The genomic origins of the world's first farmers.

The precise genetic origins of the first Neolithic farming populations in Europe and Southwest Asia, as well as the processes and the timing of their differentiation, remain largely unknown. Demogenomic modeling of high-quality ancient genomes reveals that the early farmers of Anatolia and Europe emerged from a multiphase mixing of a Southwest Asian population with a strongly bottlenecked western hunter-gatherer population after the last glacial maximum. Moreover, the ancestors of the first farmers of Europe and Anatolia went through a period of extreme genetic drift during their westward range expansion, contributing highly to their genetic distinctiveness. This modeling elucidates the demographic processes at the root of the Neolithic transition and leads to a spatial interpretation of the population history of Southwest Asia and Europe during the late Pleistocene and early Holocene.

Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.

Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAFV600E/KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.

A network of transcriptional repressors modulates auxin responses.

The regulation of signalling capacity, combined with the spatiotemporal distribution of developmental signals themselves, is pivotal in setting developmental responses in both plants and animals1. The hormone auxin is a key signal for plant growth and development that acts through the AUXIN RESPONSE FACTOR (ARF) transcription factors2-4. A subset of these, the conserved class A ARFs5, are transcriptional activators of auxin-responsive target genes that are essential for regulating auxin signalling throughout the plant lifecycle2,3. Although class A ARFs have tissue-specific expression patterns, how their expression is regulated is unknown. Here we show, by investigating chromatin modifications and accessibility, that loci encoding these proteins are constitutively open for transcription. Through yeast one-hybrid screening, we identify the transcriptional regulators of the genes encoding class A ARFs from Arabidopsis thaliana and demonstrate that each gene is controlled by specific sets of transcriptional regulators. Transient transformation assays and expression analyses in mutants reveal that, in planta, the majority of these regulators repress the transcription of genes encoding class A ARFs. These observations support a scenario in which the default configuration of open chromatin enables a network of transcriptional repressors to regulate expression levels of class A ARF proteins and modulate auxin signalling output throughout development.

Inference of Locus-Specific Population Mixtures From Linked Genome-Wide Allele Frequencies.

Admixture between populations and species is common in nature. Since the influx of new genetic material might be either facilitated or hindered by selection, variation in mixture proportions along the genome is expected in organisms undergoing recombination. Various graph-based models have been developed to better understand these evolutionary dynamics of population splits and mixtures. However, current models assume a single mixture rate for the entire genome and do not explicitly account for linkage. Here, we introduce TreeSwirl, a novel method for inferring branch lengths and locus-specific mixture proportions by using genome-wide allele frequency data, assuming that the admixture graph is known or has been inferred. TreeSwirl builds upon TreeMix that uses Gaussian processes to estimate the presence of gene flow between diverged populations. However, in contrast to TreeMix, our model infers locus-specific mixture proportions employing a Hidden Markov Model that accounts for linkage. Through simulated data, we demonstrate that TreeSwirl can accurately estimate locus-specific mixture proportions and handle complex demographic scenarios. It also outperforms related D- and f-statistics in terms of accuracy and sensitivity to detect introgressed loci.

New insights into KLFs and SOXs in cancer pathogenesis, stemness, and therapy.

Despite the development of cancer therapies, the success of most treatments has been impeded by drug resistance. The crucial role of tumor cell plasticity has emerged recently in cancer progression, cancer stemness and eventually drug resistance. Cell plasticity drives tumor cells to reversibly convert their cell identity, analogous to differentiation and dedifferentiation, to adapt to drug treatment. This phenotypical switch is driven by alteration of the transcriptome. Several pluripotent factors from the KLF and SOX families are closely associated with cancer pathogenesis and have been revealed to regulate tumor cell plasticity. In this review, we particularly summarize recent studies about KLF4, KLF5 and SOX factors in cancer development and evolution, focusing on their roles in cancer initiation, invasion, tumor hierarchy and heterogeneity, and lineage plasticity. In addition, we discuss the various regulation of these transcription factors and related cutting-edge drug development approaches that could be used to drug "undruggable" transcription factors, such as PROTAC and PPI targeting, for targeted cancer therapy. Advanced knowledge could pave the way for the development of novel drugs that target transcriptional regulation and could improve the outcome of cancer therapy.

Development of a Machine Learning Modelling Tool for Predicting HIV Incidence Using Public Health Data from a County in the Southern United States.

