The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity.

The clinical success of PARP1/2 inhibitors (PARPi) prompts the expansion of their applicability beyond homologous recombination deficiency. Here, we demonstrate that the loss of the accessory subunits of DNA polymerase epsilon, POLE3 and POLE4, sensitizes cells to PARPi. We show that the sensitivity of POLE4 knockouts is not due to compromised response to DNA damage or homologous recombination deficiency. Instead, POLE4 loss affects replication speed leading to the accumulation of single-stranded DNA gaps behind replication forks upon PARPi treatment, due to impaired post-replicative repair. POLE4 knockouts elicit elevated replication stress signaling involving ATR and DNA-PK. We find POLE4 to act parallel to BRCA1 in inducing sensitivity to PARPi and counteracts acquired resistance associated with restoration of homologous recombination. Altogether, our findings establish POLE4 as a promising target to improve PARPi driven therapies and hamper acquired PARPi resistance.

Patterns and Drivers of Antifungal Prescribing in Acute Leukemia: A Retrospective Cohort Study.

Background: Patients with hematological malignancy are at high risk of invasive fungal infections (IFIs). Diagnosis is challenging, which can lead to overtreatment. Reducing exposure to inappropriate antifungal prescribing is likely to improve patient safety, but modifying prescribing behavior is difficult. We aimed to describe patterns and drivers of therapeutic antifungal prescribing in a large tertiary hemato-oncology center in the United Kingdom. Methods: We studied adults receiving treatment for acute leukemia at our center between 1 April 2019 and 14 October 2022. We developed a reproducible method to analyze routinely collected data on antifungal therapy episodes in a widely used electronic health record system. We report antifungal use in days of therapy stratified by level of diagnostic confidence, as defined by consensus diagnostic guidelines (European Organisation for Research and Treatment of Cancer/Mycoses Study Group). Results: Two hundred ninety-eight patients were included in the analysis; 21.7% of inpatient antifungal use occurred in cases of proven/probable IFI. Substantial antifungal use occurred in the absence of strong evidence of infection in patients receiving high-intensity first-line chemotherapy or approaching death (81.0% and 77.9%, respectively). Approximately 33% of high-resolution computed tomography (HRCT) reports were indeterminate for IFI. Indeterminate reports were around 8 times more likely to be followed by a new antifungal therapy episode than a negative report. Conclusions: Antifungal stewardship remains challenging in the absence of reliable diagnostics, particularly in more unwell patients. The proportion of antifungal therapy given for proven/probable infection is a new metric that will likely be useful to target antifungal stewardship programs. The thoracic HRCT report is an important contributor to diagnostic uncertainty.

Meniscal Transplant surgery or Optimised Rehabilitation full randomised trial (MeTeOR2): a study protocol.

INTRODUCTION: Pain and disability after meniscectomy can be a substantial lifelong problem. There are few treatment options, especially for young people. Non-surgical management (rehabilitation) is an option but increasingly surgeons are performing meniscal allograft transplants (MATs) for these individuals. However, this is still an uncommon procedure, and availability and usage of MAT vary widely both in the UK and internationally. It is not known which treatment option is the most effective and cost-effective. METHODS AND ANALYSIS: The Meniscal Transplant surgery or Optimised Rehabilitation trial is an international, multicentre, randomised controlled trial. The aim is to compare the clinical and cost effectiveness of MAT versus an optimised package of individualised, progressive, rehabilitation that we have called personalised knee therapy (PKT).Participants will be recruited from sites across the UK, Australia, Canada and Belgium. The planned 144 participants provide at least 90% power to detect a 10-point difference in the Knee injury and Osteoarthritis Outcome Score (KOOS4) at 24-months post randomisation (primary outcome). A prospectively planned economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including health utility, occupational status, sports participation, mental well-being, further treatment, and adverse events will be collected at 3, 6, 12, 18, and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement. ETHICS AND DISSEMINATION: The trial was approved by the London-Bloomsbury Research Ethics Committee on 19 August 2022 (22/LO/0327) and Northern Sydney Local Health District Human Research Ethics Committee, NSW, Australia on the 13 March 2023 (2022/ETH01890).Trial results will be disseminated via peer-reviewed publications, presentations at international conferences, in lay summaries and using social media as appropriate.This protocol adheres to the recommended Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. TRIAL REGISTRATION NUMBER: ISRCTN87336549.

