Fertility preservation of boys undergoing cancer treatment remains an important clinical consideration given the risk of long-term infertility. Spermatogonial stem cells, essential for spermatogenesis during adulthood, are sensitive to gonadotoxic chemotherapy. Current fertility preservation strategies include testicular tissue cryopreservation before treatment for future use to restore fertility; however, approaches to protect spermatogonia from chemotherapy-induced damage remain limited. In the UK, every day about five children receive a diagnosis of cancer. Although the majority (over 80%) will survive, some will become infertile depending on the severity of the treatment received during childhood. Currently, there are no medical treatments available to protect male fertility. This study assessed if rapamycin, a drug currently used to treat other medical conditions, that has been shown in experimental studies to help protect female fertility from cancer treatment, could be used to protect male fertility. Results showed that rapamycin did not prevent overall loss and damage of the cells that will develop into sperm. Further studies are needed to find medical strategies to preserve young boys' fertility.
Mutations in the Na+/HCO3- cotransporter NBCe1 (SLC4A4) cause proximal renal tubular acidosis (pRTA) and extrarenal symptoms including glaucoma, band kelatopathy, migraine, growth disorder, and abnormal tooth enamel. From NCBI dbSNP database, we recently identified a previously uncharacterized single nucleotide variant (SNV) R881S in NBCe1, located in hydrophilic helix 4. R881S NBCe1-A showed intracellular retention in human embryonic kidney 293 cells and its plasma membrane expression was profoundly reduced in polarized Madin-Darby canine kidney cells. Unlike WT and R881C NBCe1-A (which causes pRTA), Western blot analysis demonstrated that the R881S NBCe1-A showed a single, low-molecular-weight signal at above 100kDa. Deglycosylation study showed that R881S NBCe1-A was scarcely deglycosylated by PNGase F. Coimmunoprecipitation study demonstrated that wild-type and R881S NBCe1-A did not form heterodimer. Moreover, functional analysis using Xenopus oocytes revealed that the R881S variant had markedly reduced transport activity compared with wild-type NBCe1-A. Thus, R881S NBCe1-A shows no detectable transport activity, likely due to defective trafficking and reduced glycosylation. In contrast to the R881C mutant, however, R881S NBCe1-A fails to form dimers with wild-type NBCe1-A, suggesting the absence of a dominant-negative effect and underscoring the need for functional characterization of reported genetic variants.
Pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge characterized by an alarmingly low survival rate. Despite surgical advances and new chemotherapy combinations, currently available treatment fails to improve the overall survival of PDAC patients largely due to an immunosuppressive tumor microenvironment. Radiation can induce cell death and reprogramme the tumor microenvironment by promoting anti-tumor immune response. The cGAS-STING and RIG-I-MAVS pathways are central components of the innate immune system that detect cytosolic nucleic acids and initiate type I interferon production. This study aims to leverage radiation-induced DNA damage together with inhibition of DNA repair and cell cycle checkpoints to potentiate type I interferon response and thereby enhance anti-tumor immunogenicity in PDAC. Two different PDAC cell lines (KRAS wild-type BxPC-3 and KRAS-mutated PANC-1) were used to test two different radiation modalities (X-rays and carbon ions) and regimens (single and hypofractionated dose) in combination with ATR and CHK1 inhibitors as well as the STING agonist diABZI. Cell survival, immunogenic cell death, accumulation of cytosolic dsDNA and micronuclei, gene expression profiles, and STING- and NF-κB-dependent immune signaling were assessed. Immune activation was evaluated by incubating immune cells with supernatants from PDAC cells, followed by analysis of activation markers using spectral flow cytometry. Here we demonstrate that ATR inhibition sensitizes BxPC-3 cells to the cytotoxic effects of radiation and potentiates the immunogenic effects of carbon ions and hypofractionated X-rays (3x8 Gy). Increased accumulation of cytosolic dsDNA and micronuclei was coupled with STING-dependent IFNB1 secretion and genome-wide induction of inflammatory gene expression programs, ultimately resulting in the activation of monocytes. This was not the case for PANC-1 cells, where radiation alone exerted immunosuppressive effects on monocytes. Our results support further evaluation of ATR inhibition in combination with radiotherapy in KRAS wild-type pancreatic cancer.
