Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences.

Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations. PAPERCLIP:

Chiral superconductivity in heavy-fermion metal UTe2.

Spin-triplet superconductors are condensates of electron pairs with spin 1 and an odd-parity wavefunction1. An interesting manifestation of triplet pairing is the chiral p-wave state, which is topologically non-trivial and provides a natural platform for realizing Majorana edge modes2,3. However, triplet pairing is rare in solid-state systems and has not been unambiguously identified in any bulk compound so far. Given that pairing is usually mediated by ferromagnetic spin fluctuations, uranium-based heavy-fermion systems containing f-electron elements, which can harbour both strong correlations and magnetism, are considered ideal candidates for realizing spin-triplet superconductivity4. Here we present scanning tunnelling microscopy studies of the recently discovered heavy-fermion superconductor UTe2, which has a superconducting transition temperature of 1.6 kelvin5. We find signatures of coexisting Kondo effect and superconductivity that show competing spatial modulations within one unit cell. Scanning tunnelling spectroscopy at step edges reveals signatures of chiral in-gap states, which have been predicted to exist at the boundaries of topological superconductors. Combined with existing data that indicate triplet pairing in UTe2, the presence of chiral states suggests that UTe2 is a strong candidate for chiral-triplet topological superconductivity.

A Randomized Crossover Trial Evaluating the Impact of Cultural Dexterity Training on Surgical Residents' Knowledge, Cross-Cultural Care, Skills, and Beliefs: The Provider Awareness and Cultural dexterity Training for Surgeons (PACTS) Trial.

OBJECTIVES: This trial examines the impact of the Provider Awareness and Cultural dexterity Toolkit for Surgeons (PACTS) curriculum on surgical residents' knowledge, cross-cultural care, skills, and beliefs. SUMMARY BACKGROUND DATA: Cross-cultural training of providers may reduce healthcare outcome disparities, but its effectiveness in surgical trainees is unknown. METHODS: PACTS focuses on developing skills needed for building trust, working with patients with limited English proficiency, optimizing informed consent, and managing pain. The PACTS trial was a randomized crossover trial of 8 academic general surgery programs in the United States: The Early group ("Early") received PACTS between Periods 1 and 2, while the Delayed group ("Delayed") received PACTS between Periods 2 and 3. Residents were assessed pre- and post-intervention on Knowledge, Cross-Cultural Care, Self-Assessed Skills, and Beliefs. Chi-square and Fisher's exact tests were conducted to evaluate within- and between-intervention group differences. RESULTS: Of 406 residents enrolled, 315 were exposed to the complete PACTS curriculum. Early residents' Cross-Cultural Care (79.6% to 88.2%, P<0.0001), Self-Assessed Skills (74.5% to 85.0%, P<0.0001), and Beliefs (89.6% to 92.4%, P=0.0028) improved after PACTS; Knowledge scores (71.3% to 74.3%, P=0.0661) were unchanged. Delayed resident scores pre- to post-PACTS showed minimal improvements in all domains. When comparing the two groups at Period 2, Early residents had modest improvement in all 4 assessment areas, with statistically significant increase in Beliefs (92.4% vs 89.9%, P=0.0199). CONCLUSION: The PACTS curriculum is a comprehensive tool that improved surgical residents' knowledge, preparedness, skills, and beliefs, which will help with caring for diverse patient populations.

Race and Odds of Surgery Offer in Small Bowel and Pancreas Neuroendocrine Neoplasms.

BACKGROUND: Despite existing society guidelines, management of pancreatic (PanNEN) and small bowel (SBNEN) neuroendocrine neoplasms remains inconsistent. The purpose of this study was to identify patient- and/or disease-specific characteristics associated with increased odds of being offered surgery for PanNEN and SBNEN. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program database and the National Cancer Database (NCDB) were queried for patients with PanNEN/SBNEN. Demographic and pathologic data were compared between patients who were offered surgery and those who were not. Multivariate logistic regression was performed to identify factors independently associated with being offered surgery. RESULTS: In SEER, there were 3641 patients with PanNEN (54.7% were offered surgery) and 5720 with SBNEN (86.0% were offered surgery). On multivariate analysis of SEER, non-white race was associated with decreased odds of surgery offer for SBNEN [odds ratio (OR) 0.58, p < 0.001], but not PanNEN (p = 0.187). In NCDB, there were 28,483 patients with PanNEN (57.5% were offered surgery) and 42,675 with SBNEN (86.9% were offered surgery). On multivariate analysis of NCDB, non-white race was also associated with decreased odds of surgery offer for SBNEN (OR 0.61, p < 0.001) but not PanNEN (p = 0.414). CONCLUSIONS: This study's findings suggest that, in addition to previously reported disparities in surgical resection and surgery refusal rates, racial/ethnic disparities also exist earlier in the course of treatment, with non-white patients being less likely to be offered surgery for SBNEN but not for PanNEN; this is potentially due to discrepancies in rates of referral to academic centers for pancreas and small bowel malignancies.

