First trimester exposure to anxiolytic and hypnotic drugs and the risks of major congenital anomalies: a United Kingdom population-based cohort study.

BACKGROUND: Despite their widespread use the effects of taking benzodiazepines and non-benzodiazepine hypnotics during pregnancy on the risk of major congenital anomaly (MCA) are uncertain. The objectives were to estimate absolute and relative risks of MCAs in children exposed to specific anxiolytic and hypnotic drugs taken in the first trimester of pregnancy, compared with children of mothers with depression and/or anxiety but not treated with medication and children of mothers without diagnosed mental illness during pregnancy. METHODS: We identified singleton children born to women aged 15-45 years between 1990 and 2010 from a large United Kingdom primary care database. We calculated absolute risks of MCAs for children with first trimester exposures of different anxiolytic and hypnotic drugs and used logistic regression with a generalised estimating equation to compare risks adjusted for year of childbirth, maternal age, smoking, body mass index, and socioeconomic status. RESULTS: Overall MCA prevalence was 2.7% in 1,159 children of mothers prescribed diazepam, 2.9% in 379 children with temazepam, 2.5% in 406 children with zopiclone, and 2.7% in 19,193 children whose mothers had diagnosed depression and/or anxiety but no first trimester drug exposures. When compared with 2.7% in 351,785 children with no diagnosed depression/anxiety nor medication use, the adjusted odds ratios were 1.02 (99% confidence interval 0.63-1.64) for diazepam, 1.07 (0.49-2.37) for temazepam, 0.96 (0.42-2.20) for zopiclone and 1.27 (0.43-3.75) for other anxiolytic/hypnotic drugs and 1.01 (0.90-1.14) for un-medicated depression/anxiety. Risks of system-specific MCAs were generally similar in children exposed and not exposed to such medications. CONCLUSIONS: We found no evidence for an increase in MCAs in children exposed to benzodiazepines and non-benzodiazepine hypnotics in the first trimester of pregnancy. These findings suggest that prescription of these drugs during early pregnancy may be safe in terms of MCA risk, but findings from other studies are required before safety can be confirmed

Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study

OBJECTIVE: To estimate risks of major congenital anomaly (MCA) among children of mothers prescribed antidepressants during early pregnancy or diagnosed with depression but without antidepressant prescriptions. DESIGN: Population-based cohort study. SETTING: Linked UK maternal–child primary care records. POPULATION: A total of 349 127 singletons liveborn between 1990 and 2009. METHODS: Odds ratios adjusted for maternal sociodemographics and comorbidities (aORs) were calculated for MCAs, comparing women with first-trimester selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) and women with diagnosed but unmedicated depression, or women without diagnosed depression. MAIN OUTCOME MEASURES: Fourteen system-specific MCA groups classified according to the European Surveillance of Congenital Anomalies and five specific heart anomaly groups. RESULTS: Absolute risks of MCA were 2.7% (95% confidence interval, 95% CI, 2.6–2.8%) in children of mothers without diagnosed depression, 2.8% (95% CI 2.5–3.2%) in children of mothers with unmedicated depression, and 2.7% (95% CI 2.2–3.2%) and 3.1% (95% CI 2.2–4.1%) in children of mothers with SSRIs or TCAs, respectively. Compared with women without depression, MCA overall was not associated with unmedicated depression (aOR 1.07, 95% CI 0.96–1.18), SSRIs (aOR 1.01, 95% CI 0.88–1.17), or TCAs (aOR 1.09, 95% CI 0.87–1.38). Paroxetine was associated with increased heart anomalies (absolute risk 1.4% in the exposed group compared with 0.8% in women without depression; aOR 1.78, 95% CI 1.09–2.88), which decreased marginally when compared with women with diagnosed but unmedicated depression (aOR 1.67, 95% CI 1.00–2.80). CONCLUSIONS: Overall MCA risk did not increase with maternal depression or with antidepressant prescriptions. Paroxetine was associated with increases of heart anomalies, although this could represent a chance finding from a large number of comparisons undertaken

The diagnostic accuracy of clinical tests for anterior cruciate ligament tears are comparable but the Lachman test has been previously overestimated: a systematic review and meta-analysis

