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Establishing scalable nanomaterials synthesis protocols remains a bottleneck towards their commercialisation and, thus, a topic of intense research and development. Herein, we present an automated machine-learning microfluidic platform capable of synthesising optically active nanomaterials from target spectra originating from prior experience, theorised or published. Implementing unsupervised Bayesian optimisation with Gaussian processes reduces the optimisation time and the need for prior knowledge to initiate the process. Using PTFE tubing and connectors enables facile change in reactor design. Ultimately, the platform substitutes the labour-intensive trial-and-error synthesis and provides a pathway to standardisation and volume synthesis, slowing down the translation and commercialisation of high-quality nanomaterials. As a proof-of-concept, Ag nanoplates and Prussian-blue nanoparticle protocols were optimised and validated for volume production.

Kleefstra Syndrome (KS) is a rare monogenetic syndrome, caused by haploinsufficiency of the euchromatic histone methyl transferase 1 (EHMT1) gene, an important regulator of neurodevelopment. The clinical features of KS include intellectual disability, autistic behavior and gastrointestinal problems. The gut microbiota, an important modifier of the gut‐brain‐axis, may constitute an unexplored mechanism underlying clinical KS variation. We investigated the gut microbiota composition of 23 individuals with KS (patients) and 40 of their family members, to test whether (1) variation in the gut microbiota associates with KS diagnosis and (2) variation within the gut microbiota relates with KS syndrome symptoms. Both alpha and beta diversity of patients were different from their family members. Genus Coprococcus3 was lower in abundance in patients compared to family members. Moreover, abundance of genus Merdibacterwas lower in patients versus family members, but only in participants reporting intestinal complaints. Within the patient group, behavioral problems explained 7% of beta diversity variance. Also, within this group, we detected higher levels of Atopobiaceae – unculturedand RuminococcaceaeSubdoligranulum associated with higher symptom severity. These significant signatures in the gut microbiota composition in patients with KS suggest that microbiota differences are part of the KS phenotype.

During the last ice age, the Laurentide Ice Sheet exhibited extreme iceberg discharge events that are recorded in North Atlantic sediments1. These Heinrich events have far-reaching climate impacts, including widespread disruptions to hydrological and biogeochemical cycles2–4. They occurred during Heinrich stadials—cold periods with strongly weakened Atlantic overturning circulation5–7. Heinrich-type variability is not distinctive in Greenland water isotope ratios, a well-dated site temperature proxy8, complicating efforts to assess their regional climate impact and phasing against Antarctic climate change. Here we show that Heinrich events have no detectable temperature impact on Greenland and cooling occurs at the onset of several Heinrich stadials, and that both types of Heinrich variability have a distinct imprint on Antarctic climate. Antarctic ice cores show accelerated warming that is synchronous with increases in methane during Heinrich events, suggesting an atmospheric teleconnection9, despite the absence of a Greenland climate signal. Greenland ice-core nitrogen stable isotope ratios, a sensitive temperature proxy, indicate an abrupt cooling of about three degrees Celsius at the onset of Heinrich Stadial 1 (17.8 thousand years before present, where present is defined as 1950). Antarctic warming lags this cooling by 133 ± 93 years, consistent with an oceanic teleconnection. Paradoxically, proximal sites are less affected by Heinrich events than remote sites, suggesting spatially complex event dynamics.

