A case of possible transfusion-acquired malaria in Zaragoza, Spain.

We present the case of a 75-year-old patient diagnosed with malaria, a native of Zaragoza, Spain, despite having no travel history to malaria-endemic regions. Following an extensive investigation, transfusion emerged as the most probable mode of transmission.

Correction: Evaluation of a community-based HIV test and start program in a conflict affected rural area of Yambio County, South Sudan.

[This corrects the article DOI: 10.1371/journal.pone.0254331.].

Aster-B-dependent estradiol synthesis protects female mice from diet-induced obesity.

Aster proteins mediate the nonvesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). However, the importance of nonvesicular sterol movement for physiology and pathophysiology in various tissues is incompletely understood. Here we show that loss of Aster-B leads to diet-induced obesity in female but not in male mice, and that this sex difference is abolished by ovariectomy. We further demonstrate that Aster-B deficiency impairs nonvesicular cholesterol transport from the PM to the ER in ovaries in vivo, leading to hypogonadism and reduced estradiol synthesis. Female Aster-B-deficient mice exhibit reduced locomotor activity and energy expenditure, consistent with established effects of estrogens on systemic metabolism. Administration of exogenous estradiol ameliorates the diet-induced obesity phenotype of Aster-B-deficient female mice. These findings highlight the key role of Aster-B-dependent nonvesicular cholesterol transport in regulating estradiol production and protecting females from obesity.

Dynamic nature of BRAF or KRAS p.G12C mutations in second-line therapy for advanced colorectal cancer patients: do early and late effects exist?

INTRODUCTION: The mitogen-activated protein kinase (MAPK) signalling network aberrations in metastatic colorectal cancer (mCRC) generate intrinsic dynamic effects and temporal variations that are crucial but often overlooked in clinical trial populations. Here, we investigate the time-varying impact of MAPK pathway mutation genotype on each treatment line's contribution to the overall clinical course. METHODS: The PROMETEO study focused on mCRC patients undergoing second-line treatment at 20 hospitals. We evaluated genotypes and employed flexible models to analyse the dynamic effect of each mutation. RESULTS: We examined data derived from 1160 patients. The effects of KRAS G12C or G12V, and BRAF V600E are clearly time-varying, with unexpected consequences such as the deleterious effect of BRAF V600E vs other genotypes dissipating over time when subjects receive antiangiogenics, or KRAS G12V and G12C showing increasing aggressiveness over time. Thus, contrary to expectations, the 12-month survival rate from the second line for those who survived >6 months was 49.9% (95% CI, 32.7-67.3) for KRAS G12C and 59% (95% CI, 38.5-80.6) for BRAF V600E. CONCLUSIONS: The dynamic perspective is essential for understanding the behaviour of tumours with specific genotypes, especially from the second line onward. This may be relevant in patient monitoring and treatment decision-making, particularly in cases with distinct mutations.

Antibiotic susceptibility patterns of pathogens isolated from hospitalized patients with advanced HIV disease (AHD) in Bihar, India.

Objectives: To describe the prevalence of common bacterial pathogens and antibiotic susceptibility patterns amongst advanced HIV disease (AHD) patients admitted between May 2019 and March 2021 to a Médecins Sans Frontières (MSF)-supported AHD inpatient unit in Bihar, India. Methods: A retrospective analysis of routinely collected demographic, clinical and microbiological data. Antibacterial susceptibility testing was done by an accredited referral laboratory using the modified Kirby-Bauer disc diffusion method. Results: A total of 238 isolates from 577 patients were identified through culture testing. Patient median (IQR) age was 38 (31-45) years, and 75% were male. Predominant sample types included blood (600; 38%), urine (266; 17%) and sputum (178; 11%). Of the isolated bacteria, Escherichia coli (80; 13.9%) was the most prevalent, followed by Klebsiella pneumonia (54; 9.4%), Pseudomonas aeruginosa (22; 3.8%), Klebsiella oxytoca (10; 1.7%), Proteus mirabilis (9; 1.6%), and Acinetobacter baumannii (7; 1.2%). The resistance pattern showed that most bacterial isolates were highly resistant to commonly prescribed antibiotics such as third-generation cephalosporins, fluoroquinolones and co-trimoxazole. Most pathogens were moderately resistant to antibiotics from the WHO Watch group, such as meropenem and piperacillin/tazobactam. In contrast, isolates were more susceptible to aminoglycosides, such as amikacin, gentamicin and nitrofurantoin. Conclusions: In Bihar, inpatients with AHD displayed a concerning array of antibiotic-resistant infections. This study provides a starting point from which further work on antimicrobial resistance in this vulnerable cohort of patients can be conducted.