Abstract Purpose The diagnostic accuracy of clinical tests for anterior cruciate ligament injury has been reported in previous systematic reviews. Numerous studies in these reviews include subjects with additional knee ligament injury, which could affect the sensitivity of the tests. Meta-analyses have also been performed using methods that do not account for the non-independence of sensitivity and specificity, potentially overestimating diagnostic accuracy. The aim of this study was to report the diagnostic accuracy of clinical tests for anterior cruciate ligament tears (partial and complete) without concomitant knee ligament injury. Methods A systematic review with meta-analysis was performed according to the PRISMA guidelines. Meta-analyses included studies reporting the specificity and/or sensitivity of tests with or without concomitant meniscal injury. Where possible, pooled diagnostic estimates were calculated with bivariate random-effects modelling to determine the most accurate effect sizes. Diagnostic accuracy values are presented for the anterior drawer, Lachman, Lever sign and pivot shift tests overall and in acute or post-acute presentations. Results Pooled estimates using a bivariate model for overall sensitivity and specificity respectively were as follows: anterior drawer test 83% [95% CI, 77–88] and 85% [95% CI, 64–95]; Lachman test 81% [95% CI, 73–87] and 85% [95% CI, 73–92]; pivot shift test 55% [95% CI, 47–62] and 94% [95% CI, 88–97]; Lever sign test 83% [95% CI, 68–92] and 91% [95% CI, 83–95]. For specific presentations, the sensitivity and specificity of the Lachman test, respectively, were: complete tears 68% [95% CI, 54–79] and 79% [95% CI, 51–93]; post-acute injuries 70% [95% CI, 57–80] and 77% [95% CI, 53–91]. Conclusions The pivot shift and Lever sign were the best tests overall for ruling in or ruling out an anterior cruciate ligament tear, respectively. The diagnostic accuracy of the Lachman test, particularly in post-acute presentations and for complete tears, is lower than previously reported. Further research is required to establish more accurate estimates for the Lachman test in acute presentations and partial ligament tears using bivariate analysis. Level of evidence III. </jats:sec

Measurement of S-phase duration of adult stem cells in the flatworm Macrostomum lignano by double replication labelling and quantitative colocalization analysis

Platyhelminthes are highly attractive models for addressing fundamental aspects of stem cell biology in vivo. These organisms possess a unique stem cell system comprised of neoblasts that are the only proliferating cells during adulthood. We have investigated T-s (S-phase duration) of neoblasts during homoeostasis and regeneration in the flatworm, Macrostomum lignano. A double immunohistochemical technique was used, performing sequential pulses with the thymidine analogues CldU (chlorodeoxyuridine) and IdU (iododeoxyuridine), separated by variable chase times in the presence of colchicine. Owing to the localized nature of the fluorescent signals (cell nuclei) and variable levels of autofluorescence, standard intensity-based colocalization analyses could not be applied to accurately determine the colocalization. Therefore, an object-based colocalization approach was devised to score the relative number of double-positive cells. Using this approach, T-s (S-phase duration) in the main population of neoblasts was similar to 13 h. During early regeneration, no significant change in T-s was observed

Identification of C-β-d-Glucopyranosyl Azole-Type Inhibitors of Glycogen Phosphorylase That Reduce Glycogenolysis in Hepatocytes: In Silico Design, Synthesis, in Vitro Kinetics, and ex Vivo Studies

