Localised Cdr1as activity is required for fear extinction memory.

Circular RNAs (circRNAs) comprise a novel class of regulatory RNAs that are abundant in the brain, particularly within synapses. They are highly stable, dynamically regulated, and display a range of functions, including serving as decoys for microRNAs and proteins and, in some cases, circRNAs also undergo translation. Early work in animal models revealed an association between circRNAs and neurodegenerative and neuropsychiatric disorders; however, little is known about the link between circRNA function and memory. To address this, we examined circRNA in synaptosomes derived from the medial prefrontal cortex of fear extinction-trained male C57BL/6J mice and found 12,837 circRNAs that were enriched at the synapse, including cerebellar degeneration-related protein 1 antisense RNA (Cdr1as). Targeted knockdown of Cdr1as in the neural processes of the infralimbic cortex led to impaired fear extinction memory. These findings highlight the involvement of localised circRNA activity at the synapse in memory formation.

Racial/ethnic and Gender Inequalities in Third Grade Children's Self-perceived STEM Competencies.

Studies have sought to understand the underrepresentation of women and racial/ethnic minority groups in STEM, but less attention has been paid to primary school students. Using data from a nationally-representative sample, this study identified factors influencing US third-grade children's self-perceived competencies in math and science, while controlling for their actual abilities. Results indicate that girls had degraded self-perceptions of their math competencies compared to boys, but similar self-rated science competencies. Black students exhibited buoyed self-perceived math competencies, while Hispanic and indigenous students underestimated their science competencies. Students who reported being satisfied with parental attention, friends, and neighborhood had higher self-perceived competencies in both math and science.

Radiographic pseudosubluxation of the shoulder in pediatric proximal humeral fractures.

This study was undertaken to determine the incidence, need for intervention, and time to resolution of pseudosubluxation of the shoulder in pediatric proximal humerus fractures. One hundred and ninety-nine radiographs (199 x-rays) were analyzed for pseudosubluxation of the shoulder following pediatric proximal humeral fractures. Pseudosubluxation occurs when the center of the humeral head aligns with the inferior one-fourth of the glenoid. Fourteen patients met the inclusion criteria for pseudosubluxation. The nonoperative cohort consisted of 100 females and 93 males and the operative cohort consisted of 3 males and 3 females. Total 14 children out of 199 had pseudosubluxation. Ten pseudosubluxations were seen 7 days postinjury and four were noted immediately after injury. Pseudosubluxation was seen in nine boys (64%) and five girls (36%) in the nonoperative group. Increased relative risk (RR) was associated with: fall >3 m (RR = 25.7; 95% CI, 2.7-244.0), motorized transport (RR = 11.7; 95% CI, 1.41-96.03) and sports injuries (RR = 11.0, 95% CI, 1.2-100). No statistical analysis was conducted on the operative group given the small sample. This study establishes incidence, risk factors and expected clinical course for pseudosubluxation following proximal humerus fractures. The overall incidence in the nonoperative cohort was 7.3%, radiographic evidence of pseudosubluxation resolution was available for (n = 10) patients with 100% resolution by 6 weeks. There were no readmissions or complications in the 14 patients. Pseudosubluxation occurrence was significantly increased in four mechanisms: falls >3 m, sports trauma and motor transportation. This study provides the natural history and risk factors for pseudosubluxation following proximal humerus fractures. Pseudosubluxation is more likely to occur in higher energy fracture mechanisms and will resolve without treatment. Level of Evidence: Level III, retrospective cohort.

Shrimp Parvovirus Circular DNA Fragments Arise From Both Endogenous Viral Elements and the Infecting Virus.

