Trends and Distribution of IPAAs in the United States: Becoming Harder to Find in Colon and Rectal Surgery Residency Training?

BACKGROUND: There has been concern among colon and rectal surgery residency programs in the United States that IPAA procedures have been decreasing, but evidence is limited. OBJECTIVE: The study aimed to evaluate the number of IPAAs performed by colon and rectal surgery residents in the United States and analyze the distribution of these cases on a national level. DESIGN: Retrospective. SETTINGS: The Accreditation Council for Graduate Medical Education Case Log National Data Reports were used to evaluate the number of IPAAs performed by residents from 2005 to 2021. The Nationwide Inpatient Sample database was used to identify all patients undergoing these procedures from 2005 to 2019. PATIENTS: All IPAA procedures regardless of indication. MAIN OUTCOME MEASURES: The primary outcome was the number of IPAAs performed by residents yearly. The secondary outcome was the national distribution of these procedures. RESULTS: Among colon and rectal surgery residents, case log data revealed an increase in mean and total number of IPAAs from 2005 to 2013, followed by a decline in both metrics after 2013. Despite the decrease, the mean number of cases per resident remained fewer than 6 between 2011 and 2021. A weighted national estimate of 48,532 IPAA patients were identified in the Nationwide Inpatient Sample database. A significant decrease was noted in the number of IPAAs after 2015 that persisted through 2019. There was a significant decrease in rural and urban nonteaching hospitals (from 2.1% to 1.6% and 25.6% to 4.3%, respectively; p < 0.001) and an increase in urbanteaching hospitals (from 72.4% to 94.1%; p < 0.001). LIMITATIONS: Nonrandomized retrospective study design. CONCLUSIONS: Despite the recent increase in the percentage of IPAAs performed at urban academic centers, there has been a decrease in cases performed by colon and rectal surgery residents. This can have significant implications for residents who graduate without adequate experience in performing this complex procedure independently, as well as training programs that may face challenges with maintaining accreditation. See Video Abstract. TENDENCIAS Y DISTRIBUCIN DE LA ANASTOMOSIS ANAL CON BOLSA ILEAL EN LOS ESTADOS UNIDOS SE EST VOLVIENDO MS DIFCIL DE ENCONTRAR EN LA CAPACITACIN DE RESIDENCIA EN CIRUGA DE COLON Y RECTO: ANTECEDENTES:Ha habido preocupación entre los programas de capacitación de residencia en cirugía de colon y recto en los Estados Unidos porque los procedimientos de anastomosis anal con bolsa ileal han estado disminuyendo; sin embargo, la evidencia es limitada.OBJETIVO:Evaluar el número de anastomosis anales con bolsa ileal realizadas por residentes de cirugía de colon y recto en los Estados Unidos y examinar la distribución de estos casos a nivel nacional.DISEÑO:Retrospectivo.AJUSTES:Se utilizaron los informes de datos nacionales del registro de casos de educación médica de posgrado del Consejo de Acreditación para examinar el número de anastomosis anales con bolsa ileal realizadas por residentes de 2005 a 2021. Se utilizó la base de datos de muestra nacional de pacientes hospitalizados para identificar a todos los pacientes sometidos a estos procedimientos de 2005 a 2019.PACIENTES:Todos los procedimientos de anastomosis anal con bolsa ileal independientemente de la indicación.MEDIDA DE RESULTADO PRINCIPAL:El resultado primario es el número de anastomosis anales con bolsa ileal realizadas por los residentes anualmente. El resultado secundario es la distribución nacional de estos procedimientos.RESULTADOS:Entre los residentes de cirugía de colon y recto, los datos de los registros de casos revelaron un aumento en el número medio y total de anastomosis anal con bolsa ileal de 2005 a 2013, seguido de una disminución en ambas métricas después de 2013. A pesar de la disminución, el número medio de casos por El residente permaneció >6 entre 2011 y 2021. Se identificó una estimación nacional ponderada de 48 532 pacientes con anastomosis anal con bolsa ileal en la base de datos de la Muestra Nacional de Pacientes Hospitalizados. Se observó una disminución significativa en el número de anastomosis anales con bolsa ileal después de 2015 que persistió hasta 2019. Hubo una disminución significativa en los hospitales no docentes rurales y urbanos (del 2,1% al 1,6% y del 25,6% al 4,3% respectivamente, p < 0,001) y un aumento en los hospitales universitarios urbanos (del 72,4% al 94,1%, p < 0,001).LIMITACIONES:Estudio retrospectivo no aleatorizado.CONCLUSIÓN:A pesar del reciente aumento en el porcentaje de anastomosis anal con bolsa ileal realizadas en centros académicos urbanos, ha habido una disminución en los casos realizados por residentes de cirugía de colon y recto. Esto puede tener implicaciones significativas para los residentes que se gradúan sin la experiencia adecuada en la realización de este complejo procedimiento de forma independiente, así como para los programas de capacitación que pueden enfrentar desafíos para mantener la acreditación. (Traduccion-AI-generated).

