Erratum: Spontaneous Domain Formation in Spherically Confined Elastic Filaments [Phys. Rev. Lett. 123, 047801 (2019)].

This corrects the article DOI: 10.1103/PhysRevLett.123.047801.

Do high-protein diets have the potential to reduce gut barrier function in a sex-dependent manner?

PURPOSE: Impaired gut barrier function is associated with systemic inflammation and many chronic diseases. Undigested dietary proteins are fermented in the colon by the gut microbiota which produces nitrogenous metabolites shown to reduce barrier function in vitro. With growing evidence of sex-based differences in gut microbiotas, we determined whether there were sex by dietary protein interactions which could differentially impact barrier function via microbiota modification. METHODS: Fermentation systems were inoculated with faeces from healthy males (n = 5) and females (n = 5) and supplemented with 0.9 g of non-hydrolysed proteins sourced from whey, fish, milk, soya, egg, pea, or mycoprotein. Microbial populations were quantified using fluorescence in situ hybridisation with flow cytometry. Metabolite concentrations were analysed using gas chromatography, solid phase microextraction coupled with gas chromatography-mass spectrometry and ELISA. RESULTS: Increased protein availability resulted in increased proteolytic Bacteroides spp (p < 0.01) and Clostridium coccoides (p < 0.01), along with increased phenol (p < 0.01), p-cresol (p < 0.01), indole (p = 0.018) and ammonia (p < 0.01), varying by protein type. Counts of Clostridium cluster IX (p = 0.03) and concentration of p-cresol (p = 0.025) increased in males, while females produced more ammonia (p = 0.02), irrespective of protein type. Further, we observed significant sex-protein interactions affecting bacterial populations and metabolites (p < 0.005). CONCLUSIONS: Our findings suggest that protein fermentation by the gut microbiota in vitro is influenced by both protein source and the donor's sex. Should these results be confirmed through human studies, they could have major implications for developing dietary recommendations tailored by sex to prevent chronic illnesses.

THREE-DECADE changes of reef cover in Pulau Layang-Layang, Malaysia using multitemporal Landsat images.

Over the years, coral reefs in the South China Sea have degraded and faced severe threats from rapid development, coral bleaching, and Crown-of-Thorns Starfish (COTS) outbreak. There is limited knowledge relating to the effects of anthropogenic disturbances and natural events on the coral reefs of Pulau Layang-Layang. This study aims to assess reef cover changes by utilizing Landsat satellite images spanning from 1989 to 2022. Using the object-based image analysis method, this study classified the reef cover into three categories: coral, rock and rubble, and sand. The supervised classification had an overall accuracy of 86.41-87.38 % and Tau's coefficients of 0.80-0.81. The results showed island development and construction of artificial bird sanctuary have led to an increase in coral cover. Furthermore, it was illustrated that the impact of COTS outbreaks in 2010 and 2020 differed significantly, with the latter showing no signs of recovery. Our study underscores the importance of timely intervention to mitigate the spread of COTS. This study provides insights into the resilience and vulnerability of these ecosystems in the face of various stressors.

Achalasia-associated megaoesophagus presenting with dyspnoea and cough.

We present an unusual case of achalasia presenting with dyspnoea and persistent cough. These symptoms persisted for months, leading to the patient undergoing a chest X-ray by her general practitioner which showed right basal consolidation and a density extending along the right mediastinum. CT scan was done which revealed megaoesophagus with a diameter of 7 cm causing tracheal compression, as well as right basal consolidation, consistent with aspiration. Further history revealed 6-month history of progressive swallowing difficulty, retrosternal chest pain and shortness of breath which worsened when eating solid foods. After thorough workup, a diagnosis of idiopathic achalasia (type II) was made. She was treated with laparoscopic Heller cardiomyotomy and Dor fundoplication with significant improvement at follow-up. Dyspnoea and respiratory symptoms are unusual presenting symptoms, suggesting a need to consider achalasia in a wider range of presentations. Successful treatment of achalasia depends on timely diagnosis and intervention prior to oesophageal failure.

