Anesthesia and its environmental impact: approaches to minimize exposure to anesthetic gases and reduce waste.

In today's era of modern healthcare, the intersection between medical practices and environmental responsibility has gained significant attention. One such area of focus is the practice of anesthesia, which plays a crucial role in various surgical procedures. Anesthetics such as nitrous oxide and volatile halogenated ethers (desflurane, isoflurane, sevoflurane) are examples of medical gases that are strong greenhouse gases that contribute to global warming. During medical procedures, most of these anesthetic agents are released into the atmosphere, which exacerbates their influence on the environment. Also anesthesia delivery systems have traditionally utilized high flow rates of gases, leading to not only excessive consumption but also a considerable environmental impact in terms of greenhouse gas emissions. However, the emergence of low-flow anesthesia (LFA) presents a promising solution for achieving emission reduction and cost savings, thereby aligning healthcare practices with sustainability goals. Understanding LFA involves the administration of anesthetic gases to patients at reduced flow rates compared to conventional high-flow methods. This practice requires precision in gas delivery, often incorporating advanced monitoring and control systems. By optimizing gas flow to match the patient's requirements, LFA minimizes wastage and excessive gas release into the environment, subsequently curbing the carbon footprint associated with healthcare operations. Decreasing volatile anesthetic delivery provides safe and effective strategies for anesthesia providers to decrease costs and reduce environmental pollution. Current literature support in favor of LFA represents an area of cost containment and an opportunity to lessen the environmental impact of anesthesia. This article will cover the concept of LFA, the distinctions between low flow and minimal flow, and the potential advantages of LFA, such as those related to patient safety, the environment, and the economy.

Post-Neutralisation Activated Clotting Time and Postoperative Transfusions in Cardiac Surgery Outcome.

OBJECTIVE: To assess the impact of post-protamine neutralisation activated clotting time (ACT) values on postoperative outcomes including chest drain output, transfusion requirements, and CICU stay, in patients undergoing cardiac surgery. STUDY DESIGN: Observational comparative study. Place and Duration of the Study: Department of Anaesthesiology, The Aga Khan University Hospital, Karachi, Pakistan, from February to August 2023. METHODOLOGY: Ethical approval was obtained to collect data from elective cardiac surgery patients' charts. A sequential sampling approach analysed the baseline and post-protamine neutralisation ACT values, categorising patients into two groups. Group A maintained ACT within 10% of baseline, while Group B deviated. The outcomes measured included transfusion needs, chest drain output, additional protamine, cardiac intensive care unit (CICU) stay, and postoperative reopening. Statistical analysis included mean, median, frequency, t-test / Mann-Whitney U test, and Chi-square test. RESULTS: The study comprised 101 patients (39 in Group A, 62 in Group B), with similar baseline health. No significant differences were found in tranexamic acid use, CICU stay, chest drain output, or transfusion rates between the groups (p >0.05). CONCLUSION: Maintaining ACT within 10% of baseline post-protamine neutralisation results in similar intraoperative and postoperative outcomes, suggesting potential benefits in avoiding the aggressive protamine therapy and ensuring haemostasis in cardiac surgery. KEY WORDS: Coronary Artery bypass grafting, Cardiopulmonary bypass, Activated clotting time (ACT), Heparin, Postoperative bleeding, Blood transfusions.

Inflammatory Status As a Predictor of Perioperative Risk in Patients Undergoing Non-Cardiac Vascular Surgery.

