Kunitz-type protease inhibitor TFPI2 remodels stemness and immunosuppressive tumor microenvironment in glioblastoma.

Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. In human GBM, TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis. Our study identifies a function for TFPI2 and supports therapeutic targeting of TFPI2 as an effective strategy for GBM.

Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma.

BACKGROUND: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients. METHODS: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models. RESULTS: CLPP expression was detected in primary and mUM patient samples. ONC201 and 212 decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis in human UM cell lines in vitro. ONC212 inhibited OXPHOS, increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models. CONCLUSIONS: Imipridones are a promising strategy for further testing and development in mUM.

Genome analyses of colistin-resistant high-risk blaNDM-5 producing Klebsiella pneumoniae ST147 and Pseudomonas aeruginosa ST235 and ST357 in clinical settings.

BACKGROUND: Colistin is a last-resort antibiotic used in extreme cases of multi-drug resistant (MDR) Gram-negative bacterial infections. Colistin resistance has increased in recent years and often goes undetected due to the inefficiency of predominantly used standard antibiotic susceptibility tests (AST). To address this challenge, we aimed to detect the prevalence of colistin resistance strains through both Vitek®2 and broth micro-dilution. We investigated 1748 blood, tracheal aspirate, and pleural fluid samples from the Intensive Care Unit (ICU), Neonatal Intensive Care Unit (NICU), and Tuberculosis and Respiratory Disease centre (TBRD) in an India hospital. Whole-genome sequencing (WGS) of extremely drug-resitant (XDR) and pan-drug resistant (PDR) strains revealed the resistance mechanisms through the Resistance Gene Identifier (RGI.v6.0.0) and Snippy.v4.6.0. Abricate.v1.0.1, PlasmidFinder.v2.1, MobileElementFinder.v1.0.3 etc. detected virulence factors, and mobile genetic elements associated to uncover the pathogenecity and the role of horizontal gene transfer (HGT). RESULTS: This study reveals compelling insights into colistin resistance among global high-risk clinical isolates: Klebsiella pneumoniae ST147 (16/20), Pseudomonas aeruginosa ST235 (3/20), and ST357 (1/20). Vitek®2 found 6 colistin-resistant strains (minimum inhibitory concentrations, MIC = 4 µg/mL), while broth microdilution identified 48 (MIC = 32-128 µg/mL), adhering to CLSI guidelines. Despite the absence of mobile colistin resistance (mcr) genes, mechanisms underlying colistin resistance included mgrB deletion, phosphoethanolamine transferases arnT, eptB, ompA, and mutations in pmrB (T246A, R256G) and eptA (V50L, A135P, I138V, C27F) in K. pneumoniae. P. aeruginosa harbored phosphoethanolamine transferases basS/pmrb, basR, arnA, cprR, cprS, alongside pmrB (G362S), and parS (H398R) mutations. Both strains carried diverse clinically relevant antimicrobial resistance genes (ARGs), including plasmid-mediated blaNDM-5 (K. pneumoniae ST147) and chromosomally mediated blaNDM-1 (P. aeruginosa ST357). CONCLUSION: The global surge in MDR, XDR and PDR bacteria necessitates last-resort antibiotics such as colistin. However, escalating resistance, particularly to colistin, presents a critical challenge. Inefficient colistin resistance detection methods, including Vitek2, alongside limited surveillance resources, accentuate the need for improved strategies. Whole-genome sequencing revealed alarming colistin resistance among K. pneumoniae and P. aeruginosa in an Indian hospital. The identification of XDR and PDR strains underscores urgency for enhanced surveillance and infection control. SNP analysis elucidated resistance mechanisms, highlighting the complexity of combatting resistance.

Characterization of direct oral anticoagulants use in adult hematopoietic stem cell transplant recipients.

Direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) treatment are of interest in oncology due to ease of administration and lack of need for therapeutic monitoring compared to other anticoagulants. Data supporting their use in patients with hematologic malignancies post-hematopoietic stem cell transplant (HCT) are limited. The purpose of the study is to characterize DOAC use in HCT patients. This multicenter, retrospective cohort analysis included allogeneic and autologous HCT recipients. The primary outcome was major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB)/minor bleeding and VTE recurrence. Of 126 patients, 91 (72.2%) patients received an autologous HCT, and 35 (27.8%) patients received an allo-HCT. No major bleeding occurred in either transplant recipient groups. In autologous HCT recipients, CRNMB/minor bleeding occurred in four (4.4%) patients and VTE recurrence occurred in one (1.1%) patient. For allogeneic HCT recipients, CRNMB/minor bleeding occurred in five (14.3%) patients and VTE recurrence occurred in two (5.7%) patients. For patients that experienced a CRNMB, five (100%) of the allogeneic HCT and two (50%) of the autologous HCT recipients were thrombocytopenic at the time of bleeding. Only 38.5% of patients who experienced a drug-drug interaction requiring DOAC dose adjustment received the appropriate dose adjustment. DOACs were associated with low rates of recurrent VTE and no major bleeding events, similar to published data on DOAC use in the general cancer patient population. This suggests that DOACs may be safe therapeutic options with proactive management of drug interactions and careful monitoring for bleeding events, especially in the allogeneic HCT population where minor bleeding rates were slightly higher.

Metabolic Enzyme Alterations and Astrocyte Dysfunction in a Murine Model of Alexander Disease With Severe Reactive Gliosis.

Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP). In this report, a mouse model of AxD (GFAPTg;Gfap+/R236H) was analyzed that contains a heterozygous R236H point mutation in murine Gfap as well as a transgene with a GFAP promoter to overexpress human GFAP. Using label-free quantitative proteomic comparisons of brain tissue from GFAPTg;Gfap+/R236H versus wild-type mice confirmed upregulation of the glutathione metabolism pathway and indicated proteins were elevated in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which had not been reported previously in AxD. Relative protein-level differences were confirmed by a targeted proteomics assay, including proteins related to astrocytes and oligodendrocytes. Of particular interest was the decreased level of the oligodendrocyte protein, 2-hydroxyacylsphingosine 1-beta-galactosyltransferase (Ugt8), since Ugt8-deficient mice exhibit a phenotype similar to GFAPTg;Gfap+/R236H mice (e.g., tremors, ataxia, hind-limb paralysis). In addition, decreased levels of myelin-associated proteins were found in the GFAPTg;Gfap+/R236H mice, consistent with the role of Ugt8 in myelin synthesis. Fabp7 upregulation in GFAPTg;Gfap+/R236H mice was also selected for further investigation due to its uncharacterized association to AxD, critical function in astrocyte proliferation, and functional ability to inhibit the anti-inflammatory PPAR signaling pathway in models of amyotrophic lateral sclerosis (ALS). Within Gfap+ astrocytes, Fabp7 was markedly increased in the hippocampus, a brain region subjected to extensive pathology and chronic reactive gliosis in GFAPTg;Gfap+/R236H mice. Last, to determine whether the findings in GFAPTg;Gfap+/R236H mice are present in the human condition, AxD patient and control samples were analyzed by Western blot, which indicated that Type I AxD patients have a significant fourfold upregulation of FABP7. However, immunohistochemistry analysis showed that UGT8 accumulates in AxD patient subpial brain regions where abundant amounts of Rosenthal fibers are located, which was not observed in the GFAPTg;Gfap+/R236H mice.

Needle-free electronically-controlled jet injector treatment with bleomycin and lidocaine is effective and well-tolerated in patients with recalcitrant keloids.

