Assessment of Non-Adherence to Anti-TB Drugs and Associated Factors Among Patients Attending TB Treatment Centers During COVID-19 Pandemic in Mogadishu, Somalia: A Cross-Sectional Study.

Background: The COVID-19 pandemic's first wave and subsequent lockdowns disrupted global healthcare systems, significantly impacting essential services including tuberculosis (TB) care. Non-adherence to anti-TB drugs is a critical concern, leading to treatment failure, drug resistance, and increased morbidity and mortality. This study assessed the rate and determinants of non-adherence to TB treatment among patients at TB centers during the first wave of the pandemic. Material and Methods: A cross-sectional study was conducted from June 15 to July 30, 2020, involving 255 TB patients at three centers in Mogadishu. Data were gathered using the Morisky Medication Adherence Scale-8 (MMAS-8) through structured interviews and analyzed using descriptive statistics and binary logistic regression. Results: The study found a 34.5% non-adherence rate during the pandemic. Key reasons for non-adherence included forgetting to take medication (33%), feeling well (29%), experiencing side effects (18%), and fear of contracting COVID-19 (16%). Significant factors associated with non-adherence were age groups 25-34 years (OR = 2.96, p = 0.024) and 35-44 years (OR = 4.55, p = 0.005), unemployment (OR = 2.57, p = 0.037), smoking (OR = 3.49, p = 0.029), tobacco use (OR = 4.15, p = 0.034), proximity to a health facility (OR = 0.44, p = 0.033), perception of healthcare providers as very friendly (OR = 0.24, p = 0.031) or friendly (OR = 0.45, p = 0.023), being in the continuous treatment phase (OR = 3.2, p < 0.001), and experiencing adverse treatment effects (OR = 2.42, p = 0.003). Conclusion: Non-adherence to anti-tuberculosis treatment was notably high in Mogadishu during the first wave of the pandemic, necessitating targeted interventions to improve adherence.

SIK2 and SIK3 Differentially Regulate Mouse Granulosa Cell Response to Exogenous Gonadotropins In Vivo.

Salt-inducible kinases (SIKs), a family of serine/threonine kinases, were found to be critical determinants of female fertility. SIK2 silencing results in increased ovulatory response to gonadotropins. In contrast, SIK3 knockout results in infertility, gonadotropin insensitivity, and ovaries devoid of antral and preovulatory follicles. This study hypothesizes that SIK2 and SIK3 differentially regulate follicle growth and fertility via contrasting actions in the granulosa cells (GCs), the somatic cells of the follicle. Therefore, SIK2 or SIK3 GC-specific knockdown (SIK2GCKD and SIK3GCKD, respectively) mice were generated by crossing SIK floxed mice with Cyp19a1pII-Cre mice. Fertility studies revealed that pup accumulation over 6 months and the average litter size of SIK2GCKD mice were similar to controls, although in SIK3GCKD mice were significantly lower compared to controls. Compared to controls, gonadotropin stimulation of prepubertal SIK2GCKD mice resulted in significantly higher serum estradiol levels, whereas SIK3GCKD mice produced significantly less estradiol. Cyp11a1, Cyp19a1, and StAR were significantly increased in the GCs of gonadotropin-stimulated SIK2GCKD mice. However, Cyp11a1 and StAR remained significantly lower than controls in SIK3GCKD mice. Interestingly, Cyp19a1 stimulation in SIK3GCKD was not statistically different compared to controls. Superovulation resulted in SIK2GCKD mice ovulating significantly more oocytes, whereas SIK3GCKD mice ovulated significantly fewer oocytes than controls. Remarkably, SIK3GCKD superovulated ovaries contained significantly more preantral follicles than controls. SIK3GCKD ovaries contained significantly more apoptotic cells and fewer proliferating cells than controls. These data point to the differential regulation of GC function and follicle development by SIK2 and SIK3 and supports the therapeutic potential of targeting these kinases for treating infertility or developing new contraceptives.

Qualitative Interviews Exploring Adverse Event Mitigation Strategies in Adults Receiving Amikacin Liposome Inhalation Suspension.