Global Change in a Material World.

The biological structures that fill the environment around us are derived from materials produced by organisms. These biological materials are key to the mechanical function of organisms. The pathways and growth processes that produce biological materials can influence the mechanical properties of the materials, which can in turn shape the higher-level function of the system into which the materials are incorporated. Characterizing a biological system requires thorough knowledge of the underlying materials, including their mechanical function, diversity, evolution, and sensitivity to the environment. Anthropogenic activity is driving rapid and widespread changes to the natural environment and global climate, which are influencing organismal growth and physiology in myriad ways. Here, we briefly introduce a collection of articles that focus on the intersection of anthropogenic activity and the mechanical function of biological materials, as part of the "Global Change in a Material World" bundle for Integrative and Comparative Biology. In addition, we provide an analysis of the current scientific literature in this field, highlighting an urgent need to better understand how changes to our world, driven by human activity, are influencing the fundamental architecture and mechanical performance of organisms across the globe.

EGFR V834L and L858R Comutation Is Associated With Response to Osimertinib in Non-Small-Cell Lung Cancer.

Up-front osimertinib leads to clinical benefit in EGFR V834L and L858R comutated NSCLC.

Low Anterior Resection Syndrome following Restorative Proctectomy for Rectal Cancer: Can the Surgeon Have Any Meaningful Impact?

Postoperative bowel dysfunction following restorative proctectomy, commonly referred to as Low Anterior Resection Syndrome (LARS), is a common long term sequela of rectal cancer treatment. While many of the established risk factors for LARS are non-modifiable, others may be well within the surgeon's control. Several pre-, intra-, and postoperative decisions may have a significant impact on postoperative bowel function. Some of these factors include the extent of surgical resection, surgical approach, choice of anastomotic reconstruction, and use of fecal diversion. This review article summarizes the available evidence regarding how surgical decision-making can affect postoperative bowel function.

Ready, Set, Grow: From Micelles to Giant Vesicles via Biocatalytic Activation.

Controlling physicochemical processes that drive changes in supramolecular aggregates is an important objective toward creating artificial soft micro- and nanomachines. Previous research explored the morphology control of membrane-based materials subjected to externally imposed chemical stimuli. Here, we modulate the microscale morphology of pH-responsive assemblies by using biocatalysis to internally generate changes in global pH. Catalytic reactions offer flexibility in the mechanism and rate at which stimuli are introduced to responsive assemblies, ultimately enabling precision and control over size and morphology. We observed, by dynamic light scattering and fluorescence microscopy, substantial microscale differences between assemblies subjected to manually titrated pH changes compared to biocatalytically activated pH changes, including the growth of giant vesicles from micelles. Coarse-grained molecular dynamics simulations of these metastable self-assembled structures provided insight into the thermodynamics and kinetics of the preferred structures. These results demonstrate the feasibility of using biocatalytic reactions to modulate the size and morphology of supramolecular assemblies, from micelles to giant vesicles.

Beliefs about mental health treatment, treatment initiation, and suicidal behaviors among veterans and service members at-risk for suicide and not in treatment.

INTRODUCTION: Previous research has identified a variety of barriers to mental health care among military personnel and veterans, despite high rates of mental health symptoms. The current study is the first to examine beliefs about mental health treatment barriers among post-9/11 military personnel and veterans at elevated suicide risk not involved in treatment and whether these beliefs are associated with treatment initiation, engagement, or suicidal behaviors. METHODS: Four hundred and twenty-two participants reported on beliefs about treatment during a cognitive behavioral treatment session and responded to follow-up questionnaires on mental health treatment initiation, engagement, and suicidal behaviors over 12 months. Beliefs identified in the therapy session were coded thematically, and rates of treatment initiation, engagement, and suicidal behavior were examined by belief category. RESULTS: Nine belief themes emerged. Participants reporting logistical barriers and preferences about treatment type were least likely to initiate mental health treatment and participated in the fewest number of sessions, respectively. Participants endorsing beliefs about stigma or using other ways to cope were most likely to engage in suicidal behavior. CONCLUSIONS: The current findings point to specific beliefs that may identify individuals who would benefit from systemic and individual interventions for mental health treatment engagement.