Introduction: Serological surveys offer the most direct measurement to define the immunity status for numerous infectious diseases, such as COVID-19, and can provide valuable insights into understanding transmission patterns. This study describes seroprevalence changes over time in the context of the Democratic Republic of Congo, where COVID-19 case presentation was apparently largely oligo- or asymptomatic, and vaccination coverage remained extremely low. Methods: A cohort of 635 health care workers (HCW) from 5 health zones of Kinshasa and 670 of their household members was interviewed and sampled in 6 rounds between July 2020 and January 2022. At each round, information on risk exposure and a blood sample were collected. Serology was defined as positive when binding antibodies against SARS-CoV-2 spike and nucleocapsid proteins were simultaneously present. Results: The SARS-CoV-2 antibody seroprevalence was high at baseline, 17.3% (95% CI 14.4–20.6) and 7.8% (95% CI 5.5–10.8) for HCW and household members, respectively, and fluctuated over time, between 9% and 62.1%. Seropositivity was heterogeneously distributed over the health zones (p< 0.001), ranging from 12.5% (95% CI 6.6–20.8) in N’djili to 33.7% (95% CI 24.6–43.8) in Bandalungwa at baseline for HCW. Seropositivity was associated with increasing rounds adjusted Odds Ratio (aOR) 1.75 (95% CI 1.66–1.85), with increasing age aOR 1.11 (95% CI 1.02–1.20), being a female aOR 1.35 (95% CI 1.10–1.66) and being a HCW aOR 2.38 (95% CI 1.80–3.14). There was no evidence that HCW brought the COVID-19 infection back home, with an aOR of 0.64 (95% CI 0.46–0.91) of seropositivity risk among household members in subsequent surveys. There was seroreversion and seroconversion over time, and HCW had a lower risk of seroreverting than household members (aOR 0.60 (95% CI 0.42–0.86)). Conclusion: SARS-CoV-2 IgG antibody levels were high and dynamic over time in this African setting with low clinical case rates. The absence of association with health profession or general risk behaviors and with HCW positivity in subsequent rounds in HH members, shows the importance of the time-dependent, and not work-related, force of infection. Cohort seroprevalence estimates in a ‘new disease’ epidemic seem insufficient to guide policy makers for defining control strategies.

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Advances in genomic technologies and an increased understanding of the molecular pathogenesis of cancer have resulted in development of new effective, mutation-targeted therapies. In turn, these informed the development of Master Trial designs to test these therapies. The Beat Acute Myeloid Leukemia (BAML) Master Trial (Sponsor: The Leukemia & Lymphoma Society) tests several targeted therapies in patients aged ≥ 60 years with AML based on genomic profiling obtained within 7 days of study enrollment. We hypothesized that integrating operational strategies with new electronic technologies (e-technologies) might streamline the conduct and management of this Master Trial. BAML’s 5 core operational strategies revolve around the guiding principle of “patients first.” The e-technology platforms employed in BAML include: Clinical Oversight Platform: a central collaborative tool; e-Protocol/e-Source Upload/Electronic Data Capture Platform: digitizes the protocol, allows remote data monitoring, and collects/exports data in Study Data Tabulation Model format; and Data Review Platform: ingests data from different sources for clinical response and safety data reviews. The operational approaches, e-technologies and sponsor/contract research organization’s (CRO) expertise together allow: the complexity and size of the BAML Master Trial to be better managed; near real-time study data oversight; better collaboration, communication and training; improved data collection, enhanced transmission and accessibility; data integration, review and generation of reports; while maintaining data privacy, and compliance. Initial e-technology challenges were overcome through training, learning, discipline and adjustment. In conclusion, to successfully manage Master Trials, significant time should be spent re-evaluating, improving and developing new operational approaches.

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There is a need for simple, cost-effective research tools to detect developmental delay in preschool children in low- and middle-income countries where insufficient resources are often a barrier to detection and management. The Goodenough Draw-a-Person test is freely available, easily administered, and requires limited language ability and equipment; it is thus potentially useful in resource-constrained settings. We aimed to determine the diagnostic accuracy of the Draw-a-Person test to identify developmental delay in 5-year-old preschool children using the Griffiths Mental Developmental Scales-Extended Revised eye-hand coordination subquotient as the gold standard. This was a cross-sectional analysis of drawings by South African preschool children from low-income families, whose Griffiths Mental Developmental Scales-Extended Revised assessments included a human figure drawing. Draw-a-Person test quotients were estimated independently by a developmental paediatrician and two medical officers to calculate inter-rater agreement. The paediatrician’s scores were used to determine the diagnostic accuracy of the Draw-a-Person test quotient (<85) to predict developmental delay with the eye-hand coordination subquotient (<75). A total of 125 children were included, with a mean age of 60.8 months (range 59–66 months) of which 48.8% were boys. The mean Draw-a-Person test score was 94 (standard deviation 15) with 28 Draw-a-Person test scores below 85. Applying the Draw-a-Person test cut-off of 85, sensitivity of the Draw-a-Person test to the eye-hand coordination subquotient was 80% and specificity 89%. The area under the receiver operator characteristic curve was 0.87 (95% confidence interval [0.78–0.96]). The Goodenough Draw-a-Person test could thus be a useful research tool for detecting fine motor and visuoperceptual delay in South African preschool children.