INTRODUCTION: This study aimed to gain insight from patients with refractory Mycobacterium avium complex lung disease (MAC-LD) into strategies used to manage adverse events (AEs) associated with amikacin liposome inhalation suspension (ALIS). METHODS: We conducted semi-structured interviews with US patients with refractory MAC-LD prescribed ALIS in a real-world setting. Interview transcripts were analyzed and coded to identify patterns in participants' descriptions of their ALIS treatment experiences, including AEs and their disruptiveness, and AE mitigation strategies, including participants' ratings of strategies' effectiveness. Concept saturation was also assessed. RESULTS: Twenty participants (mean age 48.7 years; 80% women; mean ALIS duration 5.45 months) were interviewed. At the time of the interview, 15 participants (75%) had received ALIS for > 1 month and 13 (65%) were currently receiving ALIS. Participants described 44 unique AE mitigation strategies, which can be categorized into three groups: prepare for treatment; prevent increased emergence of AEs; and persist on treatment by mitigating AEs. Common strategies (reported by ≥ 50% of participants) included use of educational materials from the patient support program, localized management of throat irritation, and symptom management to reduce fatigue. Evidence of concept saturation was observed: no new strategies were identified in the last five interviews, which suggests the sample was robust enough to identify all mitigation strategies likely to be used by the broader patient population. CONCLUSIONS: This real-world study identified a diverse set of potential AE mitigation strategies intended to help individual patients prepare for ALIS treatment, prevent the increased emergence of certain AEs, and mitigate the impact of AEs on treatment persistence. Developing a comprehensive accounting of the types of mitigation strategies in use among patients in real-world settings can inform future investigation of the effectiveness of such strategies, and support evidence-based recommendations for treatment management.

Psychometric properties of the arabic version of occupational value with pre-defined ítems.

BACKGROUND: Perceived occupational value is closely linked with well-being and there is need worldwide for assessment tools that target this phenomenon. The Occupational Value with pre-defined items (OVal-pd), measuring three dimensions of occupational value; concrete, socio-symbolic and self-rewarding, was designed for that purpose. AIM: To pilot an Arabic version of OVal-pd and evaluate its psychometric properties in terms of content validity, factor structure, homogeneity, construct validity, test-retest stability, floor and ceiling effects, and measurement error. METHODS: Snowball sampling was used to recruit Arabic-speaking persons living in Sweden (n = 55). They completed the OVal-pd and questionnaires addressing background factors, content validity and feasibility. Confirmatory factor analysis, Spearman's rank correlation, Cronbach's α, intraclass correlation coefficients, and minimum detectable change were calculated. RESULTS: A 22-item version of the Arabic OVal-pd was found to have acceptable content validity and feasibility and the proposed three occupational value dimensions were confirmed. Good properties in terms of construct validity, internal consistency and test-retest stability were also established. No floor or ceiling effects were observed. CONCLUSION: The Arabic OVal-pd showed good validity and reliability on various psychometric aspects. SIGNIFICANCE: In today's multicultural societies, the Arabic OVal-pd can be an important tool for occupational therapists working with Arabic-speaking clients.

Nontuberculous mycobacterial pulmonary disease added burden to COPD and bronchiectasis in Japan.