Characterizing the protein-protein interaction between MDM2 and 14-3-3σ; proof of concept for small molecule stabilization.

Mouse Double Minute 2 (MDM2) is a key negative regulator of the tumor suppressor protein p53. MDM2 overexpression occurs in many types of cancer and results in the suppression of WT p53. The 14-3-3 family of adaptor proteins are known to bind MDM2 and the 14-3-3σ isoform controls MDM2 cellular localization and stability to inhibit its activity. Therefore, small molecule stabilization of the 14-3-3σ/MDM2 protein-protein interaction (PPI) is a potential therapeutic strategy for the treatment of cancer. Here, we provide a detailed biophysical and structural characterization of the phosphorylation-dependent interaction between 14-3-3σ and peptides that mimic the 14-3-3 binding motifs within MDM2. The data show that di-phosphorylation of MDM2 at S166 and S186 is essential for high affinity 14-3-3 binding and that the binary complex formed involves one MDM2 di-phosphorylated peptide bound to a dimer of 14-3-3σ. However, the two phosphorylation sites do not simultaneously interact so as to bridge the 14-3-3 dimer in a 'multivalent' fashion. Instead, the two phosphorylated MDM2 motifs 'rock' between the two binding grooves of the dimer, which is unusual in the context of 14-3-3 proteins. In addition, we show that the 14-3-3σ-MDM2 interaction is amenable to small molecule stabilization. The natural product fusicoccin A forms a ternary complex with a 14-3-3σ dimer and an MDM2 di-phosphorylated peptide resulting in the stabilization of the 14-3-3σ/MDM2 PPI. This work serves as a proof-of-concept of the drugability of the 14-3-3/MDM2 PPI and paves the way toward the development of more selective and efficacious small molecule stabilizers.

Anti-allodynic and anti-hyperalgesic activity of (±)-licarin A in neuropathic rats via NO-cyclic-GMP-ATP-sensitive K+ channel pathway.

The study aimed to examine the effect of intraperitoneal and intrathecal (±)-licarin A in neuropathic pain induced by L5 and L6 spinal nerve ligation (SNL) in male Wistar rats and the possible involvement of the NO-cGMP-ATP-sensitive K+ channel pathway. Neuropathic pain signs (allodynia and hyperalgesia) were evaluated on postoperative Day 14 using von Frey filaments. Single intraperitoneal (0.01, 0.1, 1, and 10 mg/kg) and intrathecal (0.01, 0.1, 1, and 10 µg/rat) administration of (±)-licarin A improved allodynia and hyperalgesia. The (±)-licarin A-induced anti-allodynic and anti-hyperalgesic activity was prevented by the intrathecal injection of  l-NAME (100 µg/rat; nonselective nitric oxide synthase inhibitor), ODQ (10 µg/rat; guanylate cyclase inhibitor), and glibenclamide (50 µg/rat; adenosine triphosphate (ATP)-sensitive K+ channel blocker). The data suggest that (±)-licarin A exerts its anti-allodynic and anti-hyperalgesic activity by activating the NO-cGMP-ATP-sensitive K+ channel pathway.

Structural insights into the complex of oncogenic KRas4BG12V and Rgl2, a RalA/B activator.

About a quarter of total human cancers carry mutations in Ras isoforms. Accumulating evidence suggests that small GTPases, RalA, and RalB, and their activators, Ral guanine nucleotide exchange factors (RalGEFs), play an essential role in oncogenic Ras-induced signalling. We studied the interaction between human KRas4B and the Ras association (RA) domain of Rgl2 (Rgl2RA), one of the RA-containing RalGEFs. We show that the G12V oncogenic KRas4B mutation changes the interaction kinetics with Rgl2RA The crystal structure of the KRas4BG12V: Rgl2RA complex shows a 2:2 heterotetramer where the switch I and switch II regions of each KRasG12V interact with both Rgl2RA molecules. This structural arrangement is highly similar to the HRasE31K:RALGDSRA crystal structure and is distinct from the well-characterised Ras:Raf complex. Interestingly, the G12V mutation was found at the dimer interface of KRas4BG12V with its partner. Our study reveals a potentially distinct mode of Ras:effector complex formation by RalGEFs and offers a possible mechanistic explanation for how the oncogenic KRas4BG12V hyperactivates the RalA/B pathway.

Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake.

Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.

Molecular diagnosis of Chagas disease: a systematic review and meta-analysis.

BACKGROUND: The complexity of the Chagas disease and its phases is impossible to have a unique test for both phases and a lot of different epidemiological scenarios. Currently, serology is the reference standard technique; occasionally, results are inconclusive, and a different diagnostic technique is needed. Some guidelines recommend molecular testing. A systematic review and meta-analysis of available molecular tools/techniques for the diagnosis of Chagas disease was performed to measure their heterogeneity and efficacy in detecting Trypanosoma cruzi infection in blood samples. METHODS: A systematic review was conducted up to July 27, 2022, including studies published in international databases. Inclusion and exclusion criteria were defined to select eligible studies. Data were extracted and presented according to PRISMA 2020 guidelines. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). A random-effects model was used to calculate pooled sensitivity, specificity, and diagnostic odds ratio (DOR). Forest plots and a summary of the receiving operating characteristics (SROC) curves displayed the outcomes. Heterogeneity was determined by I2 and Tau2 statistics and P values. Funnel plots and Deek's test were used to assess publication bias. A quantitative meta-analysis of the different outcomes in the two different clinical phases was performed. RESULTS: We identified 858 records and selected 32 papers. Studies pertained to endemic countries and nonendemic areas with adult and paediatric populations. The sample sizes ranged from 17 to 708 patients. There were no concerns regarding the risk of bias and applicability of all included studies. A positive and nonsignificant correlation coefficient (S = 0.020; P = 0.992) was obtained in the set of studies that evaluated diagnostic tests in the acute phase population (ACD). A positive and significant correlation coefficient (S = 0.597; P < 0.000) was obtained in the case of studies performed in the chronic phase population (CCD). This resulted in high heterogeneity between studies, with the master mix origin and guanidine addition representing significant sources. INTERPRETATION/CONCLUSIONS AND RELEVANCE: The results described in this meta-analysis (qualitative and quantitative analyses) do not allow the selection of the optimal protocol of molecular method for the study of Trypanosoma cruzi infection in any of its phases, among other reasons due to the complexity of this infection. Continuous analysis and optimization of the different molecular techniques is crucial to implement this efficient diagnosis in endemic areas.

Methodology for evaluating bibliographic references for works published under the Ecimed publishing label / Metodología de evaluación de referencias bibliográficas para las obras editadas bajo el sello editorial Ecimed

Introduction: what is meritorious and necessary about quality bibliographic citations and references is that they support the contents, provide reliability and allow verification and expansion of knowledge with transparency. The Ciencias Médicas Publishing House is immersed in the implementation of the quality management system, which covers all editorial processes to facilitate the publication of high-quality works. Objective: establish the methodology for evaluating the quality of citations and bibliographic references of the works to be edited. Methods: to design the methodology, a qualitative documentary research study was carried out, aimed at obtaining information through the collection, organization and analysis of documents of any kind such as bibliographic, newspaper or archival sources, both physical and digital. The methodology designed by the Mexican authors Martín and Lafuente was taken as a basis, who in 2017 published nine evaluation indicators of bibliographic references, which were analyzed, tempered and the dimensions that gave rise to the methodology were designed. For each dimension, with its criteria, indicators, norms and/or evaluation standards were built, harmonized according to the identified guidelines, thus designing the first version of the methodology. Results: after the evaluative analysis of each dimension, the final evaluation of the references of the work was carried out and for this the evaluation criteria proposed in the methodology to be implemented were output. Conclusions: the methodology for evaluating the quality of bibliographies citations that we propose for works published under the Ecimed publishing label requires an implementation and validation process. Generating quality citations for researchers that are useful in their own research contributes to Open Science.