Conventional culture methods for tuberculosis diagnosis miss differentially culturable tubercle bacteria (DCTB), which grow only in liquid assays supplemented with growth-enhancing factors. This limitation, combined with inadequate contact tracing and screening, often fails to identify asymptomatic individuals, with live bacilli detectable by enhanced culture methods. This shortfall results in undiagnosed reservoirs of bacteria, potentially fuelling ongoing transmission. In this study, we aimed to investigate whether DCTB assays provide greater sensitivity by detecting more Mycobacterium tuberculosis infections than conventional culture and whether this enhanced detection improves the resolution of intrahousehold transmission mapping. In addition, we sought to evaluate whether DCTB populations can progress to conventional culture positivity, thereby highlighting their clinical and epidemiological relevance. In this prospective observational longitudinal cohort study, drug-susceptible or rifampicin-resistant tuberculosis index participants aged 12 years or older, were recruited from primary healthcare clinics from two South African districts. Inclusion criteria were informed consent, Xpert MTB/RIF Ultra-positive results, tuberculosis symptoms (>2 weeks), provision of baseline samples, at least one consenting household contact, and documented HIV status. Household contacts of the index patients and control households were also recruited. Sputum specimens were collected at baseline and 2, 4, 8, 12, and 16 months from the index participants and household contacts. Samples were analysed by conventional mycobacterial growth indicator tube (MGIT) culture, and colony-forming unit assays to identify viable bacteria. Enhanced culture to detect DCTB involved serial dilution of sputum in liquid culture, supplemented with M tuberculosis culture filtrate as a source of growth stimulatory factors. Whole-genome sequencing (WGS) of cultured isolates was performed to trace household transmission. Between June 1, 2020, and Feb 6, 2024, 293 index participants (183 [62%] male), 701 household contacts (453 [65%] female), and 122 control participants (67 [55%] female) were enrolled. At baseline, 249 (85%) of 293 index participants and 110 (16%) of 701 household contact sputum samples were positive for M tuberculosis by MGIT conventional culture. For baseline MGIT-negative specimens, DCTB assays detected M tuberculosis in an additional 21 (7%) of 293 index participants and 26 (4%) of 701 household contacts. Over 16 months of follow-up, DCTB assays identified 61 (8·7%) of 701 additional tuberculosis-positive household contacts not detected by conventional culture. WGS-guided transmission mapping using conventional culture identified transmission in 16 (15%) of 104 households, whereas DCTB assays detected an additional 19 (18%) of 104 transmission events. No evidence of intrahousehold transmission was found in the remaining 69 (66%) of 104 tuberculosis-positive households. Over the 16-month follow-up period, conventional culture identified 233 positive household contacts, of which 195 (84%) were asymptomatic. DCTB assays detected an additional 94 cases of M tuberculosis positivity in household contacts, of which 79 (84%) were asymptomatic. In control households, tuberculosis prevalence at baseline was two (2%) of 122, with an additional three (3%) of 122 identified during follow-up. DCTB assays provide substantial value by detecting asymptomatic individuals missed by conventional culture, revealing a potentially important reservoir of subclinical infection, which could sustain transmission. In addition, DCTB detection uncovers transmission linkages missed by conventional culture, providing a more comprehensive understanding of M tuberculosis transmission dynamics and highlighting the need to incorporate enhanced culture methods into diagnostic and surveillance strategies, to strengthen early case identification and tuberculosis control efforts. National Institutes of Health.