Effect of 20 mph speed limits on traffic injuries in Edinburgh, UK: a natural experiment and modelling study.

INTRODUCTION: There is limited research evaluating 20 mph speed limit interventions, and long-term assessments are seldom conducted either globally or within the UK. This study evaluated the impact of the phased 20 mph speed limit implementation on road traffic collisions and casualties in the City of Edinburgh, UK over approximately 3 years post implementation. METHODS: We used four sets of complementary analyses for collision and casualty rates. First, we compared rates for road segments changing to 20 mph against those at 30 mph. Second, we compared rates for the seven implementation zones in the city against paired control zones. Third, we investigated citywide casualty rate trends using generalised additive model. Finally, we used simulation modelling to predict casualty rate changes based on changes in observed speeds. RESULTS: We found a 10% (95% CI -19% to 0%) greater reduction in casualties (8% for collisions) for streets that changed to 20 mph compared with those staying at 30 mph. However, the reduction was similar, 8% (95% CI -22% to 5%) for casualties (10% collisions), in streets that were already at 20 mph. In the implementation zones, we found a 20% (95% CI -22% to -8%) citywide reduction in casualties (22% for collisions) compared with control zones; this compared with a predicted 10% (95% CI -18% to -2%) reduction in injuries based on the changes in speed and traffic volume. Citywide casualties dropped 17% (95% CI 13% to 22%) 3 years post implementation, accounting for trend. CONCLUSION: Our results indicate that the introduction of 20 mph limits resulted in a reduction in collisions and casualties 3 years post implementation. However, the effect exceeded expectations from changes in speed alone, possibly due to a wider network effect.

Identification of Human-Generated vs AI-Generated Research Abstracts by Health Care Professionals.

This survey study assesses the ability of health care professionals to discern whether abstracts were written by investigators or by an artificial intelligence (AI) chatbot.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

A systematic review of artificial intelligence tools for chronic pulmonary embolism on CT pulmonary angiography.

Background: Chronic pulmonary embolism (PE) may result in pulmonary hypertension (CTEPH). Automated CT pulmonary angiography (CTPA) interpretation using artificial intelligence (AI) tools has the potential for improving diagnostic accuracy, reducing delays to diagnosis and yielding novel information of clinical value in CTEPH. This systematic review aimed to identify and appraise existing studies presenting AI tools for CTPA in the context of chronic PE and CTEPH. Methods: MEDLINE and EMBASE databases were searched on 11 September 2023. Journal publications presenting AI tools for CTPA in patients with chronic PE or CTEPH were eligible for inclusion. Information about model design, training and testing was extracted. Study quality was assessed using compliance with the Checklist for Artificial Intelligence in Medical Imaging (CLAIM). Results: Five studies were eligible for inclusion, all of which presented deep learning AI models to evaluate PE. First study evaluated the lung parenchymal changes in chronic PE and two studies used an AI model to classify PE, with none directly assessing the pulmonary arteries. In addition, a separate study developed a CNN tool to distinguish chronic PE using 2D maximum intensity projection reconstructions. While another study assessed a novel automated approach to quantify hypoperfusion to help in the severity assessment of CTEPH. While descriptions of model design and training were reliable, descriptions of the datasets used in training and testing were more inconsistent. Conclusion: In contrast to AI tools for evaluation of acute PE, there has been limited investigation of AI-based approaches to characterising chronic PE and CTEPH on CTPA. Existing studies are limited by inconsistent reporting of the data used to train and test their models. This systematic review highlights an area of potential expansion for the field of AI in medical image interpretation.There is limited knowledge of A systematic review of artificial intelligence tools for chronic pulmonary embolism in CT. This systematic review provides an assessment on research that examined deep learning algorithms in detecting CTEPH on CTPA images, the number of studies assessing the utility of deep learning on CTPA in CTEPH was unclear and should be highlighted.

Tumor-Tailored Ionizable Lipid Nanoparticles Facilitate IL-12 Circular RNA Delivery for Enhanced Lung Cancer Immunotherapy.