Background and objective: Nontuberculous mycobacterial pulmonary disease (NTM-PD) prevalence in Japan is among the highest worldwide. COPD and bronchiectasis are common comorbidities among patients with NTM-PD, and it is challenging to treat NTM-PD in patients with these conditions. There are limited data on the incremental burden that NTM-PD adds to underlying COPD or bronchiectasis in Japan. Therefore, the objective of this study was to assess the incremental burden associated with NTM-PD in patients with pre-existing COPD and/or bronchiectasis. Methods: This nested case-control study was based on JMDC, Inc. claims data (2015-2020). Patients with COPD and/or bronchiectasis with NTM-PD (cases) were age and sex matched 1:3 to patients with COPD and/or bronchiectasis without NTM-PD (controls), resulting in three mutually exclusive patient groups (COPD, bronchiectasis or both; with or without NTM-PD). Incremental burden of NTM-PD was assessed within each group by comparing hospitalisations during the 1-year period after NTM-PD diagnosis (index) between cases and controls with both univariate analysis and multivariate analysis adjusting for pre-index comorbidities. Results: Univariate analyses in the three patient groups consistently demonstrated incremental hospitalisation burden in cases versus controls (e.g. COPD group: 20% of 492 cases versus 13% of 1476 controls had all-cause hospitalisations; 11% versus 5% had respiratory-related hospitalisations; and 6% versus 2% had COPD-related hospitalisations). Subsequent multivariate analysis further confirmed the findings. Conclusions: The substantial incremental burden of hospitalisation associated with NTM-PD in patients with COPD and/or bronchiectasis highlights the urgent need for appropriate management of NTM-PD in Japan.

Reductions in hospitalisations and emergency department visits with early antibiotic initiation in nontuberculous mycobacterial lung disease.

Background: While antibiotics are recommended for treatment of nontuberculous mycobacterial lung disease (NTMLD), the impact of early antibiotic initiation on healthcare resource utilisation is unclear. This study compared healthcare resource utilisation with early versus delayed antibiotic initiation in NTMLD. Methods: A retrospective, claims database study (Merative MarketScan) of patients diagnosed with NTMLD between 1 July 2015 and 30 June 2019. Patients were divided into early antibiotic initiation, i.e. ≤3 months after the first medical claim for NTMLD (index date), and delayed antibiotic initiation groups. Hospitalisations and outpatient visits during a 2-year post-index period were compared to baseline per treatment group; a difference-in-difference analysis compared early and delayed antibiotic initiation groups adjusting for confounding. Results: Out of 481 NTMLD treated patients, 364 (76%) and 117 (24%) comprised the early and delayed antibiotic initiation groups, respectively. The early antibiotic initiation group showed significant reductions from baseline in hospitalisations (all-cause, respiratory) and emergency department (ED) visits at follow-up. A significant increase from baseline in mean number of hospitalisations per patient was observed in the delayed antibiotic initiation group in year 1 post-index. Compared to delayed antibiotic initiation, the early antibiotic initiation group showed significantly greater reductions in all-cause hospitalisations in years 1 and 2 post-index (relative risk 0.62 (95% CI 0.41-0.95) and 0.62 (95% CI 0.39-0.98), respectively), and in respiratory-related hospitalisations. Conclusions: The early antibiotic initiation group showed significant reductions from baseline in hospitalisations and ED visits over time. Compared to delayed antibiotic initiation, early antibiotic initiation was associated with significantly greater reductions in hospitalisations.

A Case of Gradenigo's Syndrome in an Elderly Patient.

Gradenigo's syndrome (GS) presents with the classical triad of otitis media, facial pain, and abducens nerve palsy as a complication of petrous apicitis. However, in the era of increased antibiotic use, complications of petrous apicitis have become infrequent and cases of GS are not frequently seen in clinical practice. We present the case of a 76-year-old man with uncontrolled diabetes mellitus presented with a two-month history of worsening right-sided headache, right-sided facial pain and weakness, along with dysphagia, hearing loss, and right otalgia with intermittent otorrhea following a right upper molar extraction. Imaging identified the inflammatory changes and indications of petrous apicitis. Although GS has become quite rare in recent years, this case highlights the importance of the responsible use of antibiotics in treating a seemingly innocuous infection.

Chitosan decorated oleosomes loaded propranolol hydrochloride hydrogel repurposed for Candida albicans-vaginal infection.

Aim: Our investigation aims to estimate the antifungal effect of propranolol hydrochloride (PNL). Methods: Oleosomes (OLs) were fabricated by thin-film hydration and evaluated for entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and amount of drug released after 6 h Q6h (%). Results: The optimal OL showed a rounded shape with optimum characteristics. The ex-vivo permeation and confocal laser scanning microscopy verified the prolonged release and well deposition of PNL-loaded OLs-gel. The in-silico assessment demonstrated the good stability of PNL with OLs' ingredients. In vivo evaluations for PNL-loaded OLs-gel showed a good antifungal impact against Candida albicans with good safety. Conclusion: This work highlights the potential of PNL-loaded OLs-gel as a potential treatment for candida vaginal infection.