INTRODUCTION: Patients scheduled to undergo vascular surgery represent a significant population at risk of major adverse cardiac events (MACE's) post operation. This is due to a number of inflammatory mechanisms, designed to aid in post surgical recovery. A number of screening tools have been designed such as the EAGLE risk score or the Goldman and Detsky scores, to aid in identification of at-risk individuals. Recently inflammatory biomarkers have been suggested as a tool to aid in this assessment. The role of interleukins such as IL-1 and Il-6 have particularly been of interest to current research. Our hypothesis aims to test whether there is any benefit to measuring inflammatory biomarkers post operation as a tool to identify individuals at risk of MACEs. METHOD: We identified 75 eligible patients scheduled to undergo vascular surgery (bypass, EVAR or open AAA repair or endarterectomy) and measured four inflammatory biomarkers (IL-1, IL-6, ICAM-1 & CRP) pre and post operatively on days 1-4 to identify correlations and identify differences in individuals who had a MACE vs those that didn't. A MACE was defined by a rise in T troponin of 0.06 or greater or ECG changes agreed upon by two clinicians or a stroke RESULTS: Of the 75 patients, 13 were identified to have a MACE. The result showed that both IL-1 and ICAM show a significantly positive correlation between pre and post operative levels with ICAM-1 significantly positive on all 4 days and IL-1 significantly positive on days 1, 3 & 4. When comparing the significant difference in change in inflammatory biomarkers between the MACE group and non-MACE group, a significant difference was only noted in the ICAM biomarker. ICAM was significantly different between the two groups on day 1 and day 2 (t test value 0.0455 and 0.0492 respectively) but was non-significant on days 3 and 4. All other biomarkers showed no significant difference pre and post op. DISCUSSION: Overall, it is suggestable that measuring inflammatory biomarkers in vascular surgery patients is a valuable aid to clinicians in potentially identifying at-risk groups and should be used as an adjunct to already existing mechanisms available to the clinician.

The retrograde pressure cooker technique for transvenous embolization of a residual arteriovenous malformation following stereotactic radiosurgery.

Residual brain arteriovenous malformations (BAVMs) following stereotactic radiosurgery are not uncommon and the optimal subsequent management remains undetermined.1-3 Endovascular embolization has been reported as an effective treatment for residual BAVMs after radiosurgery,4 5 and has the advantage over repeat radiosurgery in selected cases as angiographic weak points can be secured immediately and the risk of radiation-induced complications is less of a concern.6 7 In this technical video (video 1), we demonstrate the transvenous embolization of a previously-irradiated arteriovenous malformation and a persistent venous pouch using the retrograde pressure cooker technique, with emphasis on the important recommendations for avoiding periprocedural complications.neurintsurg;jnis-2024-022035v1/V1F1V1Video 1Video demonstrating Onyx embolization of the residual brain arteriovenous malformation using the retrograde pressure cooker technique.

Non-cryopreserved autologous peripheral blood stem cell transplantation for multiple myeloma and lymphoma in countries with limited resources: practice considerations from the Worldwide Network for Blood and Marrow Transplantation.

Autologous peripheral blood stem cell (PBSC) transplantation is a standard treatment of multiple myeloma (MM), Hodgkin lymphoma and various subtypes of non-Hodgkin lymphoma. Cryopreservation of hematopoietic stem cells is standard practice that allows time for delivery of conditioning regimen prior to cell infusion. The aim of this Worldwide Network for Blood & Marrow Transplantation (WBMT) work was to assess existing evidence on non-cryopreserved autologous transplants through a systematic review/meta-analysis, to study feasibility and safety of this approach. We searched PubMed, Web of Science and SCOPUS for studies that utilized non-cryopreserved autologous PBSC transplantation. Identified literature was reviewed for information on mobilization, apheresis, preservation and viability, conditioning regimen, engraftment, response, and survival. Results highlight collective experience from 19 transplant centers (1686 patients), that performed autologous transplants using non-cryopreserved PBSCs. The mean of infused CD34+ was 5.6 × 106/kg. Stem cell viability at transplantation was >90% in MM and >75% in lymphomas, after a storage time of 24-144 h at +4 °C. Mean time-to-neutrophil engraftment was 12 days and 15.3 days for platelets. Pooled proportion estimates of day 100 transplant-related mortality and graft failure were 1% and 0%, respectively. Non-cryopreservation of apheresed autologous PBSCs appears feasible and safe.

DTX3L ubiquitin ligase ubiquitinates single-stranded nucleic acids.