The advancement of message RNA (mRNA) -based immunotherapies for cancer is highly dependent on the effective delivery of RNA (Ribonucleic) payloads using ionizable lipid nanoparticles (LNPs). However, the clinical application of these therapies is hindered by variable mRNA expression among different cancer types and the risk of systemic toxicity. The transient expression profile of mRNA further complicates this issue, necessitating frequent dosing and thus increasing the potential for adverse effects. Addressing these challenges, a high-throughput combinatorial method is utilized to synthesize and screen LNPs that efficiently deliver circular RNA (circRNA) to lung tumors. The lead LNP, H1L1A1B3, demonstrates a fourfold increase in circRNA transfection efficiency in lung cancer cells over ALC-0315, the industry-standard LNPs, while providing potent immune activation. A single intratumoral injection of H1L1A1B3 LNPs, loaded with circRNA encoding interleukin-12 (IL-12), induces a robust immune response in a Lewis lung carcinoma model, leading to marked tumor regression. Immunological profiling of treated tumors reveals substantial increments in CD45+ leukocytes and enhances infiltration of CD8+ T cells, underscoring the ability of H1L1A1B3 LNPs to modulate the tumor microenvironment favorably. These results highlight the potential of tailored LNP platforms to advance RNA drug delivery for cancer therapy, broadening the prospects for RNA immunotherapeutics.

Validating the knowledge represented by a self-organizing map with an expert-derived knowledge structure.

BACKGROUND: Professionals are reluctant to make use of machine learning results for tasks like curriculum development if they do not understand how the results were generated and what they mean. Visualizations of peer reviewed medical literature can summarize enormous amounts of information but are difficult to interpret. This article reports the validation of the meaning of a self-organizing map derived from the Medline/PubMed index of peer reviewed medical literature by its capacity to coherently summarize the references of a core psychiatric textbook. METHODS: Reference lists from ten editions of Kaplan and Sadock's Comprehensive Textbook of Psychiatry were projected onto a self-organizing map trained on Medical Subject Headings annotating the complete set of peer reviewed medical research articles indexed in the Medline/PubMed database (MedSOM). K-means clustering was applied to references from every edition to examine the ability of the self-organizing map to coherently summarize the knowledge contained within the textbook. RESULTS: MedSOM coherently clustered references into six psychiatric knowledge domains across ten editions (1967-2017). Clustering occurred at the abstract level of broad psychiatric practice including General/adult psychiatry, Child psychiatry, and Administrative psychiatry. CONCLUSIONS: The uptake of visualizations of published medical literature by medical experts for purposes like curriculum development depends upon validation of the meaning of the visualizations. The current research demonstrates that a self-organizing map (MedSOM) can validate the stability and coherence of the references used to support the knowledge claims of a standard psychiatric textbook, linking the products of machine learning to a widely accepted standard of knowledge.

Rapidly expanding gender-affirming care based on consensus instead of evidence justifies rigorous governance and transparency.

OBJECTIVE: Public services offering gender-affirming care to minors have rapidly expanded across Australia. Despite limited evidence of safety and efficacy, no public information about these services is routinely available. Data from freedom of information requests sent to Australian public gender services for minors is summarised. Gender service numbers increased rapidly in Queensland (2017:190 - 2022:922) and in Victoria (2019:472 - 2023:1290). Limited transparency prevented strong confidence in the number of patients receiving hormone therapy. Staff FTE employed by gender services jumped after 2020 in NSW (to 16.7 across two sites in 2023), Queensland (to 11.4 in 2023), Victoria (to 9.4 in 2022), and WA (to 10.2 in 2023). CONCLUSIONS: Despite low confidence in their safety and efficacy, the number of patients seen by public gender services has expanded rapidly since 2018. Limited transparency makes it difficult to judge the number of patients seen, treatments provided, and outcomes achieved. Safe, effective care of this vulnerable group requires clear treatment goals, and annual reporting.

Is convenience really king? Comparative evaluation of catastrophic costs due to tuberculosis in the public and private healthcare sectors of Viet Nam: a longitudinal patient cost study.