Effectiveness of pulmonary rehabilitation programmes and/or respiratory muscle training in patients with post-COVID conditions: a systematic review.

BACKGROUND: The term "post-COVID-19 condition" refers to the symptomatology that appears between four to twelve weeks after Covid-19 infection. These symptoms can persist for weeks or even months, significantly diminishing the quality of life for affected individuals. The primary objective of this study was to assess the effectiveness of pulmonary rehabilitation programs and/or respiratory muscle training on respiratory sequelae in patients with post-COVID condition. METHODS: The literature search was conducted in the following databases: PubMed, PEDro, Embase, Cochrane, Scopus, and Web of Science. Randomized clinical trials were included in which participants were aged 18 years or older. Articles were excluded if at least one of the therapies did not involve pulmonary rehabilitation or respiratory muscle training, if the participants were COVID positive, if studies lacked results, and finally, if interventions were conducted without supervision or at home. This review only encompasses supervised non-virtual interventions. This study adheres to the PRISMA statement and has been registered in the PROSPERO database (CRD42023433843). RESULTS: The outcomes obtained in the included studies are assessed across the following variables: Exercise capacity using the 6-minute walk test, Dyspnea, fatigue, Pulmonary function, Maximum inspiratory pressure, and Quality of life. CONCLUSION: Despite the absence of a specific treatment at present, it was evident from this review that a well-structured pulmonary rehabilitation program that incorporates both aerobic and muscular strength exercises along with techniques and inspiratory muscle exercises was the most effective form of treatment.

Exploring the Telephone Call Experience of Patients with Non-English Language Preference in Primary Care vs. Specialty.

BACKGROUND: Latine people, comprising 18.5% of the US population, constitute the largest ethnic minority group, with nearly one-third self-identifying as having non-English language preference (NELP). Despite the importance of the telephone in health care access, there is limited understanding of how NELP patients navigate telephone calls with primary and specialty care clinics. OBJECTIVE: This qualitative study aims to capture how Spanish speakers with NELP characterize their telephone call experiences with primary and specialty care clinics. DESIGN: Semi-structured interviews were conducted with 24 Spanish-speaking participants from primary care clinics with a sizeable proportion of patients who prefer to communicate in a language other than English at an urban academic medical center in Boston, MA. PARTICIPANTS: Participants were selected from primary care clinics that were well-equipped to serve Spanish-speaking patients. A total of 24 Spanish-speaking patients with NELP, mainly women (83%), with a mean age of 55.8 years, participated. They represented diverse countries of origin, with an average length of time in the USA of 21.7 years. APPROACH: Interview questions prompted participants to describe their telephone call experiences with front desk staff, with attention to interpreter availability, ancillary assistance, health outcomes stemming from a lack of language services, and emotional consequences of language discordance on calls. KEY RESULTS: Patients perceived primary care clinics as providing familiarity and language concordance during telephone interactions, contrasting with specialty care clinics, seen as sources of monolingual English communication. Participants utilized various strategies, such as requesting interpreters, using concise English phrases, or seeking assistance from acquaintances, relatives, or primary care clinic staff, to mitigate language barriers. CONCLUSIONS: The findings underscore significant challenges faced by Spanish-speaking patients with NELP in ambulatory specialty care telephone calls. The study emphasizes the importance of creating inclusive multilingual telephone environments, standardizing interpreter access, and reflecting the diversity of the communities served.

Assessing EUS-guided radiofrequency ablation in unresectable pancreatic ductal adenocarcinoma: a single-center historic cohort study.