Ubiquitination typically involves covalent linking of ubiquitin (Ub) to a lysine residue on a protein substrate. Recently, new facets of this process have emerged, including Ub modification of non-proteinaceous substrates like ADP-ribose by the DELTEX E3 ligase family. Here, we show that the DELTEX family member DTX3L expands this non-proteinaceous substrate repertoire to include single-stranded DNA and RNA. Although the N-terminal region of DTX3L contains single-stranded nucleic acid binding domains and motifs, the minimal catalytically competent fragment comprises the C-terminal RING and DTC domains (RD). DTX3L-RD catalyses ubiquitination of the 3'-end of single-stranded DNA and RNA, as well as double-stranded DNA with a 3' overhang of two or more nucleotides. This modification is reversibly cleaved by deubiquitinases. NMR and biochemical analyses reveal that the DTC domain binds single-stranded DNA and facilitates the catalysis of Ub transfer from RING-bound E2-conjugated Ub. Our study unveils the direct ubiquitination of nucleic acids by DTX3L, laying the groundwork for understanding its functional implications.

Trends of fully alcohol-attributable mortality rates before and during COVID-19 in the Baltic and other European countries.

AIMS: We tested the polarization hypothesis, which postulates that during times of crises, such as the COVID-19 pandemic, alcohol consumption increases among the heaviest drinkers but decreases among most other drinkers, resulting in an overall decrease in consumption among the population. We posited the increase in heavy drinking would lead to increases in 100% alcohol-attributable (AA) mortality. Furthermore, based on the high level of alcohol consumption in the Baltic countries compared to other European countries, we predicted that the increases in AA mortality would be more pronounced in these countries. METHODS: Data for 100% AA deaths were obtained from the World Health Organization for the period 2010 to 2022, and standardized to the regional age distribution for 2010. Parametric and non-parametric tests were used to test the study hypotheses. RESULTS: The mean age-standardized 100% AA mortality rate increased during the COVID-19 pandemic in the 19 European countries with data by 3.12 deaths per 100,000 population, constituting an 18% increase (tested against no change: t = 2.52; df = 18; p = 0.021). This increase was higher in the Baltic countries (mean difference = 13.41 deaths per 100,000 population; standard deviation (SD) = 7.44; 46% increase) than for other European countries (mean difference = 1.19; SD = 1.55; 8% increase). The increases in 100% AA mortality were associated with decreases in the level of alcohol consumption in the majority of countries. CONCLUSIONS: As predicted, 100% AA mortality increased in 19 European countries during the COVID-19 pandemic, with the Baltic countries seeing a higher increase. Renewed alcohol control policy efforts should be considered.

Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.

The current state of primary healthcare in Pakistan: a way forward for low-to-middle income countries.

BACKGROUND: Primary healthcare (PHC) plays a crucial role in improving health outcomes and reducing healthcare burden, especially in low-to-middle-income countries (LMICs). However, PHC has not received adequate attention in Pakistan despite its recognized importance. This study aims to examine the current state of PHC in Pakistan, identifying factors compromising its quality and effectiveness. METHODS: To find relevant data, the authors conducted a thorough literature search on PubMed, Google Scholar, and Cochrane Library from inception till 2 July 2022, without any language restriction. The following keywords were employed during the literature search, separated by Boolean operators AND, OR: "Primary Healthcare", "PHC", "Healthcare primary", "Primary Health", and "Pakistan". RESULTS: Pakistan's PHC infrastructure shows promise, with a considerable number of healthcare facilities in place. However, various factors hinder its effectiveness and compromise the quality of care provided. Insufficient investment, resource constraints, inadequate training of healthcare providers, lack of oversight, and limited access to essential medicines and equipment are some of the key challenges observed. Improving PHC in Pakistan is vital for addressing the population's healthcare needs, particularly in rural areas. Adequate investment, enhanced training programs, improved oversight mechanisms, and increased availability of essential resources are necessary to strengthen the PHC system. By prioritizing PHC and addressing the identified challenges, Pakistan can enhance healthcare access, reduce healthcare burden, and improve overall health outcomes for its population. CONCLUSION: It is high time LMICs like Pakistan recognize PHC as the most economically feasible pathway toward accomplishing healthcare targets and adopt adequate measures to elevate its standards.

Special Report: Summary of the eighth workshop of the worldwide network for blood and marrow transplantation on the status and issues related to hematopoietic stem cell transplantation in near-east countries, held in Pakistan from September 22 to 23, 2022.