Biomechanical Comparison of Three Locking Compression Plate Constructs from Three Manufacturers under Cyclic Torsional Loading in a Fracture Gap Model.

OBJECTIVE: The aim of the study was to compare the stiffness and cyclic fatigue of locking compression plate constructs from three manufacturers, DePuy Synthes (DPS), Knight Benedikt (KB), and Provet Veterinary Instrumentation (Vi), under cyclic torsion. METHODS: The constructs of DPS, KB, and Vi were assembled by fixing a 10-hole 3.5-mm stainless steel locking compression plate 1 mm away from a validated bone model with a fracture gap of 47 mm. The corresponding drill guides and locking screws were used. Three groups of six constructs were tested in cyclic torsion until failure. RESULTS: There was no significant difference in initial stiffness between DPS constructs (28.83 ± 0.84 N·m/rad) and KB constructs (28.38 ± 0.81 N·m/rad), and between KB constructs and Vi constructs (27.48 ± 0.37 N·m/rad), but the DPS constructs were significantly stiffer than the Vi constructs. The DPS constructs sustained the significantly highest number of cycles (24,833 ± 2,317 cycles) compared with KB constructs (16,167 ± 1,472 cycles) and Vi constructs (19,833 ± 4,792 cycles), but the difference between KB and Vi constructs was not significant. All constructs failed by screw damage at the shaft between the plate and the bone model. CONCLUSION: DPS constructs showed superior initial torsional stiffness and cyclic fatigue life than Vi constructs, whereas KB and Vi constructs shared comparable results. Further investigation is required to assess the clinical significance of these biomechanical differences.

Metatarsal Fractures.

Metatarsal fractures are some of the most common fractures reported in the human body. Recent advances in surgical techniques and fixation have helped facilitate healing and improved outcomes for our patients. The treatment goals of metatarsal fractures are to maintain the metatarsal parabola, sagittal position of the metatarsal heads, and a congruent metatarsophalangeal joint. Most of these injuries can be treated nonoperatively, but displaced fractures require surgical intervention to preserve normal gait biomechanics.

Childhood vaccination trends during 2019 to 2022 in Tanzania and the impact of the COVID-19 pandemic.

The COVID-19 pandemic has significantly disrupted healthcare systems at all levels globally, notably affecting routine healthcare services, such as childhood vaccination. This study examined the impact of these disruptions on routine childhood vaccination programmes in Tanzania. We conducted a longitudinal study over four years in five Tanzanian regions: Mwanza, Dar es Salaam, Mtwara, Arusha, and Dodoma. This study analyzed the trends in the use of six essential vaccines: Bacille Calmette-Guérin (BCG), bivalent Oral Polio Vaccine (bOPV), Diphtheria Tetanus Pertussis, Hepatitis-B and Hib (DTP-HepB-Hib), measles-rubella (MR), Pneumococcal Conjugate Vaccine (PCV), and Rota vaccines. We evaluated annual and monthly vaccination trends using time-series and regression analyses. Predictive modeling was performed using an autoregressive integrated moving average (ARIMA) model. A total of 32,602,734 vaccination events were recorded across the regions from 2019 to 2022. Despite declining vaccination rates in 2020, there was a notable rebound in 2021, indicating the resilience of Tanzania's immunization program. The analysis also highlighted regional differences in vaccination rates when standardized per 1000 people. Seasonal fluctuations were observed in monthly vaccination rates, with BCG showing the most stable trend. Predictive modeling of BCG indicated stable and increasing vaccination coverage by 2023. These findings underscore the robustness of Tanzania's childhood immunization infrastructure in overcoming the challenges posed by the COVID-19 pandemic, as indicated by the strong recovery of vaccination rates post-2020. We provide valuable insights into the dynamics of vaccination during a global health crisis and highlight the importance of sustained immunization efforts to maintain public health.