OBJECTIVES: The treatment of recalcitrant keloids is challenging. Although intralesional bleomycin using conventional needle injectors (CNI) is effective, it has important drawbacks, such as the need for repetitive and painful injections. Therefore, we aimed to evaluate the effectiveness, tolerability and patient satisfaction of intralesional bleomycin with lidocaine administered with a needle-free electronically-controlled pneumatic jet-injector (EPI) in recalcitrant keloids. METHODS: This retrospective study included patients with recalcitrant keloids who had received three intralesional EPI-assisted treatments with bleomycin and lidocaine. Effectiveness was assessed using the Patient and Observer Scar Assessment Scale (POSAS) at baseline and four to six weeks after the third treatment. Additionally, treatment related pain scores numeric rating scale, adverse effects, patient satisfaction and Global Aesthetic Improvement Scale (GAIS) were assessed. RESULTS: Fifteen patients with a total of >148 recalcitrant keloids were included. The median total POSAS physician- and patient-scores were respectively 40 and 41 at baseline, and reduced with respectively 7 and 6-points at follow-up ( p < 0.001; p < 0.001). The median pain scores during EPI-assisted injections were significantly lower compared to CNI-assistant injections, (2.5 vs. 7.0, respectively ( p < 0.001)). Adverse effects were mild. Overall, patients were "satisfied" or "very satisfied" with the treatments (14/15, 93.3%). The GAIS was "very improved" in one patient, "improved" in nine patients and "unaltered" in four patients. CONCLUSIONS: EPI-assisted treatment with bleomycin and lidocaine is an effective, well tolerated, patient-friendly alternative for CNI in patients with recalcitrant keloid scars. Randomized controlled trials are warranted to confirm our findings and improve the clinical management of recalcitrant keloids.

Evidence-Based Unani Pharmacotherapeutics for the Treatment of Non-Alcoholic Fatty Liver Disease: A Mechanistic Review.

Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as a global health crisis, affecting a quarter of the world's population, and is anticipated to become a leading cause of liver transplantation and hepatocellular carcinoma by 2030. Conventional pharmacotherapy for NAFLD remains imperfect. In this context, Unani medicine offers a promising alternative for managing NAFLD. Objective: This review aims to compile information on Unani medications used for the treatment of NAFLD, aiming to provide evidence of their efficacy and delve into the mechanisms through which these Unani drugs exert their therapeutic effects in NAFLD. Methods: A comprehensive exploration of classical Unani literature was conducted, referencing well-established texts to extract pertinent information regarding NAFLD and its treatment in Unani Medicine. Electronic databases, including PubMed, Science Direct, and Google Scholar, were systematically searched to gather information on the efficacy of Unani drugs in the treatment of NAFLD. Results: Unani medicine offers a rich repository of single herbs and compound formulations. There is a description of about 32 single herbs and 18 compound formulations for the treatment of NAFLD. These drugs act due to their Musakhkhin (calorific), Mudirr (diuretics), Mufattih (deobstruent), Muqawwῑ-i-Jigar (hepatoprotective), and Muhallilat (anti-inflammatory) action. The bioactive components present in these drugs possess antioxidant, hypolipidemic, anti-inflammatory, hypoglycemic, and hepatoprotective activities. These actions of Unani drugs closely align with the multifaceted nature of NAFLD pathogenesis, and thus effective in the treatment of NAFLD. Conclusion: The findings led us to conclude that the use of Unani medicines can improve clinical outcomes in NAFLD, as demonstrated by various clinical and experimental trials. However, further clinical trials are essential to provide a safe and effective option for addressing this prevalent liver condition.

Curcumin coating: a novel solution to mitigate inherent carbon nanotube toxicity.

Multi-walled Carbon Nanotubes (MWCNTs) are inert structures with high aspect ratios that are widely used as vehicles for targeted drug delivery in cancer and many other diseases. They are largely non-toxic in nature however, when cells are exposed to these nanotubes for prolonged durations or at high concentrations, they show certain adverse effects. These include cytotoxicity, inflammation, generation of oxidative stress, and genotoxicity among others. To combat such adverse effects, various moieties can be attached to the surface of these nanotubes. Curcumin is a known anti-inflammatory, antioxidant and cytoprotective compound derived from a medicinal plant called Curcuma longa. In this study, we have synthesized and characterized Curcumin coated-lysine functionalized MWCNTs and further evaluated the cytoprotective, anti-inflammatory, antioxidant and antiapoptotic effect of Curcumin coating on the surface of MWCNTs. The results show a significant decrease in the level of inflammatory molecules like IL-6, IL-8, IL-1ß, TNFα and NFκB in cells exposed to Curcumin-coated MWCNTs as compared to the uncoated ones at both transcript and protein levels. Further, compared to the uncoated samples, there is a reduction in ROS production and upregulation of antioxidant enzyme-Catalase in the cells treated with Curcumin-coated MWCNTs. Curcumin coating also helped in recovery of mitochondrial membrane potential in the cells exposed to MWCNTs. Lastly, cells exposed to Curcumin-coated MWCNTs showed reduced cell death as compared to the ones exposed to uncoated MWCNTs. Our findings suggest that coating of Curcumin on the surface of MWCNTs reduces its ability to cause inflammation, oxidative stress, and cell death.