The eighth workshop of the Worldwide Network for Blood and Marrow Transplantation (WBMT) was held in Islamabad, Pakistan, from September 22 to 23, 2022, aiming to foster hematopoietic stem cell transplant (HSCT) activity in the World Health Organization (WHO) Eastern Mediterranean Region (EMRO). Participating countries, including Pakistan, Oman, Iran, and Saudi Arabia, reported increased HSCT in the last few years, whereas others from the EMRO and beyond, including Qatar, United Arab Emirates, Nepal, and Bangladesh, started HSCT recently and have developed HSCT programs with excellent results. During educational sessions and open dialog, participating teams and international experts from the WBMT shared their experience and discussed minimum essential requirements for establishing and expanding HSCT in emerging countries, indications for HSCT training and dissemination of knowledge, stem cell donor selection and safety, quality assurance in transplant centers, and the value and importance of transplant outcome databases. International support, collaboration, and local engagement, including government participation and WHO assistance, are valuable in increasing HSCT access worldwide.

Assessing generalizability of an AI-based visual test for cervical cancer screening.

A number of challenges hinder artificial intelligence (AI) models from effective clinical translation. Foremost among these challenges is the lack of generalizability, which is defined as the ability of a model to perform well on datasets that have different characteristics from the training data. We recently investigated the development of an AI pipeline on digital images of the cervix, utilizing a multi-heterogeneous dataset of 9,462 women (17,013 images) and a multi-stage model selection and optimization approach, to generate a diagnostic classifier able to classify images of the cervix into "normal", "indeterminate" and "precancer/cancer" (denoted as "precancer+") categories. In this work, we investigate the performance of this multiclass classifier on external data not utilized in training and internal validation, to assess the generalizability of the classifier when moving to new settings. We assessed both the classification performance and repeatability of our classifier model across the two axes of heterogeneity present in our dataset: image capture device and geography, utilizing both out-of-the-box inference and retraining with external data. Our results demonstrate that device-level heterogeneity affects our model performance more than geography-level heterogeneity. Classification performance of our model is strong on images from a new geography without retraining, while incremental retraining with inclusion of images from a new device progressively improves classification performance on that device up to a point of saturation. Repeatability of our model is relatively unaffected by data heterogeneity and remains strong throughout. Our work supports the need for optimized retraining approaches that address data heterogeneity (e.g., when moving to a new device) to facilitate effective use of AI models in new settings.

Obliged to follow your command: examining how and when servant leadership affects service performance.

PURPOSE: This study is undertaken to explain how servant leadership affects employees' service performance through their felt obligation toward their leaders. Furthermore, the study explores how the relationship between felt obligation and service performance is moderated by performance pressure. DESIGN/METHODOLOGY/APPROACH: The data were collected from 312 manager-subordinate dyads working in private sector hospitals of Karachi. The data were analyzed through covariance-based structural equation modeling. FINDINGS: The study found that employees' performance is affected by servant leadership and felt obligation toward managers. Furthermore, the study found that felt obligation toward leader mediates the relationship between servant leadership and employees' performance. Finally, the study found that the relationship between felt obligation toward leader and employees' performance was not contingent upon perceived performance pressure. ORIGINALITY/VALUE: The study confirms the mediating role of felt obligation toward leaders linking servant leadership to employees' service performance. The study also tests the moderating role of performance pressure influencing the relationship between relationship between felt obligation toward leaders and employees' service performance.

Early versus Delayed Vitrectomy for Vitreous Haemorrhage Secondary to Proliferative Diabetic Retinopathy.