Lumbar disc herniation (LDH) is a major cause of low back pain and may require surgical intervention when conservative or non-surgical treatment fails. In Korea, herbal medicine is commonly used as part of non-surgical care; however, its long-term effect on the risk of lumbar surgery has been difficult to assess because herbal decoctions have historically not been recorded in national insurance claims data. We conducted a retrospective cohort study by linking electronic health records (EHRs) from four Korean medical hospitals with National Health Insurance claims data. Patients newly diagnosed with LDH (ICD-10 M51) between 2016 and 2017 were included. The index date was defined as 1 year after the first hospital visit, and patients were followed until 31 July 2021. Exposure was defined as receiving herbal decoction for ≥30 days versus <30 days during the 1-year period between the entry date and index date. Patients with red-flag conditions or those who underwent lumbar surgery before the index date were excluded from the study. Propensity score matching (1:1) was performed using age, sex, insurance type, Charlson Comorbidity Index, and baseline leg pain numeric rating scale. Lumbar surgery was identified using procedure codes for discectomy, laminectomy, or spinal fusion. Kaplan-Meier analysis and Cox proportional hazards models were used to estimate the association between herbal decoction use and surgery. Among 6,669 eligible patients, 2,504 received herbal decoction for ≥30 days. After propensity score matching, 2,473 patients remained in each group, with good balance across baseline covariates (standardized mean differences <0.1). The ≥30-day group showed a significantly lower cumulative incidence of lumbar surgery compared with the <30-day group (2.63% vs. 3.64%; log-rank p = 0.033). Across sequential Cox regression models, longer herbal decoction use was consistently associated with a reduced risk of lumbar surgery, hazard ratio (HR) 0.71 (95% CI 0.51-0.97). In this real-world study linking EHR and claims data, herbal decoction use for ≥30 days was associated with a lower risk of subsequent lumbar spine surgery in patients with LDH. These findings suggest that herbal medicine may be an effective non-surgical treatment option and warrant confirmation in prospective and randomized studies.
Antimicrobial resistance (AMR) is a major global challenge to human and animal health. The genomic element (e.g. chromosome, plasmid, and genomic islands) and neighbouring genes associated with an AMR gene play a major role in its function, regulation, evolution, and propensity to undergo lateral gene transfer. Therefore, characterizing these genomic contexts is vital for effective AMR surveillance, risk assessment, and stewardship. Metagenomic sequencing is widely used to identify AMR genes in microbial communities but fragmentary short-read data do not directly provide this critical contextual information. Assembly of these reads provides some contextual information but fails to recover many mobile genetic elements. Here, we introduce Sarand, a method retaining some of the sensitivity of read-based methods while providing the genomic context of assembly by extracting AMR genes and their associated context directly from metagenomic assembly graphs. Sarand uses BLAST-based homology searches with coverage statistics to identify and visualize AMR gene contexts while filtering false chimeric contexts. Using both real and simulated metagenomic data, we show that Sarand outperforms metagenomic assembly and other recently developed graph-based tools in terms of precision and sensitivity for this problem. Sarand enables effective extraction of metagenomic AMR gene contexts to better characterize AMR evolutionary dynamics within complex microbial communities.
Abdominal aortic aneurysm (AAA) rupture is a life-threatening event, yet current rupture risk assessment based on aneurysm size and growth rate fails to fully predict outcomes. Intraluminal thrombus (ILT), present in most AAAs, may influence wall mechanics and rupture potential, but the relationship between its microstructure and mechanical behavior remains poorly understood. This study first analysed the human ILT morphology using synchrotron radiation-based phase-contrast micro-computed tomography (SR-PhC-μCT). Then for the first time stress-relaxation compression was applied in-situ to ILT, enabling high-resolution visualization of fibrin fibers and pores under mechanical load. Phase-contrast imaging revealed layer-specific differences observed by histology, and also allowed quantification of the 3D microstructure of ILTs, such as porosity, pore diameters and pore interconnections. As previously observed, ILTs exhibited non-linear viscoelastic behavior with stiffer responses in samples containing both luminal and medial layers. Our results suggest that compression causes pore collapse and fibrin fiber compaction, densifying the microstructure (porosity decreases by up to 40%), and increasing Young's modulus (by up to threefold) and secant modulus. The interlaced fiber network limits structural relaxation. Our findings provide insight into how mechanical loading could alter the microstructure of the ILT and offer a framework for studying the interactions between structure and mechanics in AAA progression. Statement of Significance: Abdominal aortic aneurysms (AAAs) are associated with high risk of rupture, a leading cause of mortality. Understanding how intraluminal thrombus (ILT) structure responds to mechanical loading is important to explore its potential role in aneurysm progression and wall weakening. We combined synchrotron phase-contrast micro-computed tomography with in-situ mechanical compression to investigate how ILT microstructure-including fibrin fibers and pores-reorganizes under strain and how these changes relate to mechanical behavior in a limited number of human samples. This methodology provides a novel framework for studying the interplay between ILT microstructure, mechanical behavior, and AAA pathology, potentially informing improved rupture risk assessment through initial insight into factors that could contribute to hypoxia related weakening, while not intended to establish general mechanisms or represent the full heterogeneity of ILT.