BACKGROUND: In Viet Nam, tuberculosis (TB) represents a devastating life-event with an exorbitant price tag, partly due to lost income from daily directly observed therapy in public sector care. Thus, persons with TB may seek care in the private sector for its flexibility, convenience, and privacy. Our study aimed to measure income changes, costs and catastrophic cost incurrence among TB-affected households in the public and private sector. METHODS: Between October 2020 and March 2022, we conducted 110 longitudinal patient cost interviews, among 50 patients privately treated for TB and 60 TB patients treated by the National TB Program (NTP) in Ha Noi, Hai Phong and Ho Chi Minh City, Viet Nam. Using a local adaptation of the WHO TB patient cost survey tool, participants were interviewed during the intensive phase, continuation phase and post-treatment. We compared income levels, direct and indirect treatment costs, catastrophic costs using Wilcoxon rank-sum and chi-squared tests and associated risk factors between the two cohorts using multivariate regression. RESULTS: The pre-treatment median monthly household income was significantly higher in the private sector versus NTP cohort (USD 868 vs USD 578; P = 0.010). However, private sector treatment was also significantly costlier (USD 2075 vs USD 1313; P = 0.005), driven by direct medical costs which were 4.6 times higher than costs reported by NTP participants (USD 754 vs USD 164; P < 0.001). This resulted in no significant difference in catastrophic costs between the two cohorts (Private: 55% vs NTP: 52%; P = 0.675). Factors associated with catastrophic cost included being a single-person household [adjusted odds ratio (aOR = 13.71; 95% confidence interval (CI): 1.36-138.14; P = 0.026], unemployment during treatment (aOR = 10.86; 95% CI: 2.64-44.60; P < 0.001) and experiencing TB-related stigma (aOR = 37.90; 95% CI: 1.72-831.73; P = 0.021). CONCLUSIONS: Persons with TB in Viet Nam face similarly high risk of catastrophic costs whether treated in the public or private sector. Patient costs could be reduced through expanded insurance reimbursement to minimize direct medical costs in the private sector, use of remote monitoring and multi-week/month dosing strategies to avert economic costs in the public sector and greater access to social protection mechanism in general.

Loss of 15-Lipoxygenase in Retinodegenerative RCS Rats.

Retinitis pigmentosa (RP) is a retinal degenerative disease associated with a diversity of genetic mutations. In a natural progression study (NPS) evaluating the molecular changes in Royal College of Surgeons (RCS) rats using lipidomic profiling, RNA sequencing, and gene expression analyses, changes associated with retinal degeneration from p21 to p60 were evaluated, where reductions in retinal ALOX15 expression corresponded with disease progression. This important enzyme catalyzes the formation of specialized pro-resolving mediators (SPMs) such as lipoxins (LXs), resolvins (RvDs), and docosapentaenoic acid resolvins (DPA RvDs), where reduced ALOX15 corresponded with reduced SPMs. Retinal DPA RvD2 levels were found to correlate with retinal structural and functional decline. Retinal RNA sequencing comparing p21 with p60 showed an upregulation of microglial inflammatory pathways accompanied by impaired damage-associated molecular pattern (DAMP) clearance pathways. This analysis suggests that ALXR/FPR2 activation can ameliorate disease progression, which was supported by treatment with an LXA4 analog, NAP1051, which was able to promote the upregulation of ALOX12 and ALOX15. This study showed that retinal inflammation from activated microglia and dysregulation of lipid metabolism were central to the pathogenesis of retinal degeneration in RP, where ALXR/FPR2 activation was able to preserve retinal structure and function.

Advancements in cardiac structures segmentation: a comprehensive systematic review of deep learning in CT imaging.