Some insects use endogenous reverse transcriptase (RT) to make variable viral copy DNA (vcDNA) fragments from viral RNA in linear (lvcDNA) and circular (cvcDNA) forms. The latter form is easy to extract selectively. The vcDNA produces small interfering RNA (siRNA) variants that inhibit viral replication via the RNA interference (RNAi) pathway. The vcDNA is also autonomously inserted into the host genome as endogenous viral elements (EVE) that can also result in RNAi. We hypothesized that similar mechanisms occurred in shrimp. We used the insect methods to extract circular viral copy DNA (cvcDNA) from the giant tiger shrimp (Penaeus monodon) infected with a virus originally named infectious hypodermal and hematopoietic necrosis virus (IHHNV). Simultaneous injection of the extracted cvcDNA plus IHHNV into whiteleg shrimp (Penaeus vannamei) resulted in a significant reduction in IHHNV replication when compared to shrimp injected with IHHNV only. Next generation sequencing (NGS) revealed that the extract contained a mixture of two general IHHNV-cvcDNA types. One showed 98 to 99% sequence identity to GenBank record AF218266 from an extant type of infectious IHHNV. The other type showed 98% sequence identity to GenBank record DQ228358, an EVE formerly called non-infectious IHHNV. The startling discovery that EVE could also give rise to cvcDNA revealed that cvcDNA provided an easy means to identify and characterize EVE in shrimp and perhaps other organisms. These studies open the way for identification, characterization and use of protective cvcDNA as a potential shrimp vaccine and as a tool to identify, characterize and select naturally protective EVE to improve shrimp tolerance to homologous viruses in breeding programs.

Population-based trends in hospitalizations due to injection drug use-related serious bacterial infections, Oregon, 2008 to 2018.

BACKGROUND: Injection drug use has far-reaching social, economic, and health consequences. Serious bacterial infections, including skin/soft tissue infections, osteomyelitis, bacteremia, and endocarditis, are particularly morbid and mortal consequences of injection drug use. METHODS: We conducted a population-based retrospective cohort analysis of hospitalizations among patients with a diagnosis code for substance use and a serious bacterial infection during the same hospital admission using Oregon Hospital Discharge Data. We examined trends in hospitalizations and costs of hospitalizations attributable to injection drug use-related serious bacterial infections from January 1, 2008 through December 31, 2018. RESULTS: From 2008 to 2018, Oregon hospital discharge data included 4,084,743 hospitalizations among 2,090,359 patients. During the study period, hospitalizations for injection drug use-related serious bacterial infection increased from 980 to 6,265 per year, or from 0.26% to 1.68% of all hospitalizations (P<0.001). The number of unique patients with an injection drug use-related serious bacterial infection increased from 839 to 5,055, or from 2.52% to 8.46% of all patients (P<0.001). While hospitalizations for all injection drug use-related serious bacterial infections increased over the study period, bacteremia/sepsis hospitalizations rose most rapidly with an 18-fold increase. Opioid use diagnoses accounted for the largest percentage of hospitalizations for injection drug use-related serious bacterial infections, but hospitalizations for amphetamine-type stimulant-related serious bacterial infections rose most rapidly with a 15-fold increase. People living with HIV and HCV experienced increases in hospitalizations for injection drug use-related serious bacterial infection during the study period. Overall, the total cost of hospitalizations for injection drug use-related serious bacterial infections increased from $16,305,129 in 2008 to $150,879,237 in 2018 (P<0.001). CONCLUSIONS: In Oregon, hospitalizations for injection drug use-related serious bacterial infections increased dramatically and exacted a substantial cost on the health care system from 2008 to 2018. This increase in hospitalizations represents an opportunity to initiate substance use disorder treatment and harm reduction services to improve outcomes for people who inject drugs.

Estimating the effectiveness of routine asymptomatic PCR testing at different frequencies for the detection of SARS-CoV-2 infections

BackgroundRoutine asymptomatic testing using RT-PCR of people who interact with vulnerable populations, such as medical staff in hospitals or care workers in care homes, has been employed to help prevent outbreaks among vulnerable populations. Although the peak sensitivity of RT-PCR can be high, the probability of detecting an infection will vary throughout the course of an infection. The effectiveness of routine asymptomatic testing will therefore depend on testing frequency and how PCR detection varies over time. MethodsWe fitted a Bayesian statistical model to a dataset of twice weekly PCR tests of UK healthcare workers performed by self-administered nasopharyngeal swab, regardless of symptoms. We jointly estimated times of infection and the probability of a positive PCR test over time following infection, we then compared asymptomatic testing strategies by calculating the probability that a symptomatic infection is detected before symptom onset and the probability that an asymptomatic infection is detected within 7 days of infection. FindingsWe estimated that the probability that the PCR test detected infection peaked at 77% (54 - 88%) 4 days after infection, decreasing to 50% (38 - 65%) by 10 days after infection. Our results suggest a substantially higher probability of detecting infections 1-3 days after infection than previously published estimates. We estimated that testing every other day would detect 57% (33-76%) of symptomatic cases prior to onset and 94% (75-99%) of asymptomatic cases within 7 days if test results were returned within a day. InterpretationOur results suggest that routine asymptomatic testing can enable detection of a high proportion of infected individuals early in their infection, provided that the testing is frequent and the time from testing to notification of results is sufficiently fast. FundingWellcome Trust, National Institute for Health Research (NIHR) Health Protection Research Unit, Medical Research Council (UKRI)