Yaacov, Levi, and Peled argue that AI-powered clinical trial matching has achieved near-expert technical accuracy yet fails to increase patient enrollment because the dominant bottleneck is systemic-involving logistics, workflow misalignment, and consent burden-not informational. They propose reframing AI's role from matching engine to trial facilitation system.
Umbilical remnant infections are common in neonatal foals and may involve one or more umbilical structures. Diagnosis relies on thorough clinical examination, ultrasonography, and hematologic evaluation. Standard care includes broad-spectrum antibiotics, with surgical resection if conservative therapy fails. Omphalophlebitis may extend to the liver, prompting consideration of umbilical vein marsupialization. Surgery is performed in dorsal recumbency with a fusiform incision around the umbilicus. The umbilical arteries and urachus are ligated and transected, with partial cystectomy when indicated, and the umbilical vein is mobilized cranially. Marsupialization is indicated when safe ligation and transection are not feasible, or when infection extends into the hepatic parenchyma. Cranial midline translocation incorporates the partially resected vein into the cranial celiotomy closure, limiting intra-abdominal contamination. However, this approach may predispose to surgical site infection and herniation, often necessitating a second surgery. In the right paramedian translocation technique, an additional paramedian incision is created for marsupialization; the stoma heals by second intention. Although this method carries a risk of contamination during exteriorization of the vein stump; protective, risk-mitigating strategies have been reported. Perioperative management includes broad-spectrum antibiotics, ideally guided by culture and sensitivity testing, along with wound care and, in some reports, flushing of the stoma. Prognosis is less favorable for foals requiring marsupialization-typically those with hepatic involvement-than for those undergoing simple omphalectomy, although favorable long-term survival has been reported. Despite limited and heterogeneous literature, umbilical vein marsupialization remains a viable surgical option in appropriately selected cases.
The intrinsic cardiac nervous system (ICNS), composed of sympathetic, parasympathetic, and sensory neurons embedded within the heart, plays a pivotal role in regulating cardiac electrophysiology and contractility. Functional imbalance within this network represents a central mechanism driving myocardial infarction, heart failure (HF), atrial fibrillation (AF), and hypertension. Despite decades of investigation, the precise pathophysiological basis of ICNS involvement in cardiovascular disease remains poorly understood. Traditional bulk RNA sequencing, which measures averaged gene expression across pooled cells, fails to capture the cellular heterogeneity of ICNS, particularly rare neuronal and glial subpopulations. Consequently, critical regulatory pathways have been obscured. Single-cell RNA sequencing (scRNA-seq) has overcome this limitation by enabling transcriptional profiling at single-cell resolution. This breakthrough has refined cellular taxonomy within the ICNS and revealed dynamic molecular networks that underlie heart-neural interactions. This review summarizes technological breakthroughs in single-cell isolation, lineage tracing, and spatial transcriptomics, and highlights key discoveries including the identification of cardiac nexus glia (CNG), arrhythmogenic neuron subtypes, and neuroimmune interactions in cardiovascular diseases. We also discuss existing methodological bottlenecks and current challenges in data integration, species translation, and clinical application, and future research goals that could bridge the gap between molecular insight and therapeutic application.