Background: Segmentation of cardiac structures is an important step in evaluation of the heart on imaging. There has been growing interest in how artificial intelligence (AI) methods-particularly deep learning (DL)-can be used to automate this process. Existing AI approaches to cardiac segmentation have mostly focused on cardiac MRI. This systematic review aimed to appraise the performance and quality of supervised DL tools for the segmentation of cardiac structures on CT. Methods: Embase and Medline databases were searched to identify related studies from January 1, 2013 to December 4, 2023. Original research studies published in peer-reviewed journals after January 1, 2013 were eligible for inclusion if they presented supervised DL-based tools for the segmentation of cardiac structures and non-coronary great vessels on CT. The data extracted from eligible studies included information about cardiac structure(s) being segmented, study location, DL architectures and reported performance metrics such as the Dice similarity coefficient (DSC). The quality of the included studies was assessed using the Checklist for Artificial Intelligence in Medical Imaging (CLAIM). Results: 18 studies published after 2020 were included. The DSC scores median achieved for the most commonly segmented structures were left atrium (0.88, IQR 0.83-0.91), left ventricle (0.91, IQR 0.89-0.94), left ventricle myocardium (0.83, IQR 0.82-0.92), right atrium (0.88, IQR 0.83-0.90), right ventricle (0.91, IQR 0.85-0.92), and pulmonary artery (0.92, IQR 0.87-0.93). Compliance of studies with CLAIM was variable. In particular, only 58% of studies showed compliance with dataset description criteria and most of the studies did not test or validate their models on external data (81%). Conclusion: Supervised DL has been applied to the segmentation of various cardiac structures on CT. Most showed similar performance as measured by DSC values. Existing studies have been limited by the size and nature of the training datasets, inconsistent descriptions of ground truth annotations and lack of testing in external data or clinical settings. Systematic Review Registration: [www.crd.york.ac.uk/prospero/], PROSPERO [CRD42023431113].

Short-term and medium-term clinical outcomes of multisystem inflammatory syndrome in children: a prospective observational cohort study.

BACKGROUND: Even though the incidence of Multisystem Inflammatory Syndrome in children (MIS-C) is decreasing cases are still reported across the world. Studying the consequences of MIS-C enhances our understanding of the disease's prognosis. The objective of this study was to assess short- and medium-term clinical outcomes of MIS-C. METHODS: Prospective observational cohort study at Municipal Children's Hospital Morozovskaya, Moscow, Russia. All children meeting the Royal College of Paediatrics and Child Health (RCPCH), Centers for Disease Control and Prevention (CDC), or the World Health Organization (WHO) MIS-C case definition admitted to the hospital between 17 May and 26 October 2020 were included in the study. All survivors were invited to attend a clinic at 2 and 6 weeks after hospital discharge. RESULTS: 37 children median age 6 years (interquartile range [IQR] 3.3-9.4), 59.5% (22/37) boys were included in the study. 48.6% (18/37) of patients required ICU care. One child died. All children had increased levels of systemic inflammatory markers during the acute event. Echocardiographic investigations identified abnormal findings in 35.1% (13/37) of children. 5.6% (2/36) of children were presenting with any symptoms six weeks after discharge. By six weeks the inflammatory markers were within the reference norms in all children. The echocardiographic evaluation showed persistent coronary dilatation in one child. CONCLUSIONS: Despite the severity of their acute MIS-C, the majority of children in our cohort fully recovered with none having elevated laboratory markers of inflammation at 6 weeks, few (< 10%) reporting persistent symptoms at 6 weeks, and only one with persistent echocardiographic abnormalities.

Ensuring Continuity of Tuberculosis Care during Social Distancing through Integrated Active Case Finding at COVID-19 Vaccination Events in Vietnam: A Cohort Study.

COVID-19 significantly disrupted tuberculosis (TB) services in Vietnam. In response, the National TB Program (NTP) integrated TB screening using mobile chest X-rays into COVID-19 vaccination events. This prospective cohort study evaluated the integrated model's yield, treatment outcomes, and costs. We further fitted regressions to identify risk factors and conduct interrupted time-series analyses in the study area, Vietnam's eight economic regions, and at the national level. At 115 events, we conducted 48,758 X-ray screens and detected 174 individuals with TB. We linked 89.7% to care, while 92.9% successfully completed treatment. The mean costs per person diagnosed with TB was $547. TB risk factors included male sex (aOR = 6.44, p < 0.001), age of 45-59 years (aOR = 1.81, p = 0.006) and ≥60 years (aOR = 1.99, p = 0.002), a history of TB (aOR = 7.96, p < 0.001), prior exposure to TB (aOR = 3.90, p = 0.001), and symptomatic presentation (aOR = 2.75, p < 0.001). There was a significant decline in TB notifications during the Delta wave and significant increases immediately after lockdowns were lifted (IRR(γ1) = 5.00; 95%CI: (2.86, 8.73); p < 0.001) with a continuous upward trend thereafter (IRR(γ2) = 1.39; 95%CI: (1.22, 1.38); p < 0.001). Similar patterns were observed at the national level and in all regions but the northeast region. The NTP's swift actions and policy decisions ensured continuity of care and led to the rapid recovery of TB notifications, which may serve as blueprint for future pandemics.