Capturing the blue-light activated state of the Phot-LOV1 domain from Chlamydomonas reinhardtii using time-resolved serial synchrotron crystallography.

Light-oxygen-voltage (LOV) domains are small photosensory flavoprotein modules that allow the conversion of external stimuli (sunlight) into intracellular signals responsible for various cell behaviors (e.g. phototropism and chloroplast relocation). This ability relies on the light-induced formation of a covalent thioether adduct between a flavin chromophore and a reactive cysteine from the protein environment, which triggers a cascade of structural changes that result in the activation of a serine/threonine (Ser/Thr) kinase. Recent developments in time-resolved crystallography may allow the activation cascade of the LOV domain to be observed in real time, which has been elusive. In this study, we report a robust protocol for the production and stable delivery of microcrystals of the LOV domain of phototropin Phot-1 from Chlamydomonas reinhardtii (CrPhotLOV1) with a high-viscosity injector for time-resolved serial synchrotron crystallography (TR-SSX). The detailed process covers all aspects, from sample optimization to data collection, which may serve as a guide for soluble protein preparation for TR-SSX. In addition, we show that the crystals obtained preserve the photoreactivity using infrared spectroscopy. Furthermore, the results of the TR-SSX experiment provide high-resolution insights into structural alterations of CrPhotLOV1 from Δt = 2.5 ms up to Δt = 95 ms post-photoactivation, including resolving the geometry of the thioether adduct and the C-terminal region implicated in the signal transduction process.

Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia.

In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors have demonstrated limited efficacy or have shown adverse effects in clinical trials, highlighting that identification of clinically safe oxidative pathway inhibitors is warranted. We performed a high-throughput drug repurposing screen designed to identify mitochondrial metabolism inhibitors in myeloid leukemia cells. This identified lomerizine, a US Food and Drug Administration (FDA)-approved voltage-gated Ca2+ channel blocker now used for the treatment of migraines, as one of the top hits. Transcriptome analysis revealed increased expression of voltage-gated CACNA1D and receptor-activated TRPC6 Ca2+ channels in CML LSCs (CD34+CD38-) compared with normal counterparts. This correlated with increased endoplasmic reticulum (ER) mass and increased ER and mitochondrial Ca2+ content in CML stem/progenitor cells. We demonstrate that lomerizine-mediated inhibition of Ca2+ uptake leads to ER and mitochondrial Ca2+ depletion, with similar effects seen after CACNA1D and TRPC6 knockdown. Through stable isotope-assisted metabolomics and functional assays, we observe that lomerizine treatment inhibits mitochondrial isocitrate dehydrogenase activity and mitochondrial oxidative metabolism and selectively sensitizes CML LSCs to imatinib treatment. In addition, combination treatment with imatinib and lomerizine reduced CML tumor burden, targeted CML LSCs, and extended survival in xenotransplantation model of human CML, suggesting this as a potential therapeutic strategy to prevent disease relapse in patients.

Gene drive and genetic sex conversion in the global agricultural pest Ceratitis capitata.

Homing-based gene drives are recently proposed interventions promising the area-wide, species-specific genetic control of harmful insect populations. Here we characterise a first set of gene drives in a tephritid agricultural pest species, the Mediterranean fruit fly Ceratitis capitata (medfly). Our results show that the medfly is highly amenable to homing-based gene drive strategies. By targeting the medfly transformer gene, we also demonstrate how CRISPR-Cas9 gene drive can be coupled to sex conversion, whereby genetic females are transformed into fertile and harmless XX males. Given this unique malleability of sex determination, we modelled gene drive interventions that couple sex conversion and female sterility and found that such approaches could be effective and tolerant of resistant allele selection in the target population. Our results open the door for developing gene drive strains for the population suppression of the medfly and related tephritid pests by co-targeting female reproduction and shifting the reproductive sex ratio towards males. They demonstrate the untapped potential for gene drives to tackle agricultural pests in an environmentally friendly and economical way.