Several C-β-d-glucopyranosyl azoles have recently been uncovered as among the most potent glycogen phosphorylase (GP) catalytic site inhibitors discovered to date. Toward further exploring their translational potential, ex vivo experiments have been performed for their effectiveness in reduction of glycogenolysis in hepatocytes. New compounds for these experiments were predicted in silico where, for the first time, effective ranking of GP catalytic site inhibitor potencies using the molecular mechanics-generalized Born surface area (MM-GBSA) method has been demonstrated. For a congeneric training set of 27 ligands, excellent statistics in terms of Pearson (RP) and Spearman (RS) correlations (both 0.98), predictive index (PI = 0.99), and area under the receiver operating characteristic curve (AU-ROC = 0.99) for predicted versus experimental binding affinities were obtained, with ligand tautomeric/ionization states additionally considered using density functional theory (DFT). Seven 2-aryl-4(5)-(β-d-glucopyranosyl)-imidazoles and 2-aryl-4-(β-d-glucopyranosyl)-thiazoles were subsequently synthesized, and kinetics experiments against rabbit muscle GPb revealed new potent inhibitors with best Ki values in the low micromolar range (5c = 1.97 μM; 13b = 4.58 μM). Ten C-β-d-glucopyranosyl azoles were then tested ex vivo in mouse primary hepatocytes. Four of these (5a–c and 9d) demonstrated significant reduction of glucagon stimulated glycogenolysis (IC50 = 30–60 μM). Structural and predicted physicochemical properties associated with their effectiveness were analyzed with permeability related parameters identified as crucial factors. The most effective ligand series 5 contained an imidazole ring, and the calculated pKa (Epik: 6.2; Jaguar 5.5) for protonated imidazole suggests that cellular permeation through the neutral state is favored, while within the cell, there is predicted more favorable binding to GP in the protonated form

Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study

OBJECTIVE: To estimate risks of major congenital anomaly (MCA) among children of mothers prescribed antidepressants during early pregnancy or diagnosed with depression but without antidepressant prescriptions. DESIGN: Population-based cohort study. SETTING: Linked UK maternal–child primary care records. POPULATION: A total of 349 127 singletons liveborn between 1990 and 2009. METHODS: Odds ratios adjusted for maternal sociodemographics and comorbidities (aORs) were calculated for MCAs, comparing women with first-trimester selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) and women with diagnosed but unmedicated depression, or women without diagnosed depression. MAIN OUTCOME MEASURES: Fourteen system-specific MCA groups classified according to the European Surveillance of Congenital Anomalies and five specific heart anomaly groups. RESULTS: Absolute risks of MCA were 2.7% (95% confidence interval, 95% CI, 2.6–2.8%) in children of mothers without diagnosed depression, 2.8% (95% CI 2.5–3.2%) in children of mothers with unmedicated depression, and 2.7% (95% CI 2.2–3.2%) and 3.1% (95% CI 2.2–4.1%) in children of mothers with SSRIs or TCAs, respectively. Compared with women without depression, MCA overall was not associated with unmedicated depression (aOR 1.07, 95% CI 0.96–1.18), SSRIs (aOR 1.01, 95% CI 0.88–1.17), or TCAs (aOR 1.09, 95% CI 0.87–1.38). Paroxetine was associated with increased heart anomalies (absolute risk 1.4% in the exposed group compared with 0.8% in women without depression; aOR 1.78, 95% CI 1.09–2.88), which decreased marginally when compared with women with diagnosed but unmedicated depression (aOR 1.67, 95% CI 1.00–2.80). CONCLUSIONS: Overall MCA risk did not increase with maternal depression or with antidepressant prescriptions. Paroxetine was associated with increases of heart anomalies, although this could represent a chance finding from a large number of comparisons undertaken

Vaccination of healthcare workers to protect patients at increased risk of acute respiratory disease: summary of a systematic review

Healthcare workers (HCWs) are at increased risk of exposure to respiratory pathogens and may transmit infection to vulnerable patients. This study summarises a recent systematic review, which aimed to assess evidence that influenza or pneumococcal vaccination of HCWs provides indirect protection for those patients most at risk of severe or complicated acute respiratory infection. A number of healthcare databases and sources of grey literature were searched using a predefined strategy, and citations screened for eligibility in accordance with specified inclusion criteria. Risk of bias was assessed using validated tools and results summarised qualitatively. Twenty papers were included in the final review, all of which considered influenza vaccination of HCW. As such, planned subanalysis of pneumococcal vaccination was discarded. The majority of primary research studies included (11/14) were conducted in long-term care facilities, but there was marked heterogeneity in terms of the population, intervention/exposure and outcomes considered. Consistency in the direction of effect was observed across several different outcome measures, suggesting that influenza vaccination of HCWs is likely to offer some protection. Further evidence is, however, required from acute care settings