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Health risk factors, status and service utilisation of adults in primary health care settings in Qatar: The HEALTHSIGHT study protocol.

BACKGROUND: The emergence of non-communicable diseases (NCDs) has been well documented in recent literature which constitute a significant global burden of disease. Qatar which has a significantly high prevalence of NCDs with early on set. Epidemiological and health service utilization information plays a central role in facilitating informed decision making and application of the fundamental principles of PHC in planning and delivery of healthcare with aim to prevent and control NCDs. To enable this, the Department of Clinical Research at Primary Health Care Corporation (PHCC), Qatar's publicly funded and largest primary care provider designed the Health Assessment Linking Trends in Health Status, Risks, and Healthcare Utilization (HEALTHSIGHT) study. This paper describes the HEALTHSIGHT study protocol. METHODS: The proposed study will use a cross sectional study design involving a random sample of participants enrolled across all 31 PHCC health centers. Individuals aged 18 and above years old registered with PHCC and hold a valid health card and contact information on PHCC's electronic medical records (EMR) will be eligible for inclusion. A stratified random sample not proportional to size sampling technique will be employed to obtain a representative sample size of the PHCC population (N = 6000). Participants will be scheduled for an appointment at a PHCC health centre where a data collector will obtain informed consent, collect vital sign information and administer a questionnaire. A phlebotomist will collect a blood sample. Health service utilization data will be extracted from PHCC's EMR. DISCUSSION: Epidemiological and health service utilization information is essential to plan and monitor primary care and public health services. The HEALTHSIGHT study, with the help of a randomly selected representative sample from Qatar's primary healthcare settings, provides a unique opportunity to capture this information. This study design will closely represent a real-world understanding of the health risk, status and utilisation and is likely to provide important data to guide primary care planning and delivery in Qatar. The proposed protocol provides an example of a robust nationwide study that be undertaken in short duration using limited resource which can be undertaken in other similar settings.

Nanocomposite alginate hydrogel loaded with propranolol hydrochloride kolliphor® based cerosomes as a repurposed platform for Methicillin-Resistant Staphylococcus aureus-(MRSA)-induced skin infection; in-vitro, ex-vivo, in-silico, and in-vivo evaluation.

Nanocomposite alginate hydrogel containing Propranolol hydrochloride (PNL) cerosomes (CERs) was prepared as a repurposed remedy for topical skin Methicillin-Resistant Staphylococcus aureus (MRSA) infection. CERs were formed via an ethanol injection technique using different ceramides, Kolliphores® as a surfactant, and Didodecyldimethylammonium bromide (DDAB) as a positive charge inducer. CERs were optimized utilizing 13. 22 mixed-factorial design employing Design-Expert® software, the assessed responses were entrapment efficiency (EE%), particle size (PS), and zeta potential (ZP). The optimum CER, composed of 5 mg DDAB, ceramide VI, and Kolliphor® RH40 showed tubular vesicles with EE% of 92.91 ± 0.98%, PS of 388.75 ± 18.99 nm, PDI of 0.363 ± 0.01, and ZP of 30.36 ± 0.69 mV. Also, it remained stable for 90 days and manifested great mucoadhesive aspects. The optimum CER was incorporated into calcium alginate to prepare nanocomposite hydrogel. The ex-vivo evaluation illustrated that PNL was permeated in a more prolonged pattern from PNL-loaded CERs nanocomposite related to PNL-composite, optimum CER, and PNL solution. Confocal laser scanning microscopy revealed a perfect accumulation of fluorescein-labeled CERs in the skin. The in-silico investigation illustrated that the PNL was stable when mixed with other ingredients in the CERs and confirmed that PNL is a promising candidate for curing MRSA. Moreover, the PNL-loaded CERs nanocomposite revealed superiority over the PNL solution in inhibiting biofilm formation and eradication. The PNL-loaded CERs nanocomposite showed superiority over the PNL-composite for treating MRSA infection in the in-vivo mice model. Histopathological studies revealed the safety of the tested formulations. In conclusion, PNL-loaded CERs nanocomposite provided a promising, safe cure for MRSA bacterial skin infection.