Postoperative Outcomes of Intracapsular Tonsillectomy With Coblation: A Systematic Review and Meta-Analysis.

OBJECTIVE: Following tonsillectomy, postoperative pain and hemorrhage from the tonsillar bed are causes of significant morbidity. Intracapsular tonsillectomy with Coblation is suggested to minimize such morbidity while remaining efficacious in long-term outcomes. This systematic review and meta-analysis assessed short-term morbidity and long-term outcomes from intracapsular tonsillectomy with Coblation, focusing primarily on posttonsillectomy hemorrhage. DATA SOURCES: Medline, Embase, and the Cochrane Library. REVIEW METHODS: Guided by PRISMA guidelines, studies on intracapsular tonsillectomy with Coblation published between December 2002 and July 2022 evaluating frequency of posttonsillectomy hemorrhage were screened. Studies without primary data were excluded. Meta-analysis was conducted using the random-effect model. The primary outcome was the proportion of patients who experienced posttonsillectomy hemorrhage. The secondary outcomes were posttonsillectomy pain, the proportion requiring revision tonsillectomy, and severity of sleep-disordered breathing measured by polysomnography outcomes. RESULTS: From 14 studies there were 9821 patients. The proportion of total posttonsillectomy hemorrhage was 1.0% (95% confidence interval [CI] 0.5%-1.6%, n = 9821). The proportion experiencing primary hemorrhage, secondary hemorrhage, and those requiring further tonsil surgery were 0.1% (95% CI 0.0%-0.1%; study n = 7), 0.8% (95% CI 0.2%-1.4%; study n = 7), and 1.4% (95% CI 0.6%-2.2%; study n = 6), respectively. Mean reduction in apnea-hypopnea index was -16.0 events per hour (95% CI -8.8 to -23.3, study n = 3) and mean increase in oxygen nadir was 5.9% (95% CI 2.6%-9.1%, study n = 3). CONCLUSION: Intracapsular tonsillectomy with Coblation has been demonstrated to have a low rate of posttonsillectomy hemorrhage. Data regarding long-term tonsil regrowth and need for reoperation were encouraging of the efficacy of this technique.

Combinatorial design of ionizable lipid nanoparticles for muscle-selective mRNA delivery with minimized off-target effects.

Ionizable lipid nanoparticles (LNPs) pivotal to the success of COVID-19 mRNA (messenger RNA) vaccines hold substantial promise for expanding the landscape of mRNA-based therapies. Nevertheless, the risk of mRNA delivery to off-target tissues highlights the necessity for LNPs with enhanced tissue selectivity. The intricate nature of biological systems and inadequate knowledge of lipid structure-activity relationships emphasize the significance of high-throughput methods to produce chemically diverse lipid libraries for mRNA delivery screening. Here, we introduce a streamlined approach for the rapid design and synthesis of combinatorial libraries of biodegradable ionizable lipids. This led to the identification of iso-A11B5C1, an ionizable lipid uniquely apt for muscle-specific mRNA delivery. It manifested high transfection efficiencies in muscle tissues, while significantly diminishing off-targeting in organs like the liver and spleen. Moreover, iso-A11B5C1 also exhibited reduced mRNA transfection potency in lymph nodes and antigen-presenting cells, prompting investigation into the influence of direct immune cell transfection via LNPs on mRNA vaccine effectiveness. In comparison with SM-102, while iso-A11B5C1's limited immune transfection attenuated its ability to elicit humoral immunity, it remained highly effective in triggering cellular immune responses after intramuscular administration, which is further corroborated by its strong therapeutic performance as cancer vaccine in a melanoma model. Collectively, our study not only enriches the high-throughput toolkit for generating tissue-specific ionizable lipids but also encourages a reassessment of prevailing paradigms in mRNA vaccine design. This study encourages rethinking of mRNA vaccine design principles, suggesting that achieving high immune cell transfection might not be the sole criterion for developing effective mRNA vaccines.