Alcohol dependence is commonly encountered in clinical practice. Accurate diagnosis using structured screening tools facilitates appropriate intervention, early screening for liver disease and referral to specialist services and mutual aid. For patients admitted to hospital, assessment of the risk of withdrawal and assertive treatment with benzodiazepines, particularly in the first 24 hours, improves patient safety by preventing withdrawal complications such as seizures and delirium. Similarly, detecting individuals at risk of, or who have, Wernicke–Korsakoff syndrome, and prescribing parenteral thiamine in adequate quantities, prevents the development of long-standing cognitive impairment. Hospital admission is an opportunity for reflection and building motivation for behaviour change, and efforts to engage with patients, establish what successes they have had in their recovery journey, and link them into local specialist and peer-led support structures ensures they have the best chance of lasting recovery.

COVAX, the international initiative supporting COVID-19 vaccination campaigns globally, is budgeted to be the costliest public health initiative in low- and middle-income countries, with over 16 billion US dollars already committed. While some claim that the target of vaccinating 70% of people worldwide is justified on equity grounds, we argue that this rationale is wrong for two reasons. First, mass COVID-19 vaccination campaigns do not meet standard public health requirements for clear expected benefit, based on costs, disease burden and intervention effectiveness. Second, it constitutes a diversion of resources from more cost-effective and impactful public health programmes, thus reducing health equity. We conclude that the COVAX initiative warrants urgent review.

The global prevalence of novel benzodiazepines (BZDs) has increased significantly in recent years with the predominant BZDs constantly changing to evade bans pertaining to specific chemical structures. As of 2020 the European Union Early Warning System (EWS) was monitoring 30 novel BZDs, 16 of which have been reported since 2016. Evidence of novel BZD-associated harms is growing and there is concern regarding their prevalence in drug-related deaths. We therefore analysed deaths in England, Wales, and Northern Ireland where novel BZDs, i.e., those that are not available on prescription via the National Health Service (NHS) in the United Kingdom, were detected at post-mortem in order to determine the circumstances surrounding novel BZD-associated fatalities.

ABSTRACTMaternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOSknockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOSgene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood.

The article discusses the 2015 Reserve Officer Training Corps (ROTC) Cadet Summer Training (CST) of the U.S. Army Forces Command (FORSCOM). It mentions the deployment of light infantry company 12th Infantry Regiment in Fort Knox, Kentucky to support the execution of the ROTC CST and to support the cadet rifle training ranges. It cites the application of M4/M16 zero target as an example of how simplified markmanship techniques can inhibit the markmanship progression of soldiers.

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis and a risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are responsible for ADMA breakdown. It has been reported that endothelial DDAH1 accounts for the majority of ADMA metabolism. However, we and others have shown strong DDAH1 expression in a range of nonendothelial cell types, suggesting that the endothelium is not the only site of metabolism. We have developed a new endothelium-specific DDAH1 knockout mouse (DDAH1En−−) to investigate the significance of endothelial ADMA in cardiovascular homeostasis.

Early initiation of antiretroviral therapy depends on an early infant diagnosis and is critical to reduce HIV-related infant mortality. We describe the implementation of a routine prevention of mother-to-child transmission program and focus on early infant diagnosis to identify opportunities to improve outcomes.