Predictors of loss to follow-up of tuberculosis cases under the DOTS programme in Namibia.

BACKGROUND: In Namibia, one out of every 25 cases of tuberculosis (TB) is "lost to follow-up" (LTFU). This has impacted negatively on national efforts to end the disease by 2035. The aim of this study was to determine the trends and predictors of LTFU under the directly observed treatment short-course (DOTS) programme in Namibia. METHODS: The study involved a retrospective longitudinal analysis of a nationwide cohort of TB cases registered under the DOTS programme in Namibia from 2006 to 2015. The trends and predictors of LTFU among cases in the National Electronic TB Register of the National TB and Leprosy Program were respectively determined by interrupted time series and multivariate logistic regression analyses using R-Studio software. RESULTS: Out of 104 203 TB cases, 3775 (3.6%) were LTFU. A quarter (26%) of cases with poor outcomes were due to LTFU. The annual decline in cases of LTFU was significant between the first (2005-2010) and second (2010-2015) medium-term plan period for TB programme implementation (p=0.002). The independent predictors of LTFU were male sex (p=0.004), 15-24 years age group (p=0.03), provider of treatment (p<0.001), intensive phase (p=0.047) and living in border/transit regions (p<0.001). HIV co-infection and TB regimen were not significant predictors of LTFU. CONCLUSIONS: There were declining trends in LTFU in Namibia. DOTS programmes should integrate socioeconomic interventions for young and middle-aged adult male TB cases to reduce LTFU.

A model to strengthen utility of quality pharmaceutical health systems data in resource-limited settings.

Background: Limited utility of quality health data undermines efforts to strengthen healthcare delivery, particularly in resource-limited settings. Few studies model the effective utility of quality pharmaceutical information system (PIS) data in sub-Saharan Africa, typified with weak health systems. Aim: To develop a model and guidelines for strengthening utility of quality PIS data in public healthcare in Namibia, a resource-limited setting. Methods: A qualitative model based on Dickoff et al. practice-oriented theory, Chinn and Jacobs' systematic approach to theory, and applied consensus techniques. Data from nationwide studies on quality and utility of PIS data in public healthcare conducted between 2018 and March 2020 informed the development of the model concepts. Pharmaceutical and public health systems experts validated the final model. Results: Overall, four preliminary national studies that recruited 58 PIS focal persons at 38 public health facilities and national level informed the development of four model concepts. The model describes concepts on access, management, dissemination, and utility of quality PIS data. Activities to implement the model in practice include grass-root integration of real-time automated pharmaceutical intelligence systems to collect, consolidate, monitor, and report PIS data. Strengthening coordination, human resources, and technical capacity through support supervisory systems at grass-root facilities are key activities. PIS focal persons at health facility and national level are agents to implement these activities among recipients, that is, healthcare professionals at points of care. Guidelines for implementation of the model at point of care are included. Experts described the model as clear, simple, comprehensive, and integration of pharmaceutical intelligence systems at point of care as novel and of importance to enhance utility of quality PIS data in resource-limited settings. Conclusion: While utility of quality PIS data is limited in Namibia, advantages of the model are encouraging, toward building resilient pharmaceutical intelligence systems at grass roots in resource-limited countries, where there are not only weak health systems, but high burden of misuse of medicines.

Effective integration of pharmacovigilance systems at public health facilities in resource-limited settings: A qualitative study.