BACKGROUND: Recent advancements in Machine Learning (ML) have significantly improved the accuracy of models predicting HIV incidence. These models typically utilize electronic medical records and patient registries. This study aims to broaden the application of these tools by utilizing de-identified public health datasets for notifiable sexually transmitted infections (STIs) from a southern U.S. County known for high HIV incidence rates. The goal is to assess the feasibility and accuracy of ML in predicting HIV incidence, which could potentially inform and enhance public health interventions. METHODS: We analyzed two de-identified public health datasets, spanning January 2010 to December 2021, focusing on notifiable STIs. Our process involved data processing and feature extraction, including sociodemographic factors, STI cases, and social vulnerability index (SVI) metrics. Various ML algorithms were trained and evaluated for predicting HIV incidence, using metrics such as accuracy, precision, recall, and F1 score. RESULTS: The study included 85,224 individuals, with 2,027 (2.37%) newly diagnosed with HIV during the study period. The ML models demonstrated high performance in predicting HIV incidence among males and females. Influential predictive features for males included age at STI diagnosis, previous STI information, provider type, and SVI. For females, they included age, ethnicity, previous STIs information, overall SVI, and race. CONCLUSIONS: The high accuracy of our ML models in predicting HIV incidence highlights the potential of using public health datasets for public health interventions such as tailored HIV testing and prevention. While these findings are promising, further research is needed to translate these models into practical public health applications.

C-terminal deletion of RelA protein is suggested as a possible cause of infective endocarditis recurrence with Enterococcus faecium.

Infective endocarditis (IE) caused by Enterococcus spp. represents the third most common cause of IE, with high rates of relapse compared with other bacteria. Interestingly, late relapses (>6 months) have only been described in Enterococcus faecalis, but here we describe the first reported IE relapse with Enterococcus faecium more than a year (17 months) after the initial endocarditis episode. Firstly, by multi locus sequence typing (MLST), we demonstrated that both isolates (EF646 and EF641) belong to the same sequence type (ST117). Considering that EF641 was able to overcome starvation and antibiotic treatment conditions surviving for a long period of time, we performed bioinformatic analysis in identifying potential genes involved in virulence and stringent response. Our results showed a 13-nucleotide duplication (positions 1638-1650) in the gene relA, resulting in a premature stop codon, with a loss of 167 amino acids from the C-terminal domains of the RelA enzyme. RelA mediates the stringent response in bacteria, modulating levels of the alarmone guanosine tetraphosphate (ppGpp). The relA mutant (EF641) was associated with lower growth capacity, the presence of small colony variants, and higher capacity to produce biofilms (compared with the strain EF646), but without differences in antimicrobial susceptibility patterns according to standard procedures during planktonic growth. Instead, EF641 demonstrated tolerance to high doses of teicoplanin when growing in a biofilm. We conclude that all these events would be closely related to the long-term survival of the E. faecium and the late relapse of the IE. These data represent the first clinical evidence of mutations in the stringent response (relA gene) related with E. faecium IE relapse.

Genomic epidemiology of third-generation cephalosporin-resistant Escherichia coli from Argentinian pig and dairy farms reveals animal-specific patterns of co-resistance and resistance mechanisms.

Control measures are being introduced globally to reduce the prevalence of antibiotic resistance (ABR) in bacteria on farms. However, little is known about the current prevalence and molecular ecology of ABR in bacterial species with the potential to be key opportunistic human pathogens, such as Escherichia coli, on South American farms. Working with 30 dairy cattle farms and 40 pig farms across two provinces in central-eastern Argentina, we report a comprehensive genomic analysis of third-generation cephalosporin-resistant (3GC-R) E. coli, which were recovered from 34.8% (cattle) and 47.8% (pigs) of samples from fecally contaminated sites. Phylogenetic analysis revealed substantial diversity suggestive of long-term horizontal and vertical transmission of 3GC-R mechanisms. CTX-M-15 and CTX-M-2 were more often produced by isolates from dairy farms, while CTX-M-8 and CMY-2 and co-carriage of amoxicillin/clavulanate resistance and florfenicol resistance were more common in isolates from pig farms. This suggests different selective pressures for antibiotic use in these two animal types. We identified the ß-lactamase gene blaROB, which has previously only been reported in the family Pasteurellaceae, in 3GC-R E. coli. blaROB was found alongside a novel florfenicol resistance gene, ydhC, also mobilized from a pig pathogen as part of a new composite transposon. As the first comprehensive genomic survey of 3GC-R E. coli in Argentina, these data set a baseline from which to measure the effects of interventions aimed at reducing on-farm ABR and provide an opportunity to investigate the zoonotic transmission of resistant bacteria in this region. IMPORTANCE: Little is known about the ecology of critically important antibiotic resistance among bacteria with the potential to be opportunistic human pathogens (e.g., Escherichia coli) on South American farms. By studying 70 pig and dairy cattle farms in central-eastern Argentina, we identified that third-generation cephalosporin resistance (3GC-R) in E. coli was mediated by mechanisms seen more often in certain species and that 3GC-R pig E. coli were more likely to be co-resistant to florfenicol and amoxicillin/clavulanate. This suggests that on-farm antibiotic usage is key to selecting the types of E. coli present on these farms. 3GC-R E. coli and 3GC-R plasmids were diverse, suggestive of long-term circulation in this region. We identified the de novo mobilization of the resistance gene blaROB from pig pathogens into E. coli on a novel mobile genetic element, which shows the importance of surveying poorly studied regions for antibiotic resistance that might impact human health.

Vagal sparing gastrectomy: A systematic review and meta-analysis.

Radical gastrectomy is associated with significant functional complications. In appropriate patients may be amenable to less invasive resection aimed at preserving the vagal trunks. The aim of this systematic review and meta-analysis is to assess the functional consequences and oncological safety of vagal sparing gastrectomy (VSG) compared to conventional non-vagal sparing gastrectomy (CG). A systematic review of four databases was undertaken for studies published between 1/11990 and 15/122021, comparing patients who underwent VSG to CG. We meta-analysed the following outcomes: operative time, blood loss, nodal yield, days to flatus, body weight changes, as well as the incidence of post-operative cholelithiasis, diarrhoea, delayed gastric emptying, and dumping syndrome. Thirty studies were included in the meta-analysis with a selection of studies qualitatively analysed. VSG was associated with a lower rate of cholelithiasis (OR 0.25, 95% CI 0.15-0.41, p<0.010) and early dumping syndrome (OR 0.42, 95% CI 0.21 - 0.86; p=0.02), less blood loss (MD -51 ml, 95% CI -89.11 to -12.81 ml, p=0.009), less long term weight loss (MD 2.03%, 95% CI 0.31-3.76%, p=0.02) and a faster time to flatus (MD -0.42 days, 95% CI -0.48 - 0.36, p<0.001). There was no significant difference in nodal harvest, overall survival, and all other endpoints. VSG significantly reduces the incidence of post-operative cholelithiasis and dumping syndrome, decreases weight loss and facilitates an earlier return of gut motility. Although technically more challenging, VSG should be considered for prophylactic surgery.

Ametropia detection using a novel, compact wavefront autorefractor.

INTRODUCTION: Despite the well-known reproducibility issues of subjective refraction, most studies evaluating autorefractors compared differences between the device and subjective refraction. This work evaluated the performance of a novel handheld Hartmann-Shack-based autorefractor using an alternative protocol, which considered the inherent variability of subjective refraction. METHODS: Participants underwent an initial measurement with a desktop autorefractor, two subjective refractions (SR1 and SR2) and a final measurement with the QuickSee Free (QSFree) portable autorefractor. Autorefractor performance was evaluated by comparing the differences between the QSFree and each of the subjective refractions with the difference between the subjective refractions (SR1 vs. SR2) using Bland-Altman analysis and percentage of agreement. RESULTS: A total of 75 subjects (53 ± 14 years) were enrolled in the study. The average difference in the absolute spherical equivalent (M) between the QSFree and the SR1 and SR2 was ±0.24 and ±0.02 D, respectively, that is, very similar or smaller than the SR1 versus SR2 difference (±0.26 D). Average differences in astigmatic components were found to be negligible. The results demonstrate that differences between QSFree and both subjective refractions in J0 and J45 were within ±0.50 D for at least 96% of the measurements. The limits of agreement (LOAs) of the differences between QSFree and SR1, as well as QSFree and SR2, were higher than those observed between SR1 and SR2 for M, J0 and J45 . CONCLUSIONS: A protocol was designed and validated for the evaluation of a refractive device to account for the variability of subjective refraction. This protocol was used to evaluate a novel portable autorefractor and observed a smaller difference between the device and subjective refractions than the difference between the two subjective refraction measurements in terms of mean bias error, although the standard deviation was higher.

An Augmented Reality Visualization System for Simulated Multirotor Aerial Vehicles.

Multirotors Aerial Vehicles are special class of Unmanned Aerial Vehicles with many practical applications. The growing demand for this class of aircraft requires tools that speed up their development. Simulated environments have gained increasing importance, as they facilitate testing and prototyping solutions, where virtual environments allow real-time interaction with simulated models, with similar behavior to real systems. More recently, the use of Augmented Reality has allowed an increasing experience of immersion and integration between the virtual world and a real scenario. This work proposes the use of Augmented Reality technology and a simulated model of a multirotor to create an interactive flight environment, aiming to improve the user experience in the analysis of simulated models. For this purpose, a smartphone was adopted as a hardware platform, a game engine is used as a basis for the development of the Augmented Reality application, that represents a numerical simulation of the flight dynamics and the control system of a multirotor, and a game controller is adopted for user interaction. The resulting system demonstrates that Augmented Reality is a viable technology that can be used to increase the possibilities of evaluating simulated systems.

Lifetime milk production of Holstein cattle in the humid tropics compared to Holstein-Gyr and Holstein-Brahman crosses.

Crossbred cattle are commonly used for milk production in the tropics, combining the potential benefits of pure breeds with the heterosis effects of the offspring. However, no comprehensive assessment of lifetime productivity for crossbred versus purebred cattle in low-altitude tropical environments has been carried out. The present study compares the lifetime productivity of purebred Holstein (HO, n = 17,269), Gyr (GY4, n = 435), and Brahman (BR4, n = 622) with crossbreds Gyr × Holstein (GY × HO, n = 5521) and Brahman×Holstein (BR × HO, n = 5429) cows from dairy farms located in low and medium altitude tropical regions in Costa Rica. The production traits of interest were age at first calving (AFC), days open (DO), milk production per lactation (TMP), lactation length (LLEN), age at culling (ACUL), and number of lactations (NLAC). Estimates of heterosis were also calculated. The AFC for GY × HO crosses (33-34 months) was not significantly different (p > .05) from HO (33.8 months). For BR × HO crosses, a significant (p < .05) decrease in AFC (BR3HO1 35.6 months, BR2HO2 34.5 months, and BR1H03 33.3 months) was observed as the fraction of HO breed increased. Estimates of heterosis for AFC were favourable for both crosses, of a magnitude close to 3%. The DO for F1 crosses (GY2HO2 94 days; BR2HO2 96 days) was significantly (p < .05) lower than HO (123 days). Estimates of heterosis for DO were also favourable and above 15% for both crosses. The TMP and LLEN were higher for HO (TMP = 5003 kg; LLEN = 324 days) compared with GY × HO (TMP = 4428 to 4773 kg; LLEN = 298 to 312 days) and BR × HO (TMP = 3950 to 4761 kg; LLEN = 273 to 313 days) crosses. Heterosis for TMP was favourable but low for both crosses, with a magnitude below 3.0%. The NLAC for HO (4.6 lactations) was significantly (p < .05) lower than F1 (GY2HO2, 5.8 lactations; BR2HO2, 5.4 lactations). Heterosis for NLAC was above 6.0% for both crosses. Overall, estimates of lifetime income over feed costs per cow on average were USD 2637 (30.3%) and USD 734 (8.4%) higher in F1 GY × HO and BR × HO, respectively, compared to HO. In conclusion, crossbred animals, specifically those with Gyr and Brahman genetics, extend the productive lifespan, increasing economic returns.

Mortality risk in infants receiving therapeutic care for malnutrition: A secondary analysis.

Small and nutritionally at-risk infants aged under 6 months (<6 months) are at high risk of death, but important evidence gaps exist on how to best identify them. We aimed to determine associations between anthropometric deficits and mortality among infants <6 months admitted to inpatient therapeutic care. A secondary analysis of 2002-2008 data included 5034 infants aged <6 months from 12 countries. We estimated the prevalence, concurrence, and severity of wasted, stunted, and underweight, as stand-alone indicators, and using the Composite Index of Anthropometric Failure (CIAF), which combines these indicators into six subgroups of single and multiple anthropometric deficits and into one combined indicator called CIAF. We used logistic regression to examine the association of different anthropometric deficits with in-programme mortality. Among 3692 infants aged <6 months with complete data, 3539 (95.8%) were underweight, 3058 (82.8%) were wasted, 2875 (77.8%) were stunted and 3575 (96.8%) had CIAF. Infants with multiple anthropometric deficits were presented with significantly lower anthropometric indices, that is, they were more severely wasted, stunted and underweight. A total of 141 infants died during inpatient therapeutic care. Among these, severely wasted (116) and severely underweight (138) infants had higher odds of mortality than normal infants (odds ratio [OR] = 2.1, 95% confidence interval [CI]: 1.2-2.7, p = 0.009, and OR = 3.3, 95% CI: 0.8-13.6, p = 0.09, respectively). Boys had higher odds of inpatient mortality than girls (OR = 1.40, 95% CI: 1.02-1.92, p = 0.03). Mortality was only observed in infants <6 months presenting multiple anthropometric deficits, although their odds of mortality were not significant, for example, OR = 2.4, 95% CI: 0.5-10.0, p = 0.21 for stunted, wasted and underweight infants <6 months. In conclusion, multiple anthropometric deficits (CIAF) is common among infants <6 months and may be reported in nutrition care programmes and surveys. Both weight-for-length/height z-score and weight-for-age z-score were found to be useful indicators for programme admission and in-programme prognosis. Future work needs to explore which better accounts for admission bias. Boys appear to be most at-risk of dying while receiving malnutrition therapeutic care. Programmes should ensure that all infants receive timely, evidence-based, effective care.

Evaluation of conditional cash transfers and mHealth audio messaging in reduction of risk factors for childhood malnutrition in internally displaced persons camps in Somalia: A 2 × 2 factorial cluster-randomised controlled trial.

BACKGROUND: Cash transfer programmes are increasingly used in humanitarian contexts to help address people's needs across multiple sectors. However, their impact on the key objectives of reducing malnutrition and excess mortality remains unclear. mHealth interventions show great promise in many areas of public health, but evidence for their impact on reducing the risk factors for malnutrition is uncertain. We therefore implemented a trial to determine the impacts of 2 interventions in a protracted humanitarian context, a cash transfer conditionality and mHealth audio messages. METHODS AND FINDINGS: A 2 × 2 factorial cluster-randomised trial was implemented in camps for internally displaced people (IDP) near Mogadishu, Somalia, starting in January 2019. The main study outcomes were assessed at midline and endline and included coverage of measles vaccination and the pentavalent immunisation series, timely vaccination, caregiver's health knowledge, and child diet diversity. Twenty-three clusters (camps) were randomised to receive or not receive conditional cash transfers (CCTs) and an mHealth intervention, and 1,430 households were followed up over 9 months. All camps received cash transfers made at emergency humanitarian level (US$70/household/month) for 3 months followed by a further 6 months at a safety net level (US$35). To be eligible to receive cash, households in camps receiving CCT were required to take their children <5 years age to attend a single health screening at a local clinic and were issued with a home-based child health record card. Participants in camps receiving the mHealth intervention were asked (but not required) to listen to a series of audio messages about health and nutrition that were broadcast to their mobile phone twice a week for 9 months. Participants and investigators were not blinded. Adherence to both interventions was monitored monthly and found to be high (>85%). We conducted intention-to-treat analysis. During the humanitarian intervention phase, the CCT improved coverage of measles vaccination (MCV1) from 39.2% to 77.5% (aOR 11.7, 95% CI [5.2, 26.1]; p < 0.001) and completion of the pentavalent series from 44.2% to 77.5% (aOR 8.9, 95% CI [2.6, 29.8]; p = < 0.001). By the end of the safety net phase, coverage remained elevated from baseline at 82.2% and 86.8%, respectively (aOR 28.2, 95% CI [13.9, 57.0]; p < 0.001 and aOR 33.8, 95% CI [11.0, 103.4]; p < 0.001). However, adherence to timely vaccination did not improve. There was no change in the incidence of mortality, acute malnutrition, diarrhoea, or measles infection over the 9 months of follow-up. Although there was no evidence that mHealth increased Mother's knowledge score (aOR 1.32, 95% CI [0.25, 7.11]; p = 0.746) household dietary diversity increased from a mean of 7.0 to 9.4 (aOR 3.75, 95% CI [2.04, 6.88]; p < 0.001). However, this was not reflected by a significant increase in child diet diversity score, which changed from 3.19 to 3.63 (aOR 2.1, 95% CI [1.0, 4.6]; p = 0.05). The intervention did not improve measles vaccination, pentavalent series completion, or timely vaccination, and there was no change in the incidence of acute malnutrition, diarrhoea, measles infection, exclusive breastfeeding, or child mortality. No significant interactions between the interventions were found. Study limitations included the limited time available to develop and test the mHealth audio messages and the necessity to conduct multiple statistical tests due to the complexity of the study design. CONCLUSIONS: A carefully designed conditionality can help achieve important public health benefits in humanitarian cash transfer programmes by substantially increasing the uptake of child vaccination services and, potentially, other life-saving interventions. While mHealth audio messages increased household diet diversity, they failed to achieve any reductions in child morbidity, malnutrition, or mortality. TRIAL REGISTRATION: ISRCTN ISRCTN24757827. Registered November 5, 2018.

Optimal Timing of Perioperative Chemical Thromboprophylaxis in Elective Major Abdominal Surgery: A Systematic Review and Meta-analysis.

OBJECTIVE: To investigate the effect of the timing of chemoprophylaxis on venous thromboembolisms (VTEs) and bleeding rates in patients undergoing major abdominal surgery. BACKGROUND: Postoperative bleeding and VTE incur significant morbidity, mortality, and health care costs. Chemoprophylaxis is used routinely to prevent VTEs but increases bleeding risk. The perioperative timing of chemoprophylaxis initiation may influence both VTE and bleeding risks. The optimal window for commencing chemoprophylaxis in the perioperative period is unclear. METHODS: MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were searched using PRISMA guidelines. Randomized trials and cohort studies published between January 1, 2000 to May 10, 2022, which reported on chemoprophylaxis timing as well as the incidence of VTE and bleeding after elective abdominal surgery were meta-analyzed. RESULTS: From 6175 studies, 14 (24,922 patients) were meta-analyzed. Bariatric (4 studies), antireflux (1 study), hepato-pancreatic-biliary (5 studies), colorectal (1 study), ventral hernia (1 study), and major intra-abdominal surgeries (2 studies) were included. Chemoprophylaxis was initiated before skin closure in 10,403 patients, and postoperatively in 14,519 patients. Both symptomatic [risk ratios (RR), 0.81; 95% CI, 0.45-1.43; P =0.460] and overall (RR, 0.74; 95% CI, 0.45-1.24; P =0.250) VTE rates were comparable between study groups. Compared with postoperative chemoprophylaxis, early usage increased the risk of all bleeding (RR, 1.56; 95% CI, 1.13-2.15; P =0.007), major bleeding (RR, 1.63; 95% CI, 1.16-2.28; P =0.005), blood transfusion (RR, 1.48; 95% CI, 1.24-1.76; P <0.001), and reintervention (RR, 1.94; 95% CI, 1.19-3.18; P =0.008). CONCLUSIONS: Our findings advocate for initiating chemoprophylaxis postoperatively in elective abdominal surgery to minimize bleeding risk without compromising VTE protection.

Advancing Multicomponent Strategies to Macrobicyclic Peptides.

Macrocyclization of peptides is typically used to fix specific bioactive conformations and improve their pharmacological properties. Recently, macrobicyclic peptides have received special attention owing to their capacity to mimic protein structures or be key components of peptide-drug conjugates. Here, we describe the development of novel synthetic strategies for two distinctive types of peptide macrobicycles. A multicomponent macrocyclo-dimerization approach is introduced for the production of interconnected ß-turns, allowing two macrocyclic rings to be formed and dimerized in one pot. Also, an on-resin double stapling strategy is described for the assembly of lactam-bridged macrobicycles with stable tertiary folds.

Tumor-Infiltrating Neutrophils after Neoadjuvant Therapy are Associated with Poor Prognosis in Esophageal Cancer.

BACKGROUND: In esophageal cancer (EC), there is a paucity of knowledge regarding the interplay between the tumor immune microenvironment and response to neoadjuvant treatment and, therefore, which factors may influence outcomes. Thus, our goal was to investigate the changes in the immune microenvironment with neoadjuvant treatment in EC by assessing the expression of immune related genes and their association with prognosis. METHODS: We examined the transcriptome of paired pre- and post-neoadjuvant treated EC specimens. Based on these findings, we validated the presence of tumor-infiltrating neutrophils using CD15+ immunohistochemistry in a discovery cohort of patients with residual pathologic disease. We developed a nomogram as a predictor of progression-free survival (PFS) incorporating the variables CD15+ cell count, tumor regression grade, and tumor grade. RESULTS: After neoadjuvant treatment, there was an increase in genes related to myeloid cell differentiation and a poor prognosis associated with high neutrophil (CD15+) counts. Our nomogram incorporating CD15+ cell count was predictive of PFS with a C-index of 0.80 (95% confidence interval [CI] 0.68-0.9) and a concordance probability estimate (CPE) of 0.77 (95% CI 0.69-0.86), which indicates high prognostic ability. The C-index and CPE of the validation cohort were 0.81 (95% CI 0.69-0.91) and 0.78 (95% CI 0.7-0.86), respectively. CONCLUSIONS: Our nomogram incorporating CD15+ cell count can potentially be used to identify patients at high risk of recurrent disease and thus stratify patients who will benefit most from adjuvant treatment.

Mpox and HIV: a Narrative Review.

PURPOSE OF REVIEW: We reviewed the available literature on mpox in People with HIV (PWH). We highlight special considerations of mpox infection related to epidemiology, clinical presentation, diagnostic and treatment considerations, prevention, and public health messaging in PWH. RECENT FINDINGS: During the 2022 mpox outbreak, PWH were disproportionally impacted worldwide. Recent reports suggest that the disease presentation, management, and prognosis of these patients, especially those with advanced HIV disease, can widely differ from those without HIV-associated immunodeficiency. Mpox can often be mild and resolve on its own in PWH with controlled viremia and higher CD4 counts. However, it can be severe, with necrotic skin lesions and protracted healing; anogenital, rectal, and other mucosal lesions; and disseminated organ systems involvement. Higher rates of healthcare utilization are seen in PWH. Supportive, symptomatic care and single or combination mpox-directed antiviral drugs are commonly used in PWH with severe mpox disease. Data from randomized clinical control trials on the efficacy of therapeutic and preventive tools against mpox among PWH are needed to better guide clinical decisions.

Barriers and Facilitators to HIV Service Access among Hispanic/Latino Gay, Bisexual, and Other Men Who Have Sex with Men in Metropolitan Atlanta-a Qualitative Analysis.

Hispanic/Latino persons are disproportionately impacted by HIV in the US, and HIV diagnoses among Hispanic/Latino men in Georgia have increased over the past decade, particularly in metropolitan Atlanta. In 2022, the Georgia Department of Public Health detected five clusters of rapid HIV transmission centered among Hispanic/Latino gay, bisexual, and other men who have sex with men (HLMSM) in metropolitan Atlanta. We conducted in-depth interviews with 65 service providers and 29 HLMSM to identify barriers and facilitators to HIV service access for HLMSM. Interviews were audio recorded, transcribed, and translated, if needed. Initial data analyses were conducted rapidly in the field to inform public health actions. We then conducted additional analyses including line-by-line coding of the interview transcripts using a thematic analytic approach. We identified four main themes. First, inequity in language access was a predominant barrier. Second, multiple social and structural barriers existed. Third, HLMSM encountered intersectional stigma. Finally, the HLMSM community is characterized by its diversity, and there is not a one-size-fits-all approach to providing appropriate care to this population. The collection of qualitative data during an HIV cluster investigation allowed us to quickly identity barriers experienced by HLMSM when accessing HIV and other medical care, to optimize public health response and action. Well-designed program evaluation and implementation research may help elucidate specific strategies and tools to reduce health disparities, ensure equitable service access for HLMSM, and reduce HIV transmission in this population.

Acute Hyperglycemia and In-Hospital Mortality in Spontaneous Intracerebral Hemorrhage.

Hyperglycemia is reported to predict worse outcome in patients with stroke, including intracerebral hemorrhage (ICH). In 83 consecutive cases of ICH at a tertiary stroke center, hyperglycemia (serum glucose >7 mmol/L) compared to normoglycemia at presentation was associated with higher rates of in-hospital mortality (51.2% vs. 26.2%, OR 2.3, CI 1.2-7.6, p = 0.02). The association with in-hospital mortality withstood adjustment for age, ICH volume, intraventricular hemorrhage, and infratentorial ICH location, but not baseline Glasgow Coma Scale. Acute hyperglycemia is associated with in-hospital mortality in spontaneous ICH patients, though this may be an indirect, rather than a causal relationship.