Dipolar skyrmions and antiskyrmions of arbitrary topological charge at room temperature.

Magnetic skyrmions are localized, stable topological magnetic textures that can move and interact with each other like ordinary particles when an external stimulus is applied. The efficient control of the motion of spin textures using spin-polarized currents opened an opportunity for skyrmionic devices such as racetrack memory and neuromorphic or reservoir computing. The coexistence of skyrmions with high topological charge in the same system promises further possibilities for efficient technological applications. In this work, we directly observe dipolar skyrmions and antiskyrmions with arbitrary topological charge in Co/Ni multilayers at room temperature. We explore the dipolar-stabilized spin objects with topological charges of up to 10 and characterize their nucleation process, their energy dependence on the topological charge and the effect of the material parameters on their stability. Furthermore, our micromagnetic simulations demonstrate spin-transfer-induced motion of these spin objects, which is important for their potential device application.

A Comparative Analysis of Polysaccharides and Ethanolic Extracts from Two Egyptian Sweet Potato Cultivars, Abees and A 195: Chemical Characterization and Immunostimulant Activities.

Sweet potato (Ipomoea batatas (L.) Lam.) belongs to family Convolvulaceae. The plant is distributed worldwide and consumed, especially for its edible tubers. Many studies have proved that the plant has variable biological activities such as antidiabetic, anti-cancer, antihypertensive, antimicrobial, and immunostimulant activities. The roots of sweet potatoes are rich in valuable phytochemical constituents that vary according to the flesh color. Our investigation focused on the chemical profiling of two Egyptian sweet potato cultivars, Abees and A 195, using UPLC-QTOF and the analysis of their polysaccharide fractions by GC-MS. Furthermore, we assessed the immunostimulant properties of these extracts in immunosuppressed mice. The study revealed that sweet potato roots contain significant concentrations of phenolic acids, including caffeoylquinic, caffeic, caffeoyl-feruloyl quinic, and p-coumaric acids, as well as certain flavonoids, such as diosmin, diosmetin, and jaceosidin, and coumarins, such as scopoletin and umbelliferone. Moreover, polysaccharides prepared from both studied cultivars were analyzed using GC-MS. Further biological analysis demonstrated that all the tested extracts possessed immunostimulant properties by elevating the level of WBCs, IL-2, TNF, and IFN-γ in the immunosuppressed mice relative to the control group with the highest values in polysaccharide fractions of A195 (the ethanolic extract showed a higher effect on TNF and IFN-γ, while its polysaccharide fraction exhibited a promising effect on IL-2 and WBCs). In conclusion, the roots of the Egyptian sweet potato cultivars Abees and A 195 demonstrated significant immunostimulant activities, which warrants further investigation through clinical studies.

Ocular Mucoadhesive and Biodegradable Sponge-Like Inserts for the Sustained and Controlled Delivery of Voriconazole; Preparation, D-optimal Factorial Optimization and in-vivo Evaluation.