BACKGROUND: Pharmacovigilance systems increase access to safe medicines and healthcare, but their integration in public healthcare remains a challenge in many countries. The main barriers to pharmacovigilance integration are attributed to high patient load and limited capacities. OBJECTIVE: To explore the challenges associated with the effective integration of pharmacovigilance systems in public healthcare in a developing country such as Namibia. METHODS: A nationwide qualitative assessment of integration of pharmacovigilance systems particularly spontaneous adverse drug reaction (ADR) reporting at public health facility level was conducted. Key informant interviews were conducted among pivotal healthcare professionals involved in pharmacovigilance. The main outcomes were themes on challenges and strategies for effective integration of PV services at the facility level. Qualitative data were collected over a one-month period (i.e., March 2019), and thematically analysed. RESULTS: Eight (8) key informants were recruited; the majority were pharmacists (n = 7) and male (n = 5). The main challenges affecting the effective integration of pharmacovigilance systems reporting at public health facilities were "weak pharmacovigilance policies and structures", "negative attitude of healthcare workers towards pharmacovigilance", and "limited capacity and support for implementation of pharmacovigilance activities". The main strategies for effective integration of PV systems at facilities included local capacity-building through continuing profession education and support, advocacy, stakeholder engagement, facility/region based pharmacovigilance champions, and facility-based policies for universal and inclusive reporting, (i.e. patients and health workers at all levels) as well as development of workable standard operational procedures. CONCLUSIONS: The pharmacovigilance systems at healthcare facilities in Namibia were observed to have sub-optimal policies, structures and support systems, and lack health care worker buy-in. There is a need for a policy framework to ensure effective and sustainable integration of pharmacovigilance activities at public healthcare facilities.

Self-Reported Screening for Rectal Sexually Transmitted Infections Among Men Who Have Sex With Men.

BACKGROUND: Rectal gonorrhea and chlamydia are common and predict human immunodeficiency virus (HIV) acquisition among men who have sex with men (MSM); however, screening for rectal sexually transmitted infections (STIs) is not routine. METHODS: In 2017, we recruited sexually active MSM in the Portland, Oregon metropolitan area through venue-based sampling. Our outcome of interest was self-reported rectal STI screening in the prior 12 months among those who had a health care visit in the same time period. Stratified by HIV status and preexposure prophylaxis (PrEP) use, we assessed the prevalence and predictors of screening. RESULTS: Of 403 participants, 162 (40.2%) reported rectal STI screening. Sixty (25.7%) of 233 HIV-negative men who did not report PrEP use in the prior 12 months; 61 (69.3%) of the 88 HIV-negative men who reported PrEP use in the prior 12 months; and, 41 (59.4%) of 69 men living with HIV-reported screening, respectively. Among HIV-negative men who did not report PrEP use in the prior 12 months, having a health care provider who offered HIV testing (adjusted prevalence ratio [aPR], 2.21; 95% confidence interval [CI], 1.38-3.52) and condomless anal sex with casual partners in the prior 12 months (aPR, 1.63; 95% CI, 1.01-2.65) were independently associated with rectal STI screening. The HIV-negative men on PrEP who had a syphilis diagnosis in the prior 12 months were more likely to be screened than those without syphilis (aPR, 1.33; 95% CI, 1.11-1.59). Men living with HIV who reported having a provider who always or often initiates conversations about sex were more likely to report screening compared with men who did not have such a provider (aPR, 1.46; 95% CI, 1.06-2.03). CONCLUSIONS: Rectal STI screening is not universal in a venue-based sample of sexually active MSM. Implementing innovative, acceptable, and accessible screening practices, enhancing health literacy around STI screening and improving provider comfort with talking about sex are paramount to increasing rectal STI screening.

Exercise Management for Young People With Type 1 Diabetes: A Structured Approach to the Exercise Consultation.

Regular physical activity during childhood is important for optimal physical and psychological development. For individuals with Type 1 Diabetes (T1D), physical activity offers many health benefits including improved glycemic control, cardiovascular function, blood lipid profiles, and psychological well-being. Despite these benefits, many young people with T1D do not meet physical activity recommendations. Barriers to engaging in a physically active lifestyle include fear of hypoglycemia, as well as insufficient knowledge in managing diabetes around exercise in both individuals and health care professionals. Diabetes and exercise management is complex, and many factors can influence an individual's glycemic response to exercise including exercise related factors (such as type, intensity and duration of the activity) and person specific factors (amount of insulin on board, person's stress/anxiety and fitness levels). International guidelines provide recommendations for clinical practice, however a gap remains in how to apply these guidelines to a pediatric exercise consultation. Consequently, it can be challenging for health care practitioners to advise young people with T1D how to approach exercise management in a busy clinic setting. This review provides a structured approach to the child/adolescent exercise consultation, based on a framework of questions, to assist the health care professional in formulating person-specific exercise management plans for young people with T1D.