BACKGROUND AND AIMS: EUS-guided radiofrequency ablation (EUS-RFA) has emerged as an alternative for the local treatment of unresectable pancreatic ductal adenocarcinoma (PDAC). We assessed the feasibility and safety of EUS-RFA in patients with unresectable PDAC. METHODS: This study followed an historic cohort compounded by locally advanced (LA-) and metastatic (m)PDAC-naïve patients who underwent EUS-RFA between October 2019 and March 2022. EUS-RFA was performed with a 19-gauge needle electrode with a 10-mm active tip for energy delivery. Study primary endpoints were feasibility, safety, and clinical follow-up, whereas secondary endpoints were performance status (PS), local control, and overall survival (OS). RESULTS: Twenty-six patients were selected: 15 with locally advanced pancreatic duct adenocarcinoma (LA-PDAC) and 11 with metastatic pancreatic duct adenocarcinoma (mPDAC). Technical success was achieved in all patients with no major adverse events. Six months after EUS-RFA, OS was seen in 11 of 26 patients (42.3%), with significant PS improvement (P = .03). Local control was achieved, with tumor reduction from 39.5 mm to 26 mm (P = .04). A post-treatment hypodense necrotic area was observed at the 6-month follow-up in 11 of 11 patients who were still alive. Metastatic disease was a significant factor for worsening OS (hazard ratio, 5.021; 95% confidence interval, 1.589-15.87; P = .004). CONCLUSIONS: EUS-RFA for the treatment of pancreatic adenocarcinoma is a minimally invasive and safe technique that may have an important role as targeted therapy for local treatment of unresectable cases and as an alternative for poor surgical candidates. Also, RFA may play a role in downstaging cancer with a potential increase in OS in nonmetastatic cases. Large prospective cohorts are required to evaluate this technique in clinical practice.

Optimal evaluation of energy yield and driving force in microbial metabolic pathway variants.

This work presents a methodology to evaluate the bioenergetic feasibility of alternative metabolic pathways for a given microbial conversion, optimising their energy yield and driving forces as a function of the concentration of metabolic intermediates. The tool, based on thermodynamic principles and multi-objective optimisation, accounts for pathway variants in terms of different electron carriers, as well as energy conservation (proton translocating) reactions within the pathway. The method also accommodates other constraints, some of them non-linear, such as the balance of conserved moieties. The approach involves the transformation of the maximum energy yield problem into a multi-objective mixed-integer linear optimisation problem which is then subsequently solved using the epsilon-constraint method, highlighting the trade-off between yield and rate in metabolic reactions. The methodology is applied to analyse several pathway alternatives occurring during propionate oxidation in anaerobic fermentation processes, as well as to the reverse TCA cycle pathway occurring during autotrophic microbial CO2 fixation. The results obtained using the developed methodology match previously reported literature and bring about insights into the studied pathways.

Long chain capsaicin analogues synthetized by CALB-CLEAs show cytotoxicity on glioblastoma cell lines.

Glioblastoma is one of the most lethal tumors, displaying striking cellular heterogeneity and drug resistance. The prognosis of patients suffering from glioblastoma after 5 years is only 5%. In the present work, capsaicin analogues bearing modifications on the acyl chain with long-chain fatty acids showed promising anti-tumoral activity by its cytotoxicity on U-87 and U-138 glioblastoma multiforme cells. The capsaicin analogues were enzymatically synthetized with cross-linked enzyme aggregates of lipase B from Candida antarctica (CALB). The catalytic performance of recombinant CALB-CLEAs was compared to their immobilized form on a hydrophobic support. After 72 h of reaction, the synthesis of capsaicin analogues from linoleic acid, docosahexaenoic acid, and punicic acid achieved a maximum conversion of 69.7, 8.3 and 30.3% with CALB-CLEAs, respectively. Similar values were obtained with commercial CALB, with conversion yields of 58.3, 24.2 and 22% for capsaicin analogues from linoleic acid, DHA and punicic acid, respectively. Olvanil and dohevanil had a significant cytotoxic effect on both U-87 and U-138 glioblastoma cells. Irrespective of the immobilization form, CALB is an efficient biocatalyst for the synthesis of anti-tumoral capsaicin derivatives. KEY POINTS: • This is the first report concerning the enzymatic synthesis of capsaicin analogues from docosahexaenoic acid and punicic acid with CALB-CLEAs. • The viability U-87 and U-138 glioblastoma cells was significantly affected after incubation with olvanil and dohevanil. • Capsaicin analogues from fatty acids obtained by CALB-CLEAs are promising candidates for therapeutic use as cytotoxic agents in glioblastoma cancer cells.