Effects of Ocean Acidification on Learning in Coral Reef Fishes

Ocean acidification has the potential to cause dramatic changes in marine ecosystems. Larval damselfish exposed to concentrations of CO2 predicted to occur in the mid- to late-century show maladaptive responses to predator cues. However, there is considerable variation both within and between species in CO2 effects, whereby some individuals are unaffected at particular CO2 concentrations while others show maladaptive responses to predator odour. Our goal was to test whether learning via chemical or visual information would be impaired by ocean acidification and ultimately, whether learning can mitigate the effects of ocean acidification by restoring the appropriate responses of prey to predators. Using two highly efficient and widespread mechanisms for predator learning, we compared the behaviour of pre-settlement damselfish Pomacentrus amboinensis that were exposed to 440 µatm CO2 (current day levels) or 850 µatm CO2, a concentration predicted to occur in the ocean before the end of this century. We found that, regardless of the method of learning, damselfish exposed to elevated CO2 failed to learn to respond appropriately to a common predator, the dottyback, Pseudochromis fuscus. To determine whether the lack of response was due to a failure in learning or rather a short-term shift in trade-offs preventing the fish from displaying overt antipredator responses, we conditioned 440 or 700 µatm-CO2 fish to learn to recognize a dottyback as a predator using injured conspecific cues, as in Experiment 1. When tested one day post-conditioning, CO2 exposed fish failed to respond to predator odour. When tested 5 days post-conditioning, CO2 exposed fish still failed to show an antipredator response to the dottyback odour, despite the fact that both control and CO2-treated fish responded to a general risk cue (injured conspecific cues). These results indicate that exposure to CO2 may alter the cognitive ability of juvenile fish and render learning ineffective

Changes in daily mental health service use and mortality at the commencement and lifting of COVID-19 ‘lockdown’ policy in 10 UK sites: a regression discontinuity in time design

Objectives: To investigate changes in daily mental health (MH) service use and mortality in response to the introduction and the lifting of the COVID-19 ‘lockdown’ policy in Spring 2020. Design: A regression discontinuity in time (RDiT) analysis of daily service-level activity. Setting and participants: Mental healthcare data were extracted from 10 UK providers. Outcome measures: Daily (weekly for one site) deaths from all causes, referrals and discharges, inpatient care (admissions, discharges, caseloads) and community services (face-to-face (f2f)/non-f2f contacts, caseloads): Adult, older adult and child/adolescent mental health; early intervention in psychosis; home treatment teams and liaison/Accident and Emergency (A&E). Data were extracted from 1 Jan 2019 to 31 May 2020 for all sites, supplemented to 31 July 2020 for four sites. Changes around the commencement and lifting of COVID-19 ‘lockdown’ policy (23 March and 10 May, respectively) were estimated using a RDiT design with a difference-in-difference approach generating incidence rate ratios (IRRs), meta-analysed across sites. Results: Pooled estimates for the lockdown transition showed increased daily deaths (IRR 2.31, 95% CI 1.86 to 2.87), reduced referrals (IRR 0.62, 95% CI 0.55 to 0.70) and reduced inpatient admissions (IRR 0.75, 95% CI 0.67 to 0.83) and caseloads (IRR 0.85, 95% CI 0.79 to 0.91) compared with the pre lockdown period. All community services saw shifts from f2f to non-f2f contacts, but varied in caseload changes. Lift of lockdown was associated with reduced deaths (IRR 0.42, 95% CI 0.27 to 0.66), increased referrals (IRR 1.36, 95% CI 1.15 to 1.60) and increased inpatient admissions (IRR 1.21, 95% CI 1.04 to 1.42) and caseloads (IRR 1.06, 95% CI 1.00 to 1.12) compared with the lockdown period. Site-wide activity, inpatient care and community services did not return to pre lockdown levels after lift of lockdown, while number of deaths did. Between-site heterogeneity most often indicated variation in size rather than direction of effect. Conclusions: MH service delivery underwent sizeable changes during the first national lockdown, with as-yet unknown and unevaluated consequences