Evaluation of 4 Algorithms to Identify Incident Syphilis Among HIV-Positive Men Who Have Sex With Men Engaged in Primary Care.

We developed 4 algorithms for syphilis among HIV-positive men who have sex with men who engaged in primary care in 2016 to 2017. Clinician-based diagnosis from chart reviews was the gold standard. Sensitivities ranged from 74.2% to 93.9%. Specificities were greater than 99% with positive and negative predictive values of greater than 95%. Algorithms that incorporated treatment data performed best.

Correlates of Self-Reported Viral Suppression Among HIV-Positive, Young, Black Men Who Have Sex With Men Participating in a Randomized Controlled Trial of An Internet-Based HIV Prevention Intervention.

BACKGROUND: Young, black men who have sex with men are disproportionately impacted by the US HIV epidemic, and HIV-positive, young, black men who have sex with men face stark disparities in HIV clinical outcomes. METHODS: We performed an observational analysis of the 199 HIV-positive black men aged 18 to 30 years followed up for 12 months in healthMpowerment, a randomized controlled trial of an Internet-based HIV prevention intervention, to identify time-varying correlates of self-reported viral suppression using relative risk (RR) regression. RESULTS: Retention at the 12-month visit was 84%. One hundred five (65%) of 162 participants reported being undetectable at baseline. At 3, 6, and 12 months, 83 (72%) of 115, 84 (82%) of 103, and 101 (86%) of 117 reported an undetectable viral load, respectively. In a multivariable model, participants who reported homelessness (RR, 0.85; 95% confidence interval [CI], 0.72-0.99), who had clinically significant depressive symptoms (RR, 0.88; 95% CI, 0.79-0.98), and who used methamphetamine or crack (RR, 0.61; 95% CI, 0.38-0.96) were less likely to report an undetectable viral load. Young men who engaged in condomless insertive anal intercourse were more likely to report viral suppression (RR, 1.14; 95% CI, 1.04-1.24). CONCLUSION: HIV care for young, black men who have sex with men must be multidimensional to address medical needs in the context of mental health, substance use, and housing insecurity.

Cytokine profile of patients with leptospirosis in Sabah, Malaysia

Background: Leptospirosis is a zoonotic disease withsymptoms ranging from a mild, febrile illness to a severeform with multiorgan failure. Severe leptospirosis mayrequire medical interventions in the form of dialysis and/ormechanical ventilation and often leads to mortality. Anexaggerated host immune response—in particular, a“cytokine storm”—that causes endothelial and organdamage is associated with the disease severity andmortality.Methods: Microscopic agglutination test (MAT)-positive andMAT-negative human serum samples (n=30) from patientswith leptospirosis were obtained from the Public HealthLaboratory, Kota Kinabalu, Sabah, Malaysia and controlserum samples (n=10) were obtained from healthy studentvolunteers. We estimated the levels of IL-1β, IL-6, IL-8, IL-10,and TNF-α in serum samples by a Luminex assay.Results: The levels of IL-6, IL-8, and IL1-β were significantlyhigher in 13% of the patients with leptospirosis compared tothe healthy controls, while the levels of IL-10 and TNF-α werenot elevated in either group.Conclusion: Our data suggest that elevated levels of IL-6, IL-8, and IL1-β may be associated with leptospirosis diseaseseverity, which requires patient follow-up for confirmation.

Maternal separation induces hippocampal changes in cadherin-1 (CDH-1) mRNA and recognition memory impairment in adolescent mice.