OBJECTIVE: To compare the clinical outcomes of early pars plana vitrectomy (PPV) versus delayed PPV in patients with first episode of vitreous hemorrhage (VH) secondary to proliferative diabetic retinopathy (PDR). DESIGN: Retrospective, comparative, interventional study. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Consecutive patients with type 1 or II diabetes diagnosed with new onset VH secondary to PDR who underwent PPV at Moorfields Eye Hospital between December 2014 and December 2016. Exclusions were prior vitrectomy, iris neovascularization, neovascular glaucoma, macular edema, or presence of tractional/rhegmatogenous retinal detachment. METHODS, INTERVENTION, OR TESTING: Patients were divided into two groups based on the timing of their surgery: early PPV (≤6 weeks) and delayed PPV (>6 weeks). Demographic and clinical features, including best-corrected visual acuity (BCVA) expressed in LogMAR at baseline and 12 months were collected. Statistical analyses, including propensity score matching, were performed using Python 3.10, Scikit-learn, Pandas, and GraphPad Prism® 10. MAIN OUTCOME MEASURES: BCVA at 12 months postoperatively, reoperation rates, and severity of complications. RESULTS: A total of 178 eyes were analyzed (48 early PPV, 130 delayed PPV). The mean (SD) number of weeks before surgery was 3.36 (SD 1.6) for the early PPV group and 22.56 (SD 17.23) for the delayed PPV group (p<0.0001). Baseline BCVA prior to PPV was similar between groups (p=0.08). At 12 months, the early PPV group had significantly better BCVA (0.40 logMAR vs. 0.67 logMAR; p=0.02). Patients without evidence of posterior vitreous detachment (PVD) on ultrasound or OCT showed more pronounced differences (0.3 logMAR vs. 0.7 logMAR; p=0.001). The early PPV group had fewer sight threatening complications (p=0.005). Multivariable logistic regression identified initial BCVA, early PPV, and absence of pre-operative panretinal photocoagulation (PRP) as significant predictors of better visual outcomes. CONCLUSIONS: Early PPV significantly improves visual outcomes and reduces severe complications in patients with VH secondary to PDR. These findings support the benefits of early surgical intervention to enhance long-term visual prognosis in these patients. However, a randomised clinical trial is warranted.

STA-9090 in combination with a statin exerts enhanced protective effects in rats fed a high-fat diet and exposed to diethylnitrosamine and thioacetamide.

Introduction: Liver fibrosis is a significant global health burden that lacks effective therapies. It can progress to cirrhosis and hepatocellular carcinoma (HCC). Aberrant hedgehog pathway activation is a key driver of fibrogenesis and cancer, making hedgehog inhibitors potential antifibrotic and anticancer agents. Methods: We evaluated simvastatin and STA-9090, alone and combined, in rats fed a high-fat diet (HFD) and exposed to diethylnitrosamine and thioacetamide (DENA/TAA). Simvastatin inhibits HMG-CoA reductase, depleting cellular cholesterol required for Sonic hedgehog (Shh) modification and signaling. STA-9090 directly inhibits HSP90 chaperone interactions essential for Shh function. We hypothesized combining these drugs may provide liver protective effects through complementary targeting of the hedgehog pathway. Endpoints assessed included liver function tests, oxidative stress markers, histopathology, extracellular matrix proteins, inflammatory cytokines, and hedgehog signaling components. Results: HFD and DENA/TAA caused aberrant hedgehog activation, contributing to fibrotic alterations with elevated liver enzymes, oxidative stress, dyslipidemia, inflammation, and collagen deposition. Monotherapies with simvastatin or STA-9090 improved these parameters, while the combination treatment provided further enhancements, including improved survival, near-normal liver histology, and compelling hedgehog pathway suppression. Discussion: Our findings demonstrate the enhanced protective potential of combined HMG CoA reductase and HSP90 inhibition in rats fed a HFD and exposed to DENA and TAA. This preclinical study could help translate hedgehog-targeted therapies to clinical evaluation for treating this major unmet need.

A Comparative Study Between Video Laryngoscope and Video Stylet for Tracheal Intubation in Patients With Simulated Cervical Fracture Injury: A Prospective Randomised Controlled Study.