Viral suppressors of RNA silencing (VSRs) are crucial for viral infection. Here, we show that a wheat (Triticum aestivum) oligosaccharyltransferase (TaOST1B) is associated with resistance to Wheat yellow mosaic virus (WYMV). TaOST1B interacts with WYMV-encoded P1 and enhances the VSR function of P1 by N-glycosylating its asparagine residue at position 116. This increases intranuclear accumulation of P1 through interaction with the nuclear transport protein TaIMP-α2 and blocks the interaction between calmodulin (CaM3) and CaM-binding transcriptional activator (CaMTA3) to suppress RNA interference. Nevertheless, nonglycosylated P1 loses its VSR function and forms aggregates triggering endoplasmic reticulum (ER) stress and is subsequently degraded by the 26S proteasome. A natural variant of TaOST1B fails to bind P1 and regulate its N-glycosylation, which induces ER stress and proteasome-mediated degradation to attenuate WYMV infection. Our study identifies an oligosaccharyltransferases as being utilized by VSR to promote viral infection, offering insights into the arms race between plants and viruses.
The binary classification of pathogens as intracellular or extracellular fails to capture the complexity of infections in vivo. We propose the metapopulation infection biology framework, in which infections comprise spatially structured, interacting subpopulations. Drawing on Klebsiella pneumoniae and Cryptococcus neoformans, we discuss how this framework generates testable predictions and informs therapeutic strategies.
Purpose: Tertiary hyperparathyroidism is a frequent complication of end-stage kidney disease that may require parathyroidectomy when medical therapy fails. Recurrent hyperparathyroidism may occur after total parathyroidectomy with autotransplantation. This study assessed the safety, feasibility, and efficacy of percutaneous ultrasound-guided ablation for implanted parathyroid glands in patients with recurrent disease after total parathyroidectomy with autotransplantation. Materials and Methods: Eleven patients with recurrent hyperparathyroidism following total parathyroidectomy with autotransplantation who underwent percutaneous ultrasound-guided ablation were retrospectively reviewed. Pre- and post-procedure serum intact parathyroid hormone, calcium, phosphate, and alkaline phosphatase levels were extracted from electronic medical records and analyzed. Ablation modalities used in the study included radiofrequency ablation, microwave ablation, and cryoablation. Procedure-related complications were recorded. Patients were followed for 12 months with serial biomarker monitoring. Technical success was defined as ≥80% ablation of implanted parathyroid glands, and clinical success as meeting at least two of the following: (1) >50% intact parathyroid hormone reduction, (2) correction of hypercalcemia, (3) discontinuation of calcimimetic therapy. Results: Technical success was achieved in 10 of 11 (90.9%) patients; one patient had incomplete ablation due to proximity of the gland to the skin. Among technically successful cases, all (100%) achieved clinical success, showing marked decreases in intact parathyroid hormone, normalization of calcium and phosphate, and reduced calcimimetic use. Transient hypocalcemia occurred in six patients, five requiring intravenous calcium replacement. No long-term complications were observed. Conclusions: Percutaneous ultrasound-guided ablation of implanted parathyroid glands is a safe and effective option for managing recurrent hyperparathyroidism, offering a viable alternative to surgery.
Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic enteric infection of ruminants characterized by persistence in intestinal macrophages following invasion through Peyer's patches. Early studies established a predominantly cell-mediated immune response during early stages of infection, yet this fails to clear mucosal infection. Recent vaccine studies demonstrate partial, region-specific protection and induction of mucosal immune responses but also reveal marked differences in responses across intestinal regions. Correlates of protection are poorly defined and key knowledge gaps remain in defining the mechanisms underlying mucosal immunity to MAP in ruminants. In this mini review, we synthesize current knowledge of host immune responses to MAP and highlight research gaps from a mucosal immunology perspective that continue to impede vaccine development. Addressing these gaps is essential to advance vaccine research for Johne's disease.
Advanced gastroesophageal adenocarcinomas (GEAs) continue to represent an area in need of new drug development. Targeting human epidermal growth factor receptor-2 (HER2) in GEAs has been standard since 2010 and continues to be an area of further development. Trastuzumab became the first targeted agent approved for GEA. Added to front-line fluoropyrimidine plus platinum chemotherapy in HER2+ metastatic disease, trastuzumab improved survival. Pembrolizumab was approved in HER2 positive GEA for those PD-L1 positive with modest benefit. Since trastuzumab's approval, other anti-HER2 agents had limited impact until 2021 with the FDA approval of trastuzumab deruxtecan. Trastuzumab deruxtecan represents an option after trastuzumab-based therapy fails. Other agents are currently being investigated. With the abundance of anti-HER2 therapies in the investigative pipeline, understanding key resistance mechanisms seen in HER2+ GEA will be the path to success. Technology advancements to provide real time precision medicine are likely in the coming years. We hope these advancements can help combat and/ or understand some of the intratumoral heterogeneity, HER2 expression changes, and tumor microenvironment resistance pathways seen in HER2+ GEA.