Advancing medical laboratory practice in Pakistan: insights from a focus group study on technologists' training needs.

BACKGROUND: The realm of medical laboratory technology (MLT) training and education is unstructured in Pakistan. The primary challenge currently confronting the workforce in MLT is the absence of standardized curricula and assessments in education and training. This was an exploratory study aiming to inquire experiences of trainees, alumni and teaching coordinators regarding the technologist training program in a single institute at Pakistan. METHODS: To gain an in depth understanding of MLT program, three focus group discussions (FGDs) were held at Department of Pathology and Laboratory Medicine, Aga Khan University, Pakistan during Feb-April 2024. A team of pathologists and educationists developed interview guides for FGDs in English. Interviews were bilingual, transcribed verbatim and coded using thematic analysis. Participants included current trainees, alumni, teaching and learning coordinators and moderators for the interview. RESULTS: A total of 29 participants were engaged; these included current MLT trainees (n = 10), alumni (n = 10), and teaching/learning coordinators and sectional supervisors (n = 9). Five main themes emerged from the analysis of FGDs: (Scott MG, Rifai N, Smith B, Oellerich M, Panteghini M, Apple F et al. The changing face of laboratory medicine: a more service and less academically oriented profession? 2015;61(2):322-9.) Recognition of key features of the MTT program, (Ferraro S, Braga F, Panteghini MJCC, Medicine L. Lab Med new Healthc Environ. 2016;54(4):523-33.) Evaluating curriculum design, (Waheed U, Ahmad M, Wazeer A, Saeed M, Saba N, Rasheed FJMJMS. Medical laboratory science education; shaping competent and skilled healthcare professionals. 2023;1(1):58-63.) Teaching and learning strategies, (Ned-Sykes R, Johnson C, Ridderhof JC, Perlman E, Pollock A, DeBoy JM. Competency guidelines for public health laboratory professionals. 2015.) Addressing the need to improve assessment methods, and (Linder RJJM, Education B. Educating medical laboratory technologists: revisiting our assumptions in the current economic and health-care environment. 2012;13(2):150-4.) Navigating the transition from a trainee to a competent technologist. CONCLUSION: Our investigation demonstrated its potential as a valuable needs assessment study, highlighting key strengths, drawbacks, and challenges of the existing MTT program. Importantly, these findings at our institute can inform further research efforts to design competency-based MLT education and training programs in Pakistan.

Trends and advances in pre- and post-harvest processing of linseed oil for quality food and health products.

Linseed is an ancient crop used for diverse purposes since the beginning of civilization. In recent times, linseed has emerged as a superfood due to its high content of health-promoting omega-3 fatty acids and other bioactive compounds. Among primary health effects, it has potential to manage hypertension, diabetes, osteoporosis, atherosclerosis, cancer, arthritis, neurological, cardiovascular diseases including blood cholesterol levels, constipation, diarrhea, and autoimmune disorders etc. due to the presence of omega-3 fatty acid, lignans, high dietary fibers, and proteins, whereas, secondary health effects comprise of relieving from various skin disorders. Due to these health-beneficial properties, interest in linseed oil necessitates the intensification of research efforts on various aspects. These include cultivation technology, varietal and genetic improvement, post-harvest processing, profiling of nutrients and bioactive compounds, pre-clinical and clinical studies, etc. The present review discussed the advances in linseed research including pre- and post-harvest processing. However, focus on the bioactive compounds present in linseed oil and their health effects are also presented. Linseed cultivation, pre- and post-harvest processing aspects are covered including climatic, edaphic, agronomic factors, type of cultivar and storage conditions etc, which impact the overall oil yield and its nutritional quality. Various emerging applications of linseed oil in functional food, nutraceutical, pharmaceutical, and cosmeceutical preparations were also presented in detail. Further, recommendations were made on linseed oil research in the field of genetics, breeding germplasm resources and genome editing for exploring its full applications as a nutrition and health product.