Purpose Video laryngoscopes were being used more often in cases of potentially difficult airways. The Karl Storz video stylet offered clear advantages over conventional laryngoscopes for patients with cervical spine fractures. This study aimed to compare the performance of the C-MAC video laryngoscope with the new Karl Storz video stylet in patients with simulated cervical fracture injuries. Material and methods The study, approved by the Board of Studies and the Ethical Committee of Jawaharlal Nehru Medical College and Hospital in Aligarh, involved 50 patients undergoing operative procedures under general anaesthesia. It was a prospective randomised controlled study on patients aged 20-60, weighing 30-80 kg, and classified as American Society of Anesthesiologists (ASA) Grades I and II, admitted for elective operative procedures. Patients were randomly assigned to two groups for intubation using different devices: the control group (N = 25) was intubated with the C-MAC (Mac blade) video laryngoscope (CM), and the study group (N = 25) was intubated with the Karl Storz video stylet (VS). The anaesthetic procedure involved a detailed pre-anesthetic check-up for all patients, including a medical history review, physical examination, and necessary tests based on age. Standard monitoring and pre-medication were administered uniformly. Anesthesia was induced and intubation was attempted using appropriate devices, following manual stabilisation of the neck. Parameters such as intubation attempts, time taken, failures, hemodynamic changes, and complications were recorded throughout the procedure. If intubation was unsuccessful, alternative measures were taken, and the operative procedure proceeded. Results The intubation success rates were compared between the two groups, CM and VS. In the CM group, all 25 patients (100%) were successfully intubated on the first attempt, while in the VS group, 23 patients (92%) were successfully intubated on the first attempt, and two patients (8%) required two attempts. The difference in the distribution of the number of attempts between the two groups was not statistically significant (p = 0.4915). The mean intubation time in the CM group was 27.24 ± 2.16 seconds, while in the VS group, the mean intubation time was significantly longer at 30.84 ± 6.81 seconds, with a statistically significant difference (p = 0.0105). Adjustment manoeuvres were required in only 4% of patients in the CM group compared to 0% in the VS group, although this difference was not statistically significant. The occurrence of blood on the device during intubation was recorded, and the distribution of patients with blood on the device among the two groups did not show a statistically significant difference (p = 0.617). Conclusion This study compared the effectiveness of two intubation devices. The C-MAC video laryngoscope showed a significantly higher rate of first-attempt successful intubations and required fewer attempts compared to the Karl Storz video stylet. The C-MAC also had shorter intubation times compared to the Karl Storz device. However, the Karl Storz video stylet demonstrated comparable performance to the C-MAC video laryngoscope in clinical settings, with both devices having similar safety profiles and minimal complications.

Evaluating the Safety and Efficacy of a Novel Glaucoma Drainage Device in High-Risk Adult Glaucoma Patients: A One-Year Pilot Study.

Background: We report on the 12-month safety and efficacy outcomes of a new non-valved glaucoma drainage device, the eyePlate-300 (Rheon Medical, Lausanne, Switzerland), in managing refractory glaucoma. Methods: A retrospective review was conducted on consecutive patients over 18 who underwent glaucoma drainage device (GDD) surgery with the eyePlate-300 after a single glaucoma consultation between February 2020 and April 2021, with at least 12 months of documented post-op follow-up. Results: A total of 16 eyes from 15 patients were included. Complete success was observed in 47% of patients and overall success in 83%. The mean IOP decreased from 31.5 mm Hg to 10.7 mm Hg (67% reduction from baseline), and the number of IOP-lowering drops was reduced from 3.1 to 0.7 at one year. The mean BCVA remained stable. No additional IOP-lowering surgeries were required, and no severe sight-threatening complications were noted. Conclusions: The initial one-year results suggest that the eyePlate could be a safe and effective device for reducing IOP in an ethnically diverse refractory glaucoma population. Further follow-up is necessary to determine the long-term safety and efficacy.

BRCA2 C-terminal clamp restructures RAD51 dimers to bind B-DNA for replication fork stability.