Decreasing Perioperative Opiate Use During Pancreaticoduodenectomy Using Transversus Abdominus Plane Blocks: A Review of the Literature.

BACKGROUND: Pancreatoduodenectomy is a highly complex surgical procedure associated with high postoperative morbidity and mortality. Treatment of postoperative pain is crucial to preventing chronic pain and further complications. Opioids are the leading treatment modality for acute postoperative pain for all surgical procedures in the US, contributing to the opioid epidemic, a crisis causing death and lifelong impairment in many patients. Multimodal analgesia techniques, such as the transversus abdominis plane (TAP) block, are suggested to reduce perioperative opioid usage. This exploratory literature review aims to investigate the use of TAP block in postoperative pain and opioid use in patients undergoing pancreatoduodenectomy. MATERIALS AND METHODS: A search strategy developed from Cochrane best practice recommendations was applied to a comprehensive search of PubMed, Scopus, and PsycINFO databases, yielding three articles of relevance in patients having pancreatic surgery. RESULTS: Previous research demonstrates TAP block efficacy in decreasing opiate consumption after major abdominal surgery; however, there is a paucity of data regarding opioid consumption in pancreatoduodenectomy patients. CONCLUSION: Research in relation to TAP block analgesia is varied given the variety of approaches, techniques, and timing of the TAP block procedure. Future research should seek to elucidate the role of TAP blocks in reducing postoperative pain and opioid consumption in pancreatoduodenectomy patients.

Regulatory Role of Fatty Acid Metabolism on Glucose-Induced Changes in Insulin and Glucagon Secretion by Pancreatic Islet Cells.

A detailed study of palmitate metabolism in pancreatic islets subject to different experimental conditions, like varying concentrations of glucose, as well as fed or starved conditions, has allowed us to explore the interaction between the two main plasma nutrients and its consequences on hormone secretion. Palmitate potentiates glucose-induced insulin secretion in a concentration-dependent manner, in a physiological range of both palmitate (0-2 mM) and glucose (6-20 mM) concentrations; at glucose concentrations lower than 6 mM, no metabolic interaction with palmitate was apparent. Starvation (48 h) increased islet palmitate oxidation two-fold, and the effect was resistant to its inhibition by glucose (6-20 mM). Consequently, labelled palmitate and glucose incorporation into complex lipids were strongly suppressed, as well as glucose-induced insulin secretion and its potentiation by palmitate. 2-bromostearate, a palmitate oxidation inhibitor, fully recovered the synthesis of complex lipids and insulin secretion. We concluded that palmitate potentiation of the insulin response to glucose is not attributable to its catabolic mitochondrial oxidation but to its anabolism to complex lipids: islet lipid biosynthesis is dependent on the uptake of plasma fatty acids and the supply of α-glycerol phosphate from glycolysis. Islet secretion of glucagon and somatostatin showed a similar dependence on palmitate anabolism as insulin. The possible mechanisms implicated in the metabolic coupling between glucose and palmitate were commented on. Moreover, possible mechanisms responsible for islet gluco- or lipotoxicity after a long-term stimulation of insulin secretion were also discussed. Our own data on the simultaneous stimulation of insulin, glucagon, and somatostatin by glucose, as well as their modification by 2-bromostearate in perifused rat islets, give support to the conclusion that increased FFA anabolism, rather than its mitochondrial oxidation, results in a potentiation of their stimulated release. Starvation, besides suppressing glucose stimulation of insulin secretion, also blocks the inhibitory effect of glucose on glucagon secretion: this suggests that glucagon inhibition might be an indirect or direct effect of insulin, but not of glucose. In summary, there seems to exist three mechanisms of glucagon secretion stimulation: 1. glucagon stimulation through the same secretion coupling mechanism as insulin, but in a different range of glucose concentrations (0 to 5 mM). 2. Direct or indirect inhibition by secreted insulin in response to glucose (5-20 mM). 3. Stimulation by increased FFA anabolism in glucose intolerance or diabetes in the context of hyperlipidemia, hyperglycemia, and hypo-insulinemia. These conclusions were discussed and compared with previous published data in the literature. Specially, we discussed the mechanism for inhibition of glucagon release by glucose, which was apparently contradictory with the secretion coupling mechanism of its stimulation.

Unlocking the Power of Light on the Skin: A Comprehensive Review on Photobiomodulation.