BRCA1 promoter methylation & its immunohistochemical correlation in sporadic breast cancer.

Background & objectives: Studies have shown that apart from hereditary breast carcinomas, breast cancer susceptibility gene 1 (BRCA1) mutations conferring to its loss are seen in sporadic breast carcinomas (SBC) as well. The aim of the present study was to assess BRCA1 methylation in females presenting at King George's Medical University, Lucknow, with SBC by both immunohistochemistry (IHC) and methylation PCR with respect to hormonal profile and various morphological prognostic parameters. The primary objective was to look for the association between BRCA1 protein expression and DNA promoter methylation. Methods: 81 mastectomy specimens from SBC of invasive breast carcinoma (no special type) were included in this study. After a detailed morphological assessment, formalin fixed paraffin embedded tissue from a representative tumour area was selected for BRCA1 IHC by heat-mediated antigen retrieval under high pH and DNA extraction and further bisulphate treatment. BRCA1 was studied for methylation by methylated and unmethylated PCR-specific primers. Results: BRCA1 promoter methylation was present in 42/81 (51.9%) participants, with significant BRCA1 protein loss (72.7%; P=0.002). A significant association between BRCA1 loss and hormonal profile was found (P=0.001); maximum in triple negative breast carcinoma (TNBC) (72%; 18/25). Most of the TNBC also harboured methylation (68%). Although not significant grade II and III tumours, lymph vascular invasion, ductal carcinoma in situ, and nodal metastasis (≥3) were seen in a higher percentage in methylated tumours. Mortality in SBC was significantly associated with BRCA1 loss (30.3%; P=0.024). Interpretation & conclusions: Study results highlight the concept of "BRCAness" in SBC as well. Hence, we can confer that identification of BRCA1 loss in SBC can make it a perfect candidate for poly ADP-ribose polymerase inhibitors or cisplatin-based therapy like hereditary ones.

Viral hepatitis amidst COVID-19 in Africa: Implications and recommendations.

Hepatitis, a significant cause of mortality worldwide, results in around 1.34 million deaths each year globally. Africa is not exempt from the plague of Hepatitis. Around 100 million estimated individuals are infected with Hepatitis B or C. Egypt has the highest prevalence of cases of Hepatitis followed by Cameroon and Burundi. The continent is severely affected by the onset of the COVID-19 pandemic, as the virus has added an additional burden on the already fragile continent. With the pandemic, it is presumable that Hepatitis like other viral diseases will pose a threat to collapsing healthcare system. Therefore, for Africa to become more resilient in the face of such menaces, including Hepatitis, further prevention policies are required to be implemented.

Reduced urothelial expression of uroplakin-IIIa in cystitis areas in bladders of postmenopausal women with recurrent urinary tract infections: pilot study.

PURPOSE: To study human bladder biopsies to investigate urothelial response to UTI, expression of uroplakin, and urothelial response after healing from cystoscopy with electrofulguration (CEF) treatment for antibiotic-recalcitrant RUTI. METHODS: Following IRB approval, cold cup bladder biopsies from "no cystitis" and "cystitis" regions were obtained from women with antibiotic-recalcitrant rUTI undergoing CEF under anesthesia. "No cystitis" and "cystitis" biopsies from 14 patients (5 had prior CEF, 9 naïve) were analyzed by immunofluorescence (IF) confocal microscopy using antibodies against uroplakin-IIIa. For an additional 6 patients (2 prior CEF, 4 naïve), only "cystitis" area biopsies were taken and analyzed. Cytokeratin 5 (marker for squamous metaplasia) staining was performed on 14 patients. RESULTS: In healthy tissue, uroplakin-IIIa staining was observed as a contiguous line on the luminal surface of umbrella cells. In "cystitis" areas for 19/20 patients, there was either no uroplakin-IIIa staining observed or spotty (+) staining. The "cystitis" regions of all patients had less intense uroplakin-IIIa staining compared to the matched "no cystitis" area in the same patient. In patients post-CEF but requiring repeat EF for persistent RUTI lesions, healed areas served as control and in 3 of 7 patients no uroplakin-IIIa staining was observed. Squamous metaplasia was observed in 10 patients. CONCLUSION: In bladders of postmenopausal women with antibiotic-recalcitrant RUTI, areas with visible cystitis expressed less uroplakin-IIIa, supporting the model of urothelial exfoliation in response to UTI.