Genetic diversity, determinants, and dissemination of Burkholderia pseudomallei lineages implicated in melioidosis in Northeast Thailand.

Melioidosis is an often-fatal neglected tropical disease caused by an environmental bacterium Burkholderia pseudomallei. However, our understanding of the disease-causing bacterial lineages, their dissemination, and adaptive mechanisms remains limited. To address this, we conduct a comprehensive genomic analysis of 1,391 B. pseudomallei isolates collected from nine hospitals in northeast Thailand between 2015 and 2018, and contemporaneous isolates from neighbouring countries, representing the most densely sampled collection to date. Our study identifies three dominant lineages, each with unique gene sets potentially enhancing bacterial fitness in the environment. We find that recombination drives lineage-specific gene flow. Transcriptome analyses of representative clinical isolates from each dominant lineage reveal increased expression of lineage-specific genes under environmental conditions in two out of three lineages. This underscores the potential importance of environmental persistence for these dominant lineages. The study also highlights the influence of environmental factors such as terrain slope, altitude, and river direction on the geographical dispersal of B. pseudomallei. Collectively, our findings suggest that environmental persistence may play a role in facilitating the spread of B. pseudomallei, and as a prerequisite for exposure and infection, thereby providing useful insights for informing melioidosis prevention and control strategies.

Advancing LGBTQ+ inclusion in STEM education and AI research.

The authors emphasize diversity, equity, and inclusion in STEM education and artificial intelligence (AI) research, focusing on LGBTQ+ representation. They discuss the challenges faced by queer scientists, educational resources, the implementation of National AI Campus, and the notion of intersectionality. The authors hope to ensure supportive and respectful engagement across all communities.

Comparison of the dosimetry of scandium-43 and scandium-44 patient organ doses in relation to commonly used gallium-68 for imaging neuroendocrine tumours.

BACKGROUND: Several research groups have explored the potential of scandium radionuclides for theragnostic applications due to their longer half-lives and equal or similar coordination chemistry between their diagnostic and therapeutic counterparts, as well as lutetium-177 and terbium-161, respectively. Unlike the gallium-68/lutetium-177 pair, which may show different in-vivo uptake patterns, the use of scandium radioisotopes promises consistent behaviour between diagnostic and therapeutic radiopeptides. An advantage of scandium's longer half-life over gallium-68 is the ability to study radiopeptide uptake over extended periods and its suitability for centralized production and distribution. However, concerns arise from scandium-44's decay characteristics and scandium-43's high production costs. This study aimed to evaluate the dosimetric implications of using scandium radioisotopes with somatostatin analogues against gallium-68 for PET imaging of neuroendocrine tumours. METHODS: Absorbed dose per injected activity (AD/IA) from the generated time-integrated activity curve (TIAC) were estimated using the radiopeptides [43/44/44mSc]Sc- and [68Ga]Ga-DOTATATE. The kidneys, liver, spleen, and red bone marrow (RBM) were selected for dose estimation studies. The EGSnrc and MCNP6.1 Monte Carlo (MC) codes were used with female (AF) and male (AM) ICRP phantoms. The results were compared to Olinda/EXM software, and the effective dose concentrations assessed, varying composition between the scandium radioisotopes. RESULTS: Our findings showed good agreement between the MC codes, with - 3 ± 8% mean difference. Kidneys, liver, and spleen showed differences between the MC codes (min and max) in a range of - 4% to 8%. This was observed for both phantoms for all radiopeptides used in the study. Compared to Olinda/EXM the largest observed difference was for the RBM, of 21% for the AF and 16% for the AM for scandium- and gallium-based radiopeptides. Despite the differences, our findings showed a higher absorbed dose on [43/44Sc]Sc-DOTATATE compared to its 68Ga-based counterpart. CONCLUSION: This study found that [43/44Sc]Sc-DOTATATE delivers a higher absorbed dose to organs at risk compared to [68Ga]Ga-DOTATATE, assuming equal distribution. This is due to the longer half-life of scandium radioisotopes compared to gallium-68. However, calculated doses are within acceptable ranges, making scandium radioisotopes a feasible replacement for gallium-68 in PET imaging, potentially offering enhanced diagnostic potential with later timepoint imaging.