Immune reconstitution inflammatory syndrome occurs in a subset of HIV-infected individuals as the immune system recovers secondary to antiretroviral therapy. An exaggerated and uncontrolled inflammatory response to antigens of viable or nonviable organisms is characteristic, with clinical deterioration despite improvement in laboratory indicators. We describe a fatal case of Mycobacterium tuberculosismeningitis immune reconstitution inflammatory syndrome in an HIV-infected child and review the literature.

ABSTRACTEarly initiation of antiretroviral therapy reduces HIV-related infant mortality. The early peak of pediatric HIV-related deaths in South Africa occurs at 3 months of age, coinciding with the earliest age at which treatment is initiated following PCR testing at 6 weeks of age. Earlier diagnosis is necessary to reduce infant mortality. The performances of the Amplicor DNA PCR, COBAS AmpliPrep/COBAS TaqMan (CAP/CTM), and Aptima assays for detecting early HIV infection (acquired in uteroand intrapartum) up to 6 weeks of age were compared. Dried blood spots (DBS) were collected at birth and at 2, 4, and 6 weeks from HIV-exposed infants enrolled in an observational cohort study in Johannesburg, South Africa. HIV status was determined at 6 weeks by DNA PCR on whole blood. Serial DBS samples from all HIV-infected infants and two HIV-uninfected, age-matched controls were tested with the 3 assays. Of 710 infants of known HIV status, 38 (5.4%) had in utero(n= 29) or intrapartum (n= 9) infections. By 14 weeks, when treatment should have been initiated, 13 (45%) in utero-infected and 2 (22%) intrapartum-infected infants had died or were lost to follow-up. The CAP/CTM and Aptima assays identified 76.3% of all infants with early HIV infections at birth and by 4 weeks were 96% sensitive. DNA PCR demonstrated lower sensitivities at birth and 4 weeks of 68.4% and 87.5%, respectively. All assays had the lowest sensitivity at 2 weeks of age. CAP/CTM was the only assay with 100% specificity at all ages. Testing at birth versus 6 weeks of age identifies a higher total number of HIV-infected infants, irrespective of the assay.

Secondary activation of the endothelin system is thought to be involved in toxic liver injury. This study tested the hypothesis that dual endothelin-converting enzyme / neutral endopeptidase blockade might be able to attenuate acute toxic liver injury. Male Sprague-Dawley rats were implanted with subcutaneous minipumps to deliver the novel compound SLV338 (10 mg/kg*d) or vehicle. Four days later they received two intraperitoneal injections of D-galactosamine (1.3 g/kg each) or vehicle at an interval of 12 hours. The animals were sacrificed 48 hours after the first injection. Injection of D-galactosamine resulted in very severe liver injury, reflected by strongly elevated plasma liver enzymes, hepatic necrosis and inflammation, and a mortality rate of 42.9 %. SLV338 treatment did not show any significant effect on the extent of acute liver injury as judged from plasma parameters, hepatic histology and mortality. Plasma measurements of SLV338 confirmed adequate drug delivery. Plasma concentrations of big endothelin-1 and endothelin-1 were significantly elevated in animals with liver injury (5-fold and 62-fold, respectively). Plasma endothelin-1 was significantly correlated with several markers of liver injury. SLV338 completely prevented the rise of plasma big endothelin-1 (p < 0.05) and markedly attenuated the rise of endothelin-1 (p = 0.055). In conclusion, dual endothelin-converting enzyme / neutral endopeptidase blockade by SLV338 did not significantly attenuate D-galactosamine-induced acute liver injury, although it largely prevented the activation of the endothelin system. An evaluation of SLV338 in a less severe model of liver injury would be of interest, since very severe intoxication might not be relevantly amenable to pharmacological interventions.

The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET/) mice, endothelial nitric oxide synthase knockout (eNOS−/−) mice, and ET/eNOS−/−mice.