The aim of this study was to formulate and optimize by statistical means mucoadhesive and biodegradable sponge-like inserts loaded with voriconazole (VCZ) which increases the contact time of the drug with the eye and sustain its release from the formula in a controlled manner. This avoids the pulsed effect reported for the drug suspension and results in reducing the number of drug instillations in the eye with the result of enhancing the patient compliance. Also, the sponge like nature of the insert reduces the foreign body sensation caused by other ocular solid dosage forms. They were prepared using casting/freeze-drying technique using five polymers namely high molecular weight chitosan (CH), sodium alginate (AL), sodium carboxy methyl cellulose (CMC), gellan gum (GG) and xanthan gum (XG). The prepared inserts were subjected to evaluations of their visual appearance, weight variation, drug content, surface pH, in-vitro release (percent drug released after 1h (Q1 (%)), mean dissolution time (MDT) and dissolution efficiency (DE)) in addition to kinetic analysis of the release data, water uptake, mucoadhesion and rheology of the forming plain polymer solution at the maximum rate of shear. The independent variables of the D-optimal factorial design were the polymer type and concentration while Q1 (%), MDT, DE, % water uptake after 15 minutes and rheology at the maximum rate of shear were chosen as dependant variables. The performed optimization process using design expert software showed an optimum formula consisting of 2 % GG. It showed slow release behavior compared to the drug suspension. FTIR and DSC studies showed that there is no interaction between VCZ and GG. The optimum formula has good in-vitro mucoadhesive properties and pH in the safe ocular range. Moreover, it showed promising in-vivo results of rapid hydration and gelling in addition to good mucoadhesive behavior when instilled in the eye, high ocular safety and biocompatibility, sustained antifungal activity in comparison to the drug suspension and finally biodegradation. So, it may be taken into consideration as an outstanding carrier for the ocular delivery of VCZ.

The role of dietitian follow-ups on nutritional outcomes post-bariatric surgery.

BACKGROUND: Current evidence recommends dietary counselling with a registered dietitian (RD) for successful weight loss after metabolic bariatric surgery; however, there are limited data on the effect of RD follow-ups on micronutrient deficiencies. This study evaluated the effects of the number of postoperative RD visits on nutritional outcomes, including weight loss and micronutrient deficiencies. OBJECTIVES: The aim of this study was to evaluate the effects of the number of postoperative registered dietitian visits on nutritional outcomes, including weight loss and micronutrient deficiencies after metabolic and bariatric surgery. SETTING: Cleveland Clinic Abu Dhabi, United Arab Emirates METHODS: This retrospective study included patients who underwent bariatric surgery between September 2015 and June 2020. Demographics, weight loss, micronutrients, and the number of postoperative RD visits were evaluated. Baseline and 12-month postsurgery outcomes were compared based on the number of RD follow-ups. RESULTS: A total of 174 primary and 46 revisions were included. Patients were 73.6% female, with a mean age of 40 years. The initial mean body mass index was 42.8 kg/m2. Number of RD visits were as follows: 0-1 (39 patients), 2 (59 patients), 3 (55 patients), and 4 or more (67 patients). Baseline (pre-operative) micronutrient values were within normal range. In comparison with the reference group (REF = 0-1 post-op RD visits), patients with 3 RD visits had 7% higher total body weight loss (P < .001) and maintained micronutrients within the normal range at 12 months postoperative. Mean differences in postoperative values were statistically significant (P < .05) for weight, vitamin B12, and vitamin D but not for hemoglobin, ferritin, calcium, folate, vitamin B1, copper, and zinc. CONCLUSION: Our study suggests that three or more RD visits during the first 12 months after bariatric surgery are associated with improved outcomes, including significant percent total body weight loss and lower rates of micronutrient deficiencies.

Efficacy of Handheld Ultrasound in Medical Education: A Comprehensive Systematic Review and Narrative Analysis.

Miniaturization has made ultrasound (US) technology ultraportable and, in association with their relatively low cost, made handheld devices attractive for medical education training programs. However, performing an ultrasound requires complex skills, and it is unclear whether handheld devices are suitable for the training of novices. Our study aimed to identify to what extent handheld US devices can be employed in medical undergraduates' and residents' education. We selected studies that evaluate the results obtained by students and/or residents who have participated in ultrasound training programs using handheld devices. The studies were included if they reported post-test (pre-test optional) achievements or a comparison with a control group (a group of experts or novices who underwent a different intervention). Twenty-six studies were selected, and their characteristics were summarized. Handheld ultrasound devices were used in training programs to learn echocardiography, abdominal, and/or musculoskeletal ultrasound. Statistically significant progress was noted in the ability of naïve participants to capture and interpret ultrasound images, but training duration influenced the outcomes. While ultrasound training using handheld devices has proven to be feasible for various body regions and purposes (e.g., better understanding of anatomy, clinical applications, etc.), the long-term impacts of handheld education interventions must be considered in addition to the short-term results to outline guidelines for targeted educational needs.