In rodents, disruption of mother-infant attachment induced by maternal separation (MS) is associated with recognition memory impairment and long-term neurobiological consequences. Particularly stress-induced modifications have been associated to disruption of cadherin (CDH) adhesion function, which plays an important role in remodeling of neuronal connection and synaptic plasticity. This study investigated the sex-dependent effect of MS on recognition memory and mRNA levels of classical type I and type II CDH and the related ß -catenin (ß -Cat) in the hippocampus and prefrontal cortex of late adolescent mice. We provided evidence that the BALB/c mice exposed to MS present deficit in recognition memory, especially females. Postnatal MS induced higher hippocampal CDH-2 and CDH-8 mRNA levels, as well as an upregulation of CDH-1 in the prefrontal cortex in both males and females. MS-reared female mice presented lower CDH-1 mRNA levels in the hippocampus. In addition, hippocampal CDH-1 mRNA levels were positively correlated with recognition memory performance in females. MS-reared male mice exhibited higher ß -Cat mRNA levels in the hippocampus. Considering sex-specific effects on CDH mRNA levels, it has been demonstrated mRNA changes in CDH-1, ß -Cat, and CDH-6 in the hippocampus, as well as CDH-1, CDH-8 and CDH-11 in the prefrontal cortex. Overall, these findings suggest a complex interplay among MS, CDH mRNA expression, and sex differences in the PFC and hippocampus of adolescent mice.

Recombinant LipL32 Protein Developed Using a Synthetic Gene Detects Leptospiraspecific Antibodies in Human Serum Samples

Background: Synthetic biology is emerging as a viable alternative for the production of recombinant antigens for diagnostic applications. It offers a safe alternative for the synthesis of antigenic principles derived from organisms that pose a high biological risk. Methods: Here, we describe an enzyme-linked immunosorbent assay (ELISA) using the synthetic recombinant LipL32 (rLipL32) protein expressed in Escherichia coli for the detection of Leptospira-specific antibodies in human serum samples. The rLipL32-based ELISA was compared with a microscopic agglutination test (MAT), which is currently used as the gold standard for the diagnosis of leptospirosis. Results: Our results showed that all the MAT-positive serum samples were positive for Leptospira-specific IgG in an ELISA, while 65% (n = 13) of these samples were also positive for Leptospira-specific IgM. In the MAT-negative serum samples, 80% and 55% of the samples were detected as negative by an ELISA for Leptospira-specific IgM and IgG, respectively. Conclusion: An ELISA using the synthetic rLipL32 antigen was able to distinguish Leptospira-specific IgM (sensitivity 65% and specificity 80%) and IgG (sensitivity 100% and specificity 55%) in human serum samples and has the potential to serve as a rapid diagnostic test for leptospirosis.

Diagnosis of tuberculous meningitis: challenges and promises

Tuberculosis (TB) which is caused by Mycobacterium tuberculosis infects primarily the lungs but it also affects other parts of the body. Tuberculous meningitis (TBM) is the most severe form of TB and has the highest mortality and morbidity rate compared to other forms of TB. It is common in young children and HIV-infected patients, but is also seen in adults. Despite anti-tuberculosis treatment, TBM is still a major cause of death and neurological sequelae as treatment given to the patients is often delayed. Early diagnosis is challenging due to the non-specific symptoms of TBM and the low number of tubercle bacilli in cerebrospinal fluid (CSF). Until now, there is no established diagnostic method that can rapidly detect M. tuberculosis in TBM patients with high sensitivity and specificity. The emergence of drug resistant M. tuberculosis strains further complicates the diagnosis and treatment regimen of TBM. This review summarizes challenges of the currently used diagnostic methods and the potential future use of molecular diagnostic methods for TBM.

Individualised second line anti-tuberculous therapy for anextensively resistant pulmonary tuberculosis (XDR PTB) in East Malaysia

Clinical experience with extensively Drug Resistant tuberculosis (XDR-TB) has not been reported in Malaysia before. We describe the clinical characteristics, risk factors, progress and therapeutic regimen for a healthcare worker with XDR-TB, who had failed therapy for multidrug resistant TB (MDR TB) in our institution. This case illustrates the risk of TB among healthcare workers in high TB-burden settings, the importance of obtaining upfront culture and susceptibility results in all new TB cases, the problem of acquired drug resistance developing during MDR-TB treatment, the challenges associated with XDR-TB treatment regimens, the value of surgical resection in refractory cases, and the major quality of life impact this disease can have on young, economically productive individuals.