support a single quantitative sugar guideline covering all health issues.