Allergic asthma is characterized by chronic airway inflammation that fails to resolve efficiently. Defective efferocytosis and metabolic reprogramming of macrophages are crucial factors in allergic diseases. While PKM2 is known to participate in phagocytosis and metabolism, its specific role in modulating asthma remains unclear. To delineate the underlying mechanisms of PKM2 in allergic asthma. We generated myeloid cell-specific LysMcrePKM2fl/fl mice, with littermate PKM2fl/fl mice serving as controls, and challenged them with ovalbumin (OVA) extract to induce allergic airway inflammation. In vivo, we assessed airway hyperresponsiveness, pulmonary inflammation, Th2 cytokine levels, apoptosis, and efferocytosis-related receptor expression. Primary bone marrow-derived macrophages(BMDMs) were isolated for in vitro evaluation of efferocytic activity under distinct polarization conditions. To investigate underlying mechanisms, we performed RNA-seq to identify PKM2 downstream targets, followed by lentiviral-mediated overexpression of the candidate molecule SLC13A3 in THP-1 cells, with validation through molecular docking, immunoprecipitation, and functional assays. We found that PKM2 is upregulated in macrophages during asthma. Myeloid cell-specific PKM2 deficiency mitigated OVA-induced Th2 inflammation and eosinophilic apoptosis while reducing airway hyperresponsiveness (AHR). Mechanistically, PKM2-expressing macrophages exhibited decreased SLC13A3 transcription, which drove activation of the PI3K-AKT and redistributed STAT6/1 ratio to impair efferocytosis. This impairment disturbed the M2/M1 balance. In vitro experiments confirmed that SLC13A3 overexpression enhanced efferocytic capacity and promoted a shift toward M2/M1 balance. Conversely, PKM2 overexpression in macrophages impaired efferocytosis and exacerbated chronic airway inflammation. Our study reveals a novel role for myeloid cell-specific PKM2 and SLC13A3 in asthma, linking efferocytosis to immune metabolism during allergic inflammation.
One objective of the College of American Pathologists/American College of Medical Genetics Cytogenetics Committee is to ensure the accurate detection and clinical interpretation of abnormalities observed by fluorescence in situ hybridization (FISH) analysis when evaluating hematologic neoplasms. To report a 20-year performance summary (2005-2024) of FISH challenges focusing on hematologic neoplasms. A retrospective review was performed from 2005 through 2024 to identify FISH challenges specifically addressing hematologic neoplasms. The overall performance of participants was evaluated to identify potential recurring errors of clinical relevance. A total of 124 hematologic neoplasm FISH challenges from 2005 to 2024 were provided to participating laboratories, including 45 paper challenges (results and/or images were provided for interpretation purposes), 43 liquid challenges (bone marrow aspirate or peripheral blood), and 36 formalin-fixed paraffin-embedded (FFPE) tissue challenges. Of the 124 challenges, 120 (97%) exceeded the required 80% consensus for grading purposes. Of the 4 failed challenges (3%), 2 (1 liquid, 1 paper) involved the interpretation of atypical FISH signal patterns; 1 (paper) involved the interpretation of FISH signal patterns correlating involvement by myeloid versus lymphoid interphase nuclei; and 1 (liquid) likely involved a specimen processing or handling error that resulted in discordant participant responses. All 36 FFPE tissue challenges exceeded the 80% consensus for grading purposes. This 20-year retrospective review demonstrates that clinical cytogenomic laboratories have been and continue to be highly proficient in the detection and interpretation of FISH abnormalities associated with hematologic neoplasms.