Incremental mortality associated with nontuberculous mycobacterial lung disease among US Medicare beneficiaries with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with nontuberculous mycobacterial lung disease (NTMLD). Both conditions are associated with increased morbidity and mortality, but data are lacking on the additional burden associated with NTMLD among patients with COPD. Thus, the goal of this study was to assess the incremental mortality risk associated with NTMLD among older adults with COPD. METHODS: A retrospective cohort study was conducted using the US Medicare claims database (2010-2017). Patients with preexisting COPD and NTMLD (cases) were matched 1:3 by age and sex with patients with COPD without NTMLD (control patients). Patients were followed up until death or data cutoff (December 31, 2017). Incremental risk of mortality was evaluated by comparing the proportions of death, annualized mortality rate, and mortality hazard rate between cases and control patients using both univariate and multivariate analyses adjusting for age, sex, comorbidities, and COPD severity. RESULTS: A total of 4,926 cases were matched with 14,778 control patients. In univariate analyses, a higher proportion of cases (vs. control patients) died (41.5% vs. 26.7%; P < 0.0001), unadjusted annual mortality rates were higher among cases (158.5 vs. 86.0 deaths/1000 person-years; P < 0.0001), and time to death was shorter for cases. This increased mortality risk was also reflected in subsequent multivariate analyses. Patients with COPD and NTMLD were more likely to die (odds ratio [95% CI], 1.39 [1.27-1.51]), had higher mortality rates (rate ratio [95% CI], 1.36 [1.28-1.45]), and had higher hazard of death (hazard ratio [95% CI], 1.37 [1.28-1.46]) than control patients. CONCLUSIONS: The substantial incremental mortality burden associated with NTMLD in patients with COPD highlights the importance of developing interventions targeting this high-risk group and may indicate an unmet need for timely and appropriate management of NTMLD.

Safety assessment of Enterococcus lactis strains complemented with comparative genomics analysis reveals probiotic and safety characteristics of the entire species.

BACKGROUND: The gut microbiota is considered a rich source for potential novel probiotics. Enterococcus genus is a normal component of a healthy gut microbiota, suggesting its vital role. Nosocomial infections caused mainly by E. facalis and E. faecium have been attributed to the plasticity of the Enterococcus genomes. In this study, we assessed the probiotic and safety characteristics of two E. lactis strains isolated from the human gut microbiota using in-vitro and in silico approaches. Additionally, the safety of the E. lactis species was evaluated using comparative genomics analysis. RESULTS: The two E. lactis strains 10NA and 50NA showed resistance to bile salts and acid tolerance with antibacterial activity against Escherichia coli, Salmonella typhi, and Clostridioides difficile. For safety assays, the two strains did not display any type of hemolysis on blood agar, and the survival of Caco-2 cells was not significantly different (P-value > 0.05) compared to the control using cell free supernatants at 100% (v/v), 50% (v/v), 10% (v/v), and 5% (v/v) concentrations. Regarding antibiotic susceptibility, both strains were sensitive to vancomycin, tetracycline, and chloramphenicol. Comprehensive whole-genome analysis revealed no concerning associations between virulence or antibiotic resistance genes and any of the identified mobile genetic elements. Comparative genome analysis with closely related E. faecium species genomes revealed the distinctive genomic safety of the E. lactis species. CONCLUSIONS: Our two E. lactis strains showed promising probiotic properties in-vitro. Their genomes were devoid of any transferable antibiotic resistance genes. In silico comparative analysis confirmed the safety of the E. lactis species. These results suggest that E. lactis species could be a potential source for safer Enterococcus probiotic supplements.

Tejocote Root's Role in Symptomatic Mobitz Type 1 Heart Block: A Compelling Case Report.