Introducción: lo meritorio y necesario de las citas y referencias bibliográficas con calidad, es que sirven de sostén a los contenidos, proporcionan fiabilidad y permiten su verificación y ampliación de conocimientos con transparencia. La Editorial Ciencias Médicas está inmersa en la implementación del sistema de gestión de la calidad, que abarca todos los procesos editoriales para facilitar la publicación de obras de elevada calidad. Objetivo: establecer la metodología de evaluación de la calidad de las citas y referencias bibliográficas de las obras a editar. Métodos: para el diseño de la metodología se realizó un estudio cualitativo, de investigación documental, dirigida a la obtención de información mediante la recopilación, organización y análisis de documentos de cualquier especie como fuentes bibliográficas, hemerográficas o archivísticas, tanto físicas como digitales. Se tomó como base la metodología diseñada por las autoras mexicanas Martín y Lafuente, quienes en 2017 publicaron nueve indicadores de evaluación de las referencias bibliográficas, los que se analizaron, atemperaron y se diseñaron las dimensiones que dieron salida a la metodología. A cada dimensión, con sus criterios, se le construyeron indicadores, normas y/o estándares de evaluación, armonizados según las pautas identificadas, quedando diseñada la primera versión de la metodología. Resultados: posterior al análisis evaluativo de cada dimensión se realizó la evaluación final de las referencias de la obra y para ello se dieron salida a los criterios de evaluación que se proponen en la metodología a implementar. Conclusiones: la metodología de evaluación de la calidad de las citas bibliografías que proponemos para las obras editadas bajo el sello editorial Ecimed, requiere de un proceso de implementación y validación. Generar citas de calidad para los investigadores y que les sean útiles en su propia investigación, tributa a la Ciencia Abierta.

Antimicrobial stewardship in primary health care programs in humanitarian settings: the time to act is now.

Fragile and conflict-affected settings bear a disproportionate burden of antimicrobial resistance, due to the compounding effects of weak health policies, disrupted medical supply chains, and lack of knowledge and awareness about antibiotic stewardship both among health care providers and health service users. Until now, humanitarian organizations intervening in these contexts have confronted the threat of complex multidrug resistant infections mainly in their surgical projects at the secondary and tertiary levels of care, but there has been limited focus on ensuring the implementation of adequate antimicrobial stewardship in primary health care, which is known to be setting where the highest proportion of antibiotics are prescribed. In this paper, we present the experience of two humanitarian organizations, Médecins sans Frontières and the International Committee of the Red Cross, in responding to antimicrobial resistance in their medical interventions, and we draw from their experience to formulate practical recommendations to include antimicrobial stewardship among the standards of primary health care service delivery in conflict settings. We believe that expanding the focus of humanitarian interventions in unstable and fragile contexts to include antimicrobial stewardship in primary care will strengthen the global response to antimicrobial resistance and will decrease its burden where it is posing the highest toll in terms of mortality.

Role of Chemical Reduction and Formulation of Graphene Oxide on Its Cytotoxicity towards Human Epithelial Bronchial Cells.

Graphene-based materials may pose a potential risk for human health due to occupational exposure, mainly by inhalation. This study was carried out on bronchial epithelial 16HBE14o- cells to evaluate the role of chemical reduction and formulation of graphene oxide (GO) on its cytotoxic potential. To this end, the effects of GO were compared to its chemically reduced form (rGO) and its stable water dispersion (wdGO), by means of cell viability reduction, reactive oxygen species (ROS) generation, pro-inflammatory mediators release and genotoxicity. These materials induced a concentration-dependent cell viability reduction with the following potency rank: rGO > GO >> wdGO. After 24 h exposure, rGO reduced cell viability with an EC50 of 4.8 µg/mL (eight-fold lower than that of GO) and was the most potent material in inducing ROS generation, in contrast to wdGO. Cytokines release and genotoxicity (DNA damage and micronucleus induction) appeared low for all the materials, with wdGO showing the lowest effect, especially for the former. These results suggest a key role for GO reduction in increasing GO cytotoxic potential, probably due to material structure alterations resulting from the reduction process. In contrast, GO formulated in a stable dispersion seems to be the lowest cytotoxic material, presumably due to its lower cellular internalization and damaging capacity.