Implementation of the European Society of Cardiology 0/3-hour accelerated diagnostic protocol, using high sensitive troponin T: a clinical practice evaluation of safety and effectiveness involving 3003 patients with suspected acute coronary syndrome.

BACKGROUND: There have been relatively few studies detailing the real-world effectiveness and safety of accelerated diagnostic protocols (ADP), using high sensitivity cardiac troponin (hs-cTn). OBJECTIVE: To analyse the safety and effectiveness of early emergency department (ED) discharge following implementation of the European Society of Cardiology (ESC) 0/3-hour ADP for suspected acute coronary syndromes (ACS). METHOD: We prospectively studied 2 cohorts of consecutive suspected ACS presentations to ED before (n=1642) and after (n=1376, 2 centres) implementation of the ESC 0/3-hour ADP incorporating limit of detection rule out. Safety was defined by MACE (major adverse cardiac events) inclusive of type 1 myocardial infarction (MI) in patients discharged from ED, and clinical effectiveness by percentage ED discharge. Continuous variables and categorical data were evaluated by independent t-test and χ2 test, respectively. Time-to-event data were analysed as survival data and converted to Kaplan-Meier curves for interpretation. RESULTS: In the preimplementation period, there was a higher prevalence of MI. Discharge from ED increased by >100% (from 27.1% to 56.5% of the cohort) with no safety signal (MACE rate 4/444 (0.9%) vs 4/769 (0.52%), p=0.430 for the 2011 and 2018 cohort, respectively). This correlated with a marked reduction in length of stay overall but a more modest reduction for those discharged from ED (6 hours 10 min vs 5 hours 25 min, p<0.001) for the 2011 and 2018 cohort, respectively. There were improvements in presentation to blood draw (163-90 min, p<0.001). Time from presentation to first ECG actually increased (16.2 vs 31.2 min, p<0.001). Analysis of hs-cTn values and ECGs revealed a maximum ED discharge rate of 69%, by applying the 0/3-hour protocol, implying potential for increasing safe ED discharge. CONCLUSIONS: Implementation of an ADP with hs-cTn is safe and effective for early rule-out and discharge of suspected ACS but require considerable resources and education to optimise maximal patient flow.

An ecological study of the factors associated with childhood tuberculosis in Nigeria

Background: Childhood tuberculosis (TB) account for about 6% of the global TB burden, but there is a paucity of data on childhood TB at the national and state level in many countries in Sub-Saharan Africa.Objective: To assess the childhood TB case notification rates and explore associated factors at the state level in Nigeria.Methods: A retrospective ecological study was carried out to determine the childhood TB case notification rates in the 36 states and the Federal Capital Territory (FCT) in Nigeria. TB data was retrieved from the National TB and Leprosy Control Programme (NTBLCP) 2014 Annual Report using a proforma. The association between TB case notification rate at the state level and the six selected explanatory variables (Human Development Index, Bacillus Calmette-Guerin [BCG] coverage, percentage underweight, HIV positivity rate, mean household size and population density) were carried out using negative binomial regression in R statistical software.Results: A total of 91, 353 TB patients were notified to the World Health Organization (WHO) in 2014 by the NTBLCP. Of these, 5463 (6%) were children aged 0-14 years. The childhood TB notification rate was 6.99/100,000 population. The highest childhood TB case notification rate was recorded in Nasarawa State followed by Lagos and Oyo States. There were significant associations between childhood TB case notification rate and HIV positivity rate, percentage underweight, household size, population density and BCG coverage.Conclusion: The study showed that childhood TB case notification rate in Nigeria was low. TB case notification rate was associated with high HIV rate, percentage underweight, household size, population density and BCG coverage. There is the urgent need to address the associated risk factors to effectively control childhood TB in Nigeria