The clinical presentation and diagnosis of Tejocote root toxicity causing Mobitz Type 1 remains a scarcely clinical phenomenon, often resulting in delayed diagnosis and treatment. This case report highlights a 30-year-old female presenting with a constellation of symptoms, including fatigue, dizziness, chest pressure, myalgias, nausea, vomiting, and peripheral tingling. Significantly, the patient had been using Tejocote root as an over-the-counter laxative acquired from Mexico. Laboratory findings revealed detectable Digoxin levels in her bloodstream, while an electrocardiogram (EKG) indicated sinus bradycardia with Mobitz Type 1 heart block. The patient was treated with a single dose of atropine 0.5 mg IV push. A repeat EKG before discharge showed resolution of the Mobitz type 1. This case underscores the potential cardiovascular repercussions of Tejocote root consumption and emphasizes the importance of heightened clinical awareness, especially in regions where such herbal supplement usage is prevalent.

The HACE1 E3 ligase mediates RAC1-dependent control of mTOR signaling complexes.

HACE1 is a HECT family E3 ubiquitin-protein ligase with broad but incompletely understood tumor suppressor activity. Here, we report a previously unrecognized link between HACE1 and signaling complexes containing mammalian target of rapamycin (mTOR). HACE1 blocks mTORC1 and mTORC2 activities by reducing mTOR stability in an E3 ligase-dependent manner. Mechanistically, HACE1 binds to and ubiquitylates Ras-related C3 botulinum toxin substrate 1 (RAC1) when RAC1 is associated with mTOR complexes, including at focal adhesions, leading to proteasomal degradation of RAC1. This in turn decreases the stability of mTOR to reduce mTORC1 and mTORC2 activity. HACE1 deficient cells show enhanced mTORC1/2 activity, which is reversed by chemical or genetic RAC1 inactivation but not in cells expressing the HACE1-insensitive mutant, RAC1K147R . In vivo, Rac1 deletion reverses enhanced mTOR expression in KRasG12D -driven lung tumors of Hace1-/- mice. HACE1 co-localizes with mTOR and RAC1, resulting in RAC1-dependent loss of mTOR protein stability. Together, our data demonstrate that HACE1 destabilizes mTOR by targeting RAC1 within mTOR-associated complexes, revealing a unique ubiquitin-dependent process to control the activity of mTOR signaling complexes.

Persistent Headaches in an Avid Hiker: A Case of Chronic Coccidioidal Meningitis.

The clinical presentation, diagnosis, treatment, and complications of coccidioidal meningitis caused by the dimorphic pathogenic fungus Coccidioides (Coccidioides immitis and Coccidioides posadasii) have been well documented in the literature. Despite the abundance of literature concerning this disease manifestation, it is not very commonly seen in clinical practice, delaying its diagnosis and treatment and leading to devastating neurological sequelae. Therefore, considering this disease process as a potential diagnosis in endemic areas is important for appropriate and timely treatment. We present the case of a 26-year-old male who was found to have chronic coccidioidal meningitis on further investigation. The patient presented as a transfer for an abnormal head MRI with a three-month history of progressive occipital headaches and shortness of breath. Associated symptoms included transit vision loss, upper extremity numbness, night sweats, decreased appetite, and weight loss. Relevant risk factors were being a hiker and living in the southwest of Texas. The patient was started on empiric ceftriaxone and vancomycin. A repeat MRI showed leptomeningeal enhancement and acute infarcts in the left temporal lobe and lentiform nucleus. Cerebrospinal fluid (CSF) analysis showed pleocytosis with lymphocytic predominance, the presence of eosinophils, elevated protein level, and an extremely low glucose level. Further workup ruled out syphilis and tuberculosis. Therefore, considering his clinical presentation, risk factors, and workup results, ceftriaxone and vancomycin were discontinued, and high-dose oral fluconazole was started, which produced a marked clinical response within the next 48 hours. A CT thorax showed findings suggestive of pulmonary coccidioidomycosis, and Coccidioides serology in both serum and CSF specimens returned positive.