Tumor suppressor protein BRCA2 acts with RAD51 in replication-fork protection (FP) and homology-directed DNA break repair (HDR). Critical for cancer etiology and therapy resistance, BRCA2 C-terminus was thought to stabilize RAD51-filaments after they assemble on single-stranded (ss)DNA. Here we determined the detailed crystal structure for BRCA2 C-terminal interaction-domain (TR2i) with ATP-bound RAD51 prior to DNA binding. In contrast to recombinogenic RAD51-filaments comprising extended ATP-bound RAD51 dimers, TR2i unexpectedly reshapes ATP-RAD51 into a unique dimer conformation accommodating double-stranded B-DNA binding unsuited for HDR initiation. Structural, biochemical, and molecular results with interface-guided mutations uncover TR2i's FP mechanism. Proline-driven secondary-structure stabilizes residue triads and spans the RAD51 dimer engaging pivotal interactions of RAD51 M210 and BRCA2 S3291/P3292, the cyclin-dependent kinase (CDK) phosphorylation site that toggles between FP during S-phase and HDR in G2. TR2i evidently acts as an allosteric clamp switching RAD51 from ssDNA to double-stranded and B-DNA binding enforcing FP over HDR.

Reorienting health systems towards Primary Health Care in South Asia.

This series, "Primary health care in South Asia", is an effort to provide region-specific, evidence-based insights for reorienting health systems towards PHC. Led by regional thinkers, this series draws lessons from five countries in South Asia: Bangladesh, India, Nepal, Pakistan, and Sri Lanka. This is the last paper in the series that outlines points for future action. We call for action in three areas. First, the changing context in the region, with respect to epidemiological shifts, urbanisation, and privatisation, presents an important opportunity to appraise existing policies on PHC and reformulate them to meet the evolving needs of communities. Second, reorienting health systems towards PHC requires concrete efforts on three pillars-integrated services, multi-sectoral collaboration, and community empowerment. This paper collates nine action points that cut across these three pillars. These action points encompass contextualising policies on PHC, scaling up innovations, allocating adequate financial resources, strengthening the governance function of health ministries, establishing meaningful public-private engagements, using digital health tools, reorganising service delivery, enabling effective change-management processes, and encouraging practice-oriented research. Finally, we call for more research-policy-practice networks on PHC in South Asia that can generate evidence, bolster advocacy, and provide spaces for cross-learning. Funding: WHO SEARO funded this paper. This source did not play any role in the design, analysis or preparation of the manuscript.

Bilateral Proximal Humerus Lesser Tuberosity Avulsions in an Adolescent Patient: A Case Report.

CASE: Fourteen-year-old boy presented with bilateral proximal humerus lesser tuberosity avulsions after swinging between 2 desks. Injuries were not visualized on radiographs but identified on magnetic resonance imaging. He underwent bilateral open reduction and internal fixation of the bony avulsions. Following repair, he returned to full activities, including sports, without limitations. CONCLUSION: Lesser tuberosity avulsions are rare injuries in the pediatric population that can be missed. Our case is a low energy noncontact mechanism resulting in bilateral injury, highlighting the importance of having a high index of suspicion for this diagnosis in adolescent patients with shoulder pain with normal radiographs.

Zero-crosstalk silicon photonic refractive index sensor with subwavelength gratings.

Silicon photonic index sensors have received significant attention for label-free bio and gas-sensing applications, offering cost-effective and scalable solutions. Here, we introduce an ultra-compact silicon photonic refractive index sensor that leverages zero-crosstalk singularity responses enabled by subwavelength gratings. The subwavelength gratings are precisely engineered to achieve an anisotropic perturbation-led zero-crosstalk, resulting in a single transmission dip singularity in the spectrum that is independent of device length. The sensor is optimized for the transverse magnetic mode operation, where the subwavelength gratings are arranged perpendicular to the propagation direction to support a leaky-like mode and maximize the evanescent field interaction with the analyte space. Experimental results demonstrate a high wavelength sensitivity of - 410 nm/RIU and an intensity sensitivity of 395 dB/RIU, with a compact device footprint of approximately 82.8 µm2. Distinct from other resonant and interferometric sensors, our approach provides an FSR-free single-dip spectral response on a small device footprint, overcoming common challenges faced by traditional sensors, such as signal/phase ambiguity, sensitivity fading, limited detection range, and the necessity for large device footprints. This makes our sensor ideal for simplified intensity interrogation. The proposed sensor holds promise for a range of on-chip refractive index sensing applications, from gas to biochemical detection, representing a significant step towards efficient and miniaturized photonic sensing solutions.