Comorbidity of depression and posttraumatic stress disorder: Outcomes from a randomized controlled trial of surf and hike therapies among service members.

OBJECTIVE: Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are commonly comorbid mental health disorders. Exercise performed in the natural environment has shown promise in relieving symptoms of each disorder separately; however, the effectiveness has seldom been studied in comorbid populations. METHOD: Data were derived from a randomized controlled trial of surf and hike therapy for active duty service members with MDD (N = 95). In this study, participants were grouped by comorbidity status (MDD, n = 37; MDD-PTSD, n = 58). Clinician-administered and self-reported measures were completed at preprogram, postprogram, and 3-month follow-up; a brief depression/anxiety measure was completed before and after each session. RESULTS: Multilevel modeling results showed clinically significant decreases in depression severity across participants from pre- to postprogram (p < .001) and within exercise sessions (p < .001), with no further change through follow-up. No significant differences emerged in depression severity change over time by comorbidity status, intervention condition, or their three-way interaction. Those with PTSD showed reductions in posttraumatic stress symptoms from pre- to postprogram (p < .001), which did not differ by intervention condition; gains were maintained at follow-up. Remission rates from MDD and PTSD diagnoses (if applicable) were significant from pre- to postprogram for both MDD-only and MDD-PTSD groups (p < .001). These improvements were maintained at 3 months. CONCLUSIONS: Both surf and hike therapies can improve MDD and PTSD symptoms, regardless of comorbidity status, suggesting utility of these interventions among service members with one or both disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Patient-specific quality assurance of dynamically-collimated proton therapy treatment plans.

BACKGROUND: The dynamic collimation system (DCS) provides energy layer-specific collimation for pencil beam scanning (PBS) proton therapy using two pairs of orthogonal nickel trimmer blades. While excellent measurement-to-calculation agreement has been demonstrated for simple cube-shaped DCS-trimmed dose distributions, no comparison of measurement and dose calculation has been made for patient-specific treatment plans. PURPOSE: To validate a patient-specific quality assurance (PSQA) process for DCS-trimmed PBS treatment plans and evaluate the agreement between measured and calculated dose distributions. METHODS: Three intracranial patient cases were considered. Standard uncollimated PBS and DCS-collimated treatment plans were generated for each patient using the Astroid treatment planning system (TPS). Plans were recalculated in a water phantom and delivered at the Miami Cancer Institute (MCI) using an Ion Beam Applications (IBA) dedicated nozzle system and prototype DCS. Planar dose measurements were acquired at two depths within low-gradient regions of the target volume using an IBA MatriXX ion chamber array. RESULTS: Measured and calculated dose distributions were compared using 2D gamma analysis with 3%/3 mm criteria and low dose threshold of 10% of the maximum dose. Median gamma pass rates across all plans and measurement depths were 99.0% (PBS) and 98.3% (DCS), with a minimum gamma pass rate of 88.5% (PBS) and 91.2% (DCS). CONCLUSIONS: The PSQA process has been validated and experimentally verified for DCS-collimated PBS. Dosimetric agreement between the measured and calculated doses was demonstrated to be similar for DCS-collimated PBS to that achievable with noncollimated PBS.

The type II secretion system as an underappreciated and understudied mediator of interbacterial antagonism.

Interbacterial antagonism involves all major phyla, occurs across the full range of ecological niches, and has great significance for the environment, clinical arena, and agricultural and industrial sectors. Though the earliest insight into interbacterial antagonism traces back to the discovery of antibiotics, a paradigm shift happened when it was learned that protein secretion systems (e.g., types VI and IV secretion systems) deliver toxic "effectors" against competitors. However, a link between interbacterial antagonism and the Gram-negative type II secretion system (T2SS), which exists in many pathogens and environmental species, is not evident in prior reviews on bacterial competition or T2SS function. A current examination of the literature revealed four examples of a T2SS or one of its known substrates having a bactericidal activity against a Gram-positive target or another Gram-negative. When further studied, the T2SS effectors proved to be peptidases that target the peptidoglycan of the competitor. There are also reports of various bacteriolytic enzymes occurring in the culture supernatants of some other Gram-negative species, and a link between these bactericidal activities and T2SS is suggested. Thus, a T2SS can be a mediator of interbacterial antagonism, and it is possible that many T2SSs have antibacterial outputs. Yet, at present, the T2SS remains relatively understudied for its role in interbacterial competition. Arguably, there is a need to analyze the T2SSs of a broader range of species for their role in interbacterial antagonism. Such investigation offers, among other things, a possible pathway toward developing new antimicrobials for treating disease.