Photobiomodulation (PBM) is a procedure that uses light to modulate cellular functions and biological processes. Over the past decades, PBM has gained considerable attention for its potential in various medical applications due to its non-invasive nature and minimal side effects. We conducted a narrative review including articles about photobiomodulation, LED light therapy or low-level laser therapy and their applications on dermatology published over the last 6 years, encompassing research studies, clinical trials, and technological developments. This review highlights the mechanisms of action underlying PBM, including the interaction with cellular chromophores and the activation of intracellular signaling pathways. The evidence from clinical trials and experimental studies to evaluate the efficacy of PBM in clinical practice is summarized with a special emphasis on dermatology. Furthermore, advancements in PBM technology, such as novel light sources and treatment protocols, are discussed in the context of optimizing therapeutic outcomes and improving patient care. This narrative review underscores the promising role of PBM as a non-invasive therapeutic approach with broad clinical applicability. Despite the need for further research to develop standard protocols, PBM holds great potential for addressing a wide range of medical conditions and enhancing patient outcomes in modern healthcare practice.

Revisiting Epigenetics Fundamentals and Its Biomedical Implications.

In light of the post-genomic era, epigenetics brings about an opportunity to better understand how the molecular machinery works and is led by a complex dynamic set of mechanisms, often intricate and complementary in many aspects. In particular, epigenetics links developmental biology and genetics, as well as many other areas of knowledge. The present work highlights substantial scopes and relevant discoveries related to the development of the term from its first notions. To our understanding, the concept of epigenetics needs to be revisited, as it is one of the most relevant and multifaceted terms in human knowledge. To redirect future novel experimental or theoretical efforts, it is crucial to compile all significant issues that could impact human and ecological benefit in the most precise and accurate manner. In this paper, the reader can find one of the widest compilations of the landmarks and epistemic considerations of the knowledge of epigenetics across the history of biology from the earliest epigenetic formulation to genetic determinism until the present. In the present work, we link the current body of knowledge and earlier pre-genomic concepts in order to propose a new definition of epigenetics that is faithful to its regulatory nature.

Establishing Normal Serum Values of Neurofilament Light Chains and Glial Fibrillary Acidic Protein Considering the Effects of Age and Other Demographic Factors in Healthy Adults.

Multiple studies have shown the importance of blood-based biomarkers indicating axonal damage (serum neurofilament light chains [sNfL]) or astroglia activation (serum glial fibrillary acidic protein [sGFAP]) for monitoring different neurological diseases. However, normal values of these variables remain to be clearly defined, partly due to the influence of different demographic factors. We investigated demographic differences in a cohort of healthy volunteers. A cross-sectional study was conducted including 116 healthy controls with ages between 18 and 69 years (67.5% females; n = 79). sNfL and sGFAP concentrations were measured using single-molecule arrays. Age and body mass index affected sNfL values, and age was found to be the most important factor. The normal values changed with age, and we established normal values for individuals younger than 45 years as <10 pg/mL and for controls older than 45 years as <15 pg/mL. We established normal values at <10 pg/mL for individuals younger than 45 years and <15 pg/mL for older individuals. Alternatively, a Z-score of 1.5 was relevant for all controls. sGFAP was only affected by age. Differences in normal values were evident by 55 years. The highest normality limit for sGFAP was 140 pg/mL for controls under 55 years and 280 for older controls. We defined normal levels for sNfL and sGFAP and their corresponding age-associated changes. These data may contribute to the application of such variables in clinical practice.

Pulsed negative pressure myofascial vacuum therapy and percutaneous electrolysis in the treatment of lateral epicondylalgia: A single-blind randomized controlled trial.