Aster-dependent non-vesicular transport facilitates dietary cholesterol uptake.

Intestinal cholesterol absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe (EZ), assists in the initial step of dietary cholesterol uptake. However, how cholesterol moves downstream of NPC1L1 is unknown. Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes, bridging NPC1L1 at the plasma membrane (PM) and ACAT2 in the endoplasmic reticulum (ER). Loss of NPC1L1 diminishes accessible PM cholesterol in enterocytes and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate cholesterol at the PM and display evidence of ER cholesterol depletion, including decreased cholesterol ester stores and activation of the SREBP-2 transcriptional pathway. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, we show that the Aster pathway can be targeted with a small molecule inhibitor to manipulate dietary cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption. One-Sentence Summary: Identification of a targetable pathway for regulation of dietary cholesterol absorption.

Point-of-care ultrasound for tuberculosis diagnosis in children: a Médecins Sans Frontières cross-sectional study in Guinea-Bissau.

OBJECTIVE: Description of tuberculosis (TB)-focused point-of-care ultrasound (POCUS) findings for children with presumptive TB. DESIGN: Cross-sectional study (July 2019 to April 2020). SETTING: Simão Mendes hospital in Bissau, a setting with high TB, HIV, and malnutrition burdens. PARTICIPANTS: Patients aged between 6 months and 15 years with presumptive TB. INTERVENTIONS: Participants underwent clinical, laboratory and unblinded clinician-performed POCUS assessments, to assess subpleural nodules (SUNs), lung consolidation, pleural and pericardial effusion, abdominal lymphadenopathy, focal splenic and hepatic lesions and ascites. Presence of any sign prompted a POCUS positive result. Ultrasound images and clips were evaluated by expert reviewers and, in case of discordance, by a second reviewer. Children were categorised as confirmed TB (microbiological diagnosis), unconfirmed TB (clinical diagnosis) or unlikely TB. Ultrasound findings were analysed per TB category and risk factor: HIV co-infection, malnutrition and age. RESULTS: A total of 139 children were enrolled, with 62 (45%) women and 55 (40%) aged <5 years; 83 (60%) and 59 (42%) were severely malnourished (SAM) and HIV-infected, respectively. TB confirmation occurred in 27 (19%); 62 (45%) had unconfirmed TB and 50 (36%) had unlikely TB. Children with TB were more likely to have POCUS-positive results (93%) compared with children with unlikely TB (34%). Common POCUS signs in patients with TB were: lung consolidation (57%), SUNs (55%) and pleural effusion (30%), and focal splenic lesions (28%). In children with confirmed TB, POCUS sensitivity was 85% (95% CI) (67.5% to 94.1%). In those with unlikely TB, specificity was 66% (95% CI 52.2% to 77.6%). Unlike HIV infection and age, SAM was associated with a higher POCUS-positivity. Cohen's kappa coefficient for concordance between field and expert reviewers ranged from 0.6 to 0.9. CONCLUSIONS: We found a high prevalence of POCUS signs in children with TB compared with children with unlikely TB. POCUS-positivity was dependent on nutritional status but not on HIV status or age. TB-focused POCUS could potentially play a supportive role in the diagnosis of TB in children. TRIAL REGISTRATION NUMBER: NCT05364593.

Impact of pneumocystosis on the Spanish health care system, 1997-2020: Profile of HIV and non-HIV immunocompromised patients.

BACKGROUND: Pneumocystis jirovecii is an opportunistic fungus recognized for causing P. jirovecii pneumonia. The global prevalence is thought to be higher than 400,000 annual cases, although detailed information about epidemiological patterns is scarce. METHODOLOGY: A retrospective longitudinal descriptive study was performed among patients with diagnosis of pneumocystosis according to Classification of Diseases 9th edition, Clinical Modification (code 136.3 for the cases from 1997 to 2015; and 10th edition code B59.0 for cases from 2016 to 2020 in Spanish public hospitals from 1 January 1997-31 December 2020. RESULTS: A total of 25289 cases were diagnosed. The period incidence rate was 2.36 (95 % CI, 2.33-2.39) cases per 100,000 person-years. Infection was more frequent among men (72.2 %) than among women (27.8 %). Comorbidity was the main characteristic of this cohort. Up to 72.3 % of pneumocystis-infected patients (18293) had HIV coinfection. During the study period, there was a progressive decrease in the number of HIV coinfected cases as the group of patients without HIV infection increased, with the largest group in 2017. The lethality rate in the cohort was 16.7 %. The global cost was €229,234,805 and the average ( ± SD) cost per patient was €9065 ( ± 9315). CONCLUSIONS: The epidemiology of pneumocystosis in Spain has changed in the last two decades. We noted in our study the possibility of a reemergence among non-HIV immunocompromised patients as patients with hematological and nonhematological neoplasia and other risk groups. The lethality of pneumocystosis continues to be high, and the underlying diseases are the main variable associated with lethality.