Perspectives of people with spinal cord injury on a pain education resource.

Introduction: Spinal cord injury (SCI) often leads to neuropathic pain that negatively affects quality of life. Several qualitative research studies in individuals with SCI who experience neuropathic pain indicate the lack of adequate information about pain. We previously developed an educational resource, the SeePain, based on scientific literature and a series of qualitative interviews of people with SCI, their significant others/family members, and SCI healthcare providers. Methods: However, to quantitatively evaluate the utility of this educational resource in a larger sample, we examined the agreement and usefulness ratings of statements regarding clarity/comprehensibility, content, and format of the SeePain, derived from the thematic analysis of our previous qualitative interviews. Participants completed a survey that provided a digital version of the SeePain and then rated their agreement/usefulness with the statements using numerical rating scales. Results: There were overall high perceived agreement and usefulness ratings regarding the SeePain's clarity, content, and format. A factor analysis reduced the agreement and usefulness ratings into 4 components (content, clarity, format, and delivery medium). Group comparisons showed that individuals with higher education were more likely to endorse electronic and website formats, and the usefulness of a shorter version of the SeePain; females and younger individuals showed greater endorsement for clarity. Finally, higher pain intensity ratings were associated with greater agreement and usefulness of the content of the SeePain. Discussion: Overall, these results support the utility of the SeePain as a source of information regarding pain that may facilitate communication about pain and its management following SCI.

A randomised trial of malaria vaccine R21/Matrix-M™ with and without antimalarial drugs in Thai adults.

In preparation for mass vaccinations with R21/Matrix-M™ combined with mass administrations of dihydroartemisinin, piperaquine, and a single low dose primaquine we assessed the tolerability, safety, and potential interactions of this combination affecting immunogenicity or pharmacokinetics. 120 healthy Thai volunteers were randomised to receive either antimalarials combined with vaccinations (n = 50), vaccinations alone (n = 50), or antimalarials only (n = 20). Three rounds of vaccines and antimalarials were administered one month apart. The vaccine was well tolerated alone and in combination with the antimalarials. None of the participants failed completion of the 3-dose vaccine course. There was no significant difference in the vaccine immunogenicity or in the pharmacokinetics of piperaquine given individually or in combination. This study supports proceeding to a large trial of mass vaccinations with R21/Matrix-M™ combined with mass antimalarial administration in Bangladesh.

Stratification to Neoadjuvant Radiotherapy in Rectal Cancer by Regimen and Transcriptional Signatures.

Response to neoadjuvant radiotherapy (RT) in rectal cancer has been associated with immune and stromal features that are captured by transcriptional signatures. However, how such associations perform across different chemoradiotherapy regimens and within individual consensus molecular subtypes (CMS) and how they affect survival remain unclear. In this study, gene expression and clinical data of pretreatment biopsies from nine cohorts of primary rectal tumors were combined (N = 826). Exploratory analyses were done with transcriptomic signatures for the endpoint of pathologic complete response (pCR), considering treatment regimen or CMS subtype. Relevant findings were tested for overall survival and recurrence-free survival. Immune and stromal signatures were strongly associated with pCR and lack of pCR, respectively, in RT and capecitabine (Cap)/5-fluorouracil (5FU)-treated patients (N = 387), in which the radiosensitivity signature (RSS) showed the strongest association. Upon addition of oxaliplatin (Ox; N = 123), stromal signatures switched direction and showed higher chances to achieve pCR than without Ox (p for interaction 0.02). Among Cap/5FU patients, most signatures performed similarly across CMS subtypes, except cytotoxic lymphocytes that were associated with pCR in CMS1 and CMS4 cases compared with other CMS subtypes (p for interaction 0.04). The only variables associated with survival were pCR and RSS. Although the frequency of pCR across different chemoradiation regimens is relatively similar, our data suggest that response rates may differ depending on the biological landscape of rectal cancer. Response to neoadjuvant RT in stroma-rich tumors may potentially be improved by the addition of Ox. RSS in preoperative biopsies provides predictive information for response specifically to neoadjuvant RT with 5FU. SIGNIFICANCE: Rectal cancers with stromal features may respond better to RT and 5FU/Cap with the addition of Ox. Within patients not treated with Ox, high levels of cytotoxic lymphocytes associate with response only in immune and stromal tumors. Our analyses provide biological insights about the outcome by different radiotherapy regimens in rectal cancer.

Chelator-Assisted Precipitation-Based Separation of the Rare Earth Elements Neodymium and Dysprosium from Aqueous Solutions.

The rare earth elements (REEs) are critical resources for many clean energy technologies, but are difficult to obtain in their elementally pure forms because of their nearly identical chemical properties. Here, an analogue of macropa, G-macropa, was synthesized and employed for an aqueous precipitation-based separation of Nd3+ and Dy3+. G-macropa maintains the same thermodynamic preference for the large REEs as macropa, but shows smaller thermodynamic stability constants. Molecular dynamics studies demonstrate that the binding affinity differences of these chelators for Nd3+ and Dy3+ is a consequence of the presence or absence of an inner-sphere water molecule, which alters the donor strength of the macrocyclic ethers. Leveraging the small REE affinity of G-macropa, we demonstrate that within aqueous solutions of Nd3+, Dy3+, and G-macropa, the addition of HCO3- selectively precipitates Dy2(CO3)3, leaving the Nd3+-G-macropa complex in solution. With this method, remarkably high separation factors of 841 and 741 are achieved for 50:50 and 75:25 mixtures. Further studies involving Nd3+:Dy3+ ratios of 95:5 in authentic magnet waste also afford an efficient separation as well. Lastly, G-macropa is recovered via crystallization with HCl and used for subsequent extractions, demonstrating its good recyclability.

Epigenetic changes regulating the epithelial-mesenchymal transition in human trophoblast differentiation.

The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both first trimester differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to two major placental pathologies, preeclampsia and placenta accreta spectrum, so characterization of the corresponding normal processes is crucial. In this report, our gene expression analysis, using purified human CTB and EVT cells, highlights an epithelial- mesenchymal transition (EMT) mechanism underlying CTB-EVT differentiation and provides a trophoblast-specific EMT signature. In parallel, DNA methylation profiling shows that CTB cells, already hypomethylated relative to non-trophoblast cell lineages, show further genome- wide hypomethylation in the transition to EVT. However, a small subgroup of genes undergoes gains of methylation (GOM) in their regulatory regions or gene bodies, associated with differential mRNA expression (DE). Prominent in this GOM-DE group are genes involved in the EMT, including multiple canonical EMT markers and the EMT-linked transcription factor RUNX1 , for which we demonstrate a functional role in modulating the migratory and invasive capacities of JEG3 trophoblast cells. This analysis of DE associated with locus-specific GOM, together with functional studies of an important GOM-DE gene, highlights epigenetically regulated genes and pathways acting in human EVT differentiation and invasion, with implications for obstetric disorders in which these processes are dysregulated.

Artemisinin-resistant malaria in Africa demands urgent action.

Investment in community health workers is essential.

Southeast Asia initiative to combat SARS-CoV-2 variants (SEACOVARIANTS) consortium.

A strong and effective COVID-19 and future pandemic responses rely on global efforts to carry out surveillance of infections and emerging SARS-CoV-2 variants and to act accordingly in real time. Many countries in Southeast Asia lack capacity to determine the potential threat of new variants, or other emerging infections. Funded by Wellcome, the Southeast Asia initiative to combat SARS-CoV-2 variants (SEACOVARIANTS) consortium aims to develop and apply a multidisciplinary research platform in Southeast Asia (SEA) for rapid assessment of the biological significance of SARS-CoV-2 variants, thereby informing coordinated local, regional and global responses to the COVID-19 pandemic. Our proposal is delivered by the Vietnam and Thailand Wellcome Africa Asia Programmes, bringing together a multidisciplinary team in Indonesia, Thailand and Vietnam with partners in Singapore, the UK and the USA. Herein we outline five work packages to deliver strengthened regional scientific capacity that can be rapidly deployed for future outbreak responses.

Our project strengthens local scientific capacity in South East Asia (SEA) and therefore enables the rapid assessment of SARS-CoV-2 variants as they emerge within the region. While COVID-19 remains a global pandemic, future emerging infections caused by a novel virus is an inevitable event, with SEA being a global hot-spot for pathogen emergence. Consequently, the research capacity built, the scientists trained and the research network formed as part of this project will lay the foundation for future locally-led outbreak responses. Our project will demonstrate that novel research platforms can be set up in other low and middle income countries to address the unprecedented challenges presented by emerging infections.

Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension.

Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.