BACKGROUND: Lateral Epicondylalgia (LE) represents one of the most common injuries of the upper limb. It is necessary to find effective treatments that reduce pain and increase functionality. PURPOSE: To determine the effects of an integrated intervention of Pulsed Negative Pressure Myofascial Vacuum Therapy (VT), Percutaneous Electrolysis (PE) and eccentric exercise (EE) in the treatment of LE compared versus Manual Therapy soft tissue mobilization (MT) and Ultrasound therapy (US) and EE. STUDY DESIGN: Single-blind randomized controlled trial. METHODS: Forty participants, with unilateral LE, were randomly divided into two groups: VT + PE + EE group (n = 20) and MT + US + EE group (n = 20). The VT + PE + EE group received one weekly session for four weeks and a regimen of EE daily at-home, and the MT + US + EE group received 10 sessions over a period of two weeks and a regimen of EE daily at-home. Numerical pain rating scale (NPRS), range of motion (ROM) pressure pain threshold (PPT) and function (PRTEE questionnaire) were measured before treatment, at the end of treatment, and at one- and three-month follow-ups. RESULTS: The statistically significant improvements were found post-treatment, favoring the VT + PE group in pain intensity (p < 0.001; ES = 0.408), PRTEE-S Pain (p = 0.001; ES = 0.377), PRTEE-S Specific function (p = 0.004; ES = 0.306) and PRTEE-S Total (p = 0.001; ES = 0.355). The VT + PE + EE treatment showed greater effectiveness than the MT + US + EE treatment at immediate post-treatment, as well as at the one-month and three-months follow-up. CONCLUSIONS: VT and PE added to an EE program could be an effective treatment for pain, ROM, PPT, and function in patients with LE.

Development of an explainable artificial intelligence model for Asian vascular wound images.

Chronic wounds contribute to significant healthcare and economic burden worldwide. Wound assessment remains challenging given its complex and dynamic nature. The use of artificial intelligence (AI) and machine learning methods in wound analysis is promising. Explainable modelling can help its integration and acceptance in healthcare systems. We aim to develop an explainable AI model for analysing vascular wound images among an Asian population. Two thousand nine hundred and fifty-seven wound images from a vascular wound image registry from a tertiary institution in Singapore were utilized. The dataset was split into training, validation and test sets. Wound images were classified into four types (neuroischaemic ulcer [NIU], surgical site infections [SSI], venous leg ulcers [VLU], pressure ulcer [PU]), measured with automatic estimation of width, length and depth and segmented into 18 wound and peri-wound features. Data pre-processing was performed using oversampling and augmentation techniques. Convolutional and deep learning models were utilized for model development. The model was evaluated with accuracy, F1 score and receiver operating characteristic (ROC) curves. Explainability methods were used to interpret AI decision reasoning. A web browser application was developed to demonstrate results of the wound AI model with explainability. After development, the model was tested on additional 15 476 unlabelled images to evaluate effectiveness. After the development on the training and validation dataset, the model performance on unseen labelled images in the test set achieved an AUROC of 0.99 for wound classification with mean accuracy of 95.9%. For wound measurements, the model achieved AUROC of 0.97 with mean accuracy of 85.0% for depth classification, and AUROC of 0.92 with mean accuracy of 87.1% for width and length determination. For wound segmentation, an AUROC of 0.95 and mean accuracy of 87.8% was achieved. Testing on unlabelled images, the model confidence score for wound classification was 82.8% with an explainability score of 60.6%. Confidence score was 87.6% for depth classification with 68.0% explainability score, while width and length measurement obtained 93.0% accuracy score with 76.6% explainability. Confidence score for wound segmentation was 83.9%, while explainability was 72.1%. Using explainable AI models, we have developed an algorithm and application for analysis of vascular wound images from an Asian population with accuracy and explainability. With further development, it can be utilized as a clinical decision support system and integrated into existing healthcare electronic systems.

BioLindlar Catalyst: Ene-Reductase-Promoted Selective Bioreduction of Cyanoalkynes to Give (Z)-Cyanoalkenes.

The direct synthesis of alkenes from alkynes usually requires the use of transition-metal catalysts. Unfortunately, efficient biocatalytic alternatives for this transformation have yet to be discovered. Herein, the selective bioreduction of electron-deficient alkynes to alkenes catalysed by ene-reductases (EREDs) is described. Alkynes bearing ketone, aldehyde, ester, and nitrile moieties have been effectively reduced with excellent conversions and stereoselectivities, observing clear trends for the E/Z ratios depending on the nature of the electron-withdrawing group. In the case of cyanoalkynes, (Z)-alkenes were obtained as the major product, and the reaction scope was expanded to a wide variety of aromatic substrates (up to >99% conversion, and Z/E stereoselectivities of up to >99/1). Other alkynes containing aldehyde, ketone, or ester functionalities also proved to be excellent substrates, and interestingly gave the corresponding (E)-alkenes. Preparative biotransformations were performed on a 0.4 mmol scale, producing the desired (Z)-cyanoalkenes with good to excellent isolated yields (63-97%). This novel reactivity has been rationalised through molecular docking by predicting the binding poses of key molecules in the ERED-pu-0006 active site.

Progressive multifocal leukoencephalopathy, advanced ductal breast carcinoma, systemic sclerosis, and checkpoint inhibitors: a therapeutic dilemma.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating central nervous system disease infection by JC virus (JCV) in patients with a significant decline in cellular immunity. No specific treatment has demonstrated efficacy, and the disease progresses to death in most patients. Recent findings have shown stabilization or improvement of PML lesions after treatment with checkpoint inhibitors (CPI) based on immune reconstitution. Nevertheless, immunotherapy may specifically cause autoimmune diseases or may deteriorate pre-existing ones. We report a case of a patient under treatment for advanced ductal breast carcinoma and systemic sclerosis, who developed PML. The therapeutic approach included withdrawal of drugs with possible immunosuppressive effect and treatment with pembrolizumab. In the absence of reliable markers to predict CPIs response and a concern for an autoimmune worsening, immunotherapy was administered late in the course of the disease. Finally, she did not experience an autoimmune disease flare-up; however, pembrolizumab could not prevent disease progression. We believe that potential autoimmune complications should not delay treatment initiation with CPIs in PML.

Multiple introgression events during the diversification history of the edible Mexican grasshopper genus Sphenarium (Orthoptera: Pyrgomorphidae).

Speciation with gene flow often leads to ambiguous phylogenetic reconstructions, reticulate patterns of relatedness and conflicting nuclear versus mitochondrial (mt) lineages. Here we employed a fragment of the COI mtDNA gene and nuclear genome-wide data (3RAD) to assess the diversification history of Sphenarium, an orthopteran genus of great economic importance in Mexico that is presumed to have experienced hybridisation events in some of its species. We carried out separate phylogenetic analyses to evaluate the existence of mito-nuclear discordance in the species relationships, and also assessed the genomic diversity and population genomic structure and investigated the existence of interspecific introgression and species limits of the taxa involved based on the nuclear dataset. The species delineation analyses discriminated all the currently recognised species, but also supported the existence of four undescribed species. The mt and nuclear topologies had four discordant species relationships that can be explained by mt introgression, where the mt haplotypes of S. purpurascens appear to have replaced those of S. purpurascens A and B, S. variabile and S. zapotecum. Moreover, our analyses supported the existence of nuclear introgression events between four species pairs that are distributed in the Sierra Madre del Sur province in southeast Mexico, with three of them occurring in the Tehuantepec Isthmus region. Our study highlights the relevance of genomic data to address the relative importance of allopatric isolation versus gene flow in speciation.

Telehealth Policy, Practice, and Education: a Position Statement of the Society of General Internal Medicine.

Telehealth services, specifically telemedicine audio-video and audio-only patient encounters, expanded dramatically during the COVID-19 pandemic through temporary waivers and flexibilities tied to the public health emergency. Early studies demonstrate significant potential to advance the quintuple aim (patient experience, health outcomes, cost, clinician well-being, and equity). Supported well, telemedicine can particularly improve patient satisfaction, health outcomes, and equity. Implemented poorly, telemedicine can facilitate unsafe care, worsen disparities, and waste resources. Without further action from lawmakers and agencies, payment will end for many telemedicine services currently used by millions of Americans at the end of 2024. Policymakers, health systems, clinicians, and educators must decide how to support, implement, and sustain telemedicine, and long-term studies and clinical practice guidelines are emerging to provide direction. In this position statement, we use clinical vignettes to review relevant literature and highlight where key actions are needed. These include areas where telemedicine must be expanded (e.g., to support chronic disease management) and where guidelines are needed (e.g., to prevent inequitable offering of telemedicine services and prevent unsafe or low-value care). We provide policy, clinical practice, and education recommendations for telemedicine on behalf of the Society of General Internal Medicine. Policy recommendations include ending geographic and site restrictions, expanding the definition of telemedicine to include audio-only services, establishing appropriate telemedicine service codes, and expanding broadband access to all Americans. Clinical practice recommendations include ensuring appropriate telemedicine use (for limited acute care situations or in conjunction with in-person services to extend longitudinal care relationships), that the choice of modality be done through patient-clinician shared decision-making, and that health systems design telemedicine services through community partnerships to ensure equitable implementation. Education recommendations include developing telemedicine-specific educational strategies for trainees that align with accreditation body competencies and providing educators with protected time and faculty development resources.