The impact of COVID-related economic shocks on household mental health in Pakistan.

We combine data collected just prior to the unfolding of COVID-19 with follow-up data from July 2020 to document the adverse economic effects of the pandemic and resulting impact on parental and child mental well-being in peri-urban Pakistan. 22% of the households in our sample are affected by job loss, with monthly income down 38% on average. Our difference-in-difference results show that job loss is associated with a 0.88 standard deviation (SD) increase in adult mental distress scores (K10), a 0.43 SD reduction in a Hope index of children's aspirations, agency and future pathways, and a 0.39 SD increase in children's depression symptoms. In addition, we observe higher levels of parental stress and anger reported by children, as well as an increase in reported prevalence of domestic violence. Overall, we document that the pandemic has disproportionately and negatively affected the economic and mental well-being of the most vulnerable households in our sample.

Review of Vaginal Approaches to Apical Prolapse Repair.

PURPOSE OF REVIEW: To review recent literature and provide up-to-date knowledge on new and important findings in vaginal approaches to apical prolapse surgery. RECENT FINDINGS: Overall prolapse recurrence rates following transvaginal apical prolapse repair range from 13.7 to 70.3% in medium- to long-term follow-up, while reoperation rates for prolapse recurrence are lower, ranging from 1 to 35%. Subjective prolapse symptoms remain improved despite increasing anatomic failure rates over time. The majority of studies demonstrated improvement in prolapse-related symptoms and quality of life in over 80% of patients 2-3 years after transvaginal repair, with similar outcomes with and without uterine preservation. Contemporary studies continue to demonstrate the safety of transvaginal native tissue repair with most adverse events occurring within the first 2 years. Transvaginal apical prolapse repair is safe and effective. It is associated with long-term improvement in prolapse-related symptoms and quality of life despite increasing rates of prolapse recurrence over time. Subjective outcomes do not correlate with anatomic outcomes.

The risk of cutaneous mucormycosis associated with COVID-19: A perspective from Pakistan.

As a developing country, Pakistan reports a high burden of fungal diseases, of which cutaneous mucormycosis remains a prominent infection, presenting as a highly invasive disease with significant mortality. Apart from a high population of at-risk individuals, multiple factors have precipitated an increment in mucormycosis cases in the country following the COVID-19 pandemic. These include increased use of corticosteroids, immunosuppression following the viral infection, prolonged stays in the intensive care unit and sub-optimal laboratory testing available in the country. This article aims to assess the potential implications of a mucormycosis epidemic on a healthcare system already strained under the COVID-19 pandemic, and provides subsequent recommendations to weather the dual challenge of two deadly pathogens.

Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing ß-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.

Resurgence of tuberculosis amid COVID-19 in Peru: Associated risk factors and recommendations.

Peru is one of the countries with the highest incidence of tuberculosis and multidrug-resistant tuberculosis in the world. Although public health measures adopted in the country have improved the care, diagnosis and management of patients with tuberculosis, there are still failures in the control of the disease in the country, especially of multidrug-resistant tuberculosis and among the prison population or people living with HIV. The COVID-19 pandemic has added a great burden to the Peruvian public health system, negatively impacting tuberculosis-focused health programs due to the diversion of resources to control the pandemic. Consequently, combat measures, epidemiological surveillance of tuberculosis cases were affected, and data point to an increase in the number of cases, especially of multidrug-resistant tuberculosis, and to the underdiagnosis of the disease. To deal with this problem and avoid a future catastrophe for the country's health system, multidisciplinary measures involving the population, health professionals and government bodies are needed. It is essential that education, diagnosis, contact screening and treatment programs are prioritised and given greater financial support. Furthermore, it is necessary to raise awareness in the population about the need for isolation and maintenance of treatment, especially among the most vulnerable populations.

Inhibition of Tumor Growth against Chemoresistant Cholangiocarcinoma by a Proapoptotic Peptide Targeting Interleukin-4 Receptor.

Cholangiocarcinoma (CCA) has a poor prognosis and high chemoresistance. Interleukin-4 receptor (IL-4R) is overexpressed in several cancer cells and plays a crucial role in tumor progression and drug resistance. IL4RPep-1, an IL-4R-binding peptide, has been identified by phage display and used for tumor targeting. In this study, we exploited IL4RPep-1 to guide the tumor-specific delivery of a proapoptotic peptide to chemoresistant CCA, thereby inhibiting tumor growth. Immunohistochemistry of human primary CCA tissues showed that IL-4R levels were upregulated in moderately to poorly differentiated types, and higher levels of IL-4R are correlated with lower survival rates in patients with CCA. IL4RPep-1 was observed to preferentially bind with high IL-4R-expressing KKU-213 human CCA cells, whereas it barely bound with low IL-4R-expressing KKU-055 cells. A hybrid of IL4RPep-1 and a proapoptotic peptide (KLAKLAK)2 (named as IL4RPep-1-KLA) induced cytotoxicity and apoptosis in KKU-213 cells and increased those levels induced by 5-fluorouracil (5-FU). IL4RPep-1-KLA was internalized in the cells and colocalized with mitochondria. Whole-body fluorescence imaging and immunohistochemical analysis of tumor tissues showed the homing of IL4RPep-1-KLA as well as IL4RPep-1 to KKU-213 tumor in mice. Systemic administration of IL4RPep-1-KLA efficiently inhibited KKU-213 tumor growth, whereas treatment with 5-FU alone did not significantly inhibit tumor growth in mice. No significant systemic side effects including liver toxicity and immunotoxicity were observed in mice during peptide treatments. These findings suggest that IL4RPep-1-KLA holds potential as a targeted therapeutic agent against chemoresistant CCA.

Unsedated Colonoscopy: Impact on Quality Indicators.

BACKGROUND: In the USA, sedation is commonly used for colonoscopies; though colonoscopy can be successfully performed without sedation, outcomes data in this setting are scarce. AIMS: To determine patient characteristics associated with undergoing unsedated colonoscopy and whether adenoma detection rate (ADR) and cecal intubation rate (CIR) differ between sedated and unsedated colonoscopy. METHODS: Using a single-center electronic endoscopy database, we identified patients who underwent outpatient colonoscopy between 2011 and 2018 with or without sedation. We used multivariable logistic regression to determine factors associated with unsedated colonoscopy, CIR, and ADR. RESULTS: We identified 24,795 patients who underwent colonoscopy during the study period. Of these, 179 patients (0.7%) underwent unsedated colonoscopy. ADR was 27.4% in sedated and 21.2% in unsedated colonoscopies (p = 0.06); CIR was 95.8% in sedated and 85.5% in unsedated patients (p < 0.01). On multivariable analysis, male sex (OR 2.06, CI 1.52-2.79) and suboptimal bowel preparation (OR 1.75, CI 1.24-2.45) were associated with undergoing unsedated colonoscopy, while higher BMI was inversely associated with unsedated colonoscopy (BMI 25-29.9: OR 0.44, CI 0.25-0.77). On multivariable analysis, colonoscopy with sedation was associated with CIR (OR 3.79, CI 2.39-6.00) and ADR (OR 1.45, OR 1.00-2.10). CONCLUSION: We found that undergoing outpatient colonoscopy with sedation as opposed to no sedation was significantly associated with a higher CIR and ADR. Our findings suggest sedation is necessary to meet current CIR and ADR guidelines; however, given the potential cost and safety benefits of unsedated colonoscopy, further investigation into methods to improve patient selection and colonoscopy quality indicators is warranted.