There is a high risk of inadequate block with spinal anesthesia for postpartum tubal ligation that could be related to inadequate intrathecal dosing. This study aimed to investigate the association between intrathecal bupivacaine dose and inadequate blocks and to assess factors associated with inadequate blocks. Patients undergoing a postpartum tubal ligation between 2003 and 2025 with spinal anesthesia with hyperbaric bupivacaine were included in this retrospective cohort study. Cases were grouped according to bupivacaine dose as low (7.5-9.75 mg), middle (10.5-12 mg), and high (≥13.5 mg). The primary outcome was the occurrence of an inadequate block, defined as supplementation with intravenous analgesics, or failed block with repeat neuraxial anesthesia or conversion to general anesthesia. Data were analyzed using Kruskal-Wallis and Fisher's exact tests and multivariable logistic regression. An inadequate block occurred in 132/594 (22.2%) patients: 3/14 (21.4%, low dose), 95/336 (28.3%, middle dose), and 34/244 (13.9%, high dose). Inadequate blocks were less likely with ≥13.5 mg bupivacaine vs. 10.5-12 mg [OR 0.48, 95% CI (0.26 to 0.86); P = 0.015], and with more recent years since start of the study [0.95 (0.9 to 1); P = 0.029]. Longer surgical duration [(1.03 (1.01 to 1.04); P < 0.001] and higher intrathecal fentanyl dose [1.03 (1 to 1.05); P = 0.043] were associated with increased odds of inadequate block. Intrathecal hyperbaric bupivacaine at a dose ≥13.5 mg was associated with lower odds of inadequate anesthesia for postpartum tubal ligation compared with 10.5-12 mg in the context of an evolving institutional practice.
This narrative review synthesizes evidence linking periodontal dysbiosis with Alzheimer's disease, all-cause dementia, and dementia-relevant mechanisms, focusing on the red complex pathogens P. gingivalis, T. denticola, and T. forsythia and on the translational meaning of periodontal therapy. A PubMed-centered literature search up to May 2026 informed this synthesis (a narrative review, not a registered systematic review or meta-analysis) of 46 periodontal-scope sources, supplemented by five contextual references identified outside the periodontal search (51 references in total). P. gingivalis shows the strongest mechanistic support, including gingipains, lipopolysaccharide, outer membrane vesicles, endothelial stress, and neuroinflammatory signaling; T. denticola shows moderate biological plausibility; and T. forsythia remains mainly hypothesis-generating. Human studies associate periodontitis, tooth loss, oral-hygiene indicators, and periodontal-care exposure with dementia-relevant outcomes, but residual confounding, reverse causation, dental-care access, and heterogeneous endpoints preclude causal inference. Notably, direct targeting of a single periodontal pathogen has not shown clinical benefit, as the gingipain inhibitor atuzaginstat failed in the GAIN trial, contrasting with the modest success of amyloid-targeting therapies. Current evidence supports graded plausibility rather than causal certainty, and a registered multi-database systematic review with neurological endpoints is needed before meta-analytic clinical claims can be made.
Bacterial endospore formation begins with a polar septum that compartmentalizes two transcriptionally distinct cells, the mother cell and forespore. In Bacillus subtilis, a complex composed of SpoIIIE, SpoIIIM and PbpG maintains compartmentalization at a septal pore during hydrolysis of septal peptidoglycan (PG), by coordinating two critical functions: chromosome translocation from the mother cell to the forespore through the septal pore and preservation of septal pore stability through SpoIIIE-PG interactions and PG synthesis. Disruption of this mechanism leads to cytoplasmic leakage, failed chromosome transfer, and reduced sporulation. Here, we identify CprV (YteV) as a safeguarding factor that maintains compartmentalization in response to septal pore stability defects. Cells lacking CprV show mild defects in compartmentalization and chromosome translocation; however, in mutants experiencing septal pore instability, loss of CprV significantly worsens these defects. Consistent with this role, CprV accumulates at the septal pore in a SpoIIIE-dependent manner when chromosome translocation is impaired. Computational analyses indicate that CprV exhibits structural similarity to Alba proteins found in Eukaryotes and Archaea and is primarily conserved in the Bacillales. Collectively, our data support a model whereby CprV monitors septal pore stability to safeguard compartmentalization during sporulation, providing insight into how cells monitor compartmental integrity during cellular remodeling.