Is babesiosis a rare zoonosis in Spain? Its impact on the Spanish Health System over 23 years.

BACKGROUND: Babesiosis is a zoonosis caused by an intraerythrocytic protozoan of the genus Babesia and transmitted mainly by ticks of the Ixodes spp. complex. There is no comprehensive global incidence in the literature, although the United States, Europe and Asia are considered to be endemic areas. In Europe, the percentage of ticks infected with Babesia spp. ranges from 0.78% to 51.78%. The incidence of babesiosis in hospitalized patients in Spain is 2.35 cases per 10,000,000 inhabitants/year. The mortality rate is estimated to be approximately 9% in hospitalized patients but can reach 20% if the disease is transmitted by transfusion. OBJECTIVE: To analyze the epidemiological impact of inpatients diagnosed with babesiosis on the National Health System (NHS) of Spain between 1997 and 2019. METHODOLOGY: A retrospective longitudinal descriptive study that included inpatients diagnosed with babesiosis [ICD-9-CM code 088.82, ICD-10 code B60.0, cases ap2016-2019] in public Spanish NHS hospitals between 1 January 1997 and 31 December 2019 was developed. Data were obtained from the minimum basic dataset (CMBD in Spanish), which was provided by the Ministerio de Sanidad, Servicios Sociales e Igualdad after the receipt of a duly substantiated request and the signing of a confidentiality agreement. MAIN FINDINGS: Twenty-nine inpatients diagnosed with babesiosis were identified in Spain between 1997 and 2019 (IR: 0.28 cases/10,000,000 person-years). A total of 82.8% of the cases were men from urban areas who were approximately 46 years old. The rate of primary diagnoses was 55.2% and the number of readmissions was 79.3%. The mean hospital stay was 20.3±19.2 days, with an estimated cost of €186,925.66. Two patients, both with secondary diagnoses of babesiosis, died in our study. CONCLUSIONS: Human babesiosis is still a rare zoonosis in Spain, with an incidence rate that has been increasing over the years. Most cases occurred in middle-aged men from urban areas between summer and autumn. The Castilla-La-Mancha and Extremadura regions recorded the highest number of cases. Given the low rate of primary diagnoses (55.2%) and the high number of readmissions (79.3%), a low clinical suspicion is likely. There was a 6.9% mortality in our study. Both patients who died were patients with secondary diagnoses of the disease.

Sohlh1 loss of function male and female infertility model impacts overall health beyond gonadal dysfunction in mice†.

Reproductive longevity is associated with health outcomes. Early menopause, loss of ovarian function, and male infertility are linked to shorter lifespan and increased adverse health outcomes. Here we examined the extragonadal effects of whole animal loss of spermatogenesis and oogenesis specific basic helix-loop-helix 1 (Sohlh1) gene in mice, a well-described mouse model of female and male infertility. Sohlh1 encodes a transcription factor that is primarily expressed in the male and female germline and regulates germline differentiation. The Sohlh1 knockout mouse model, just like human individuals with SOHLH1 loss of function, presents with hypergonadotropic hypogonadism and loss of ovarian function in females and impaired spermatogenesis in males, with a seemingly gonad restricted phenotype in both sexes. However, extragonadal phenotyping revealed that Sohlh1 deficiency leads to abnormal immune profiles in the blood and ovarian tissues of female animals, sex-specific alterations of metabolites, and behavior and cognition changes. Altogether, these results show that Sohlh1 deficiency impacts overall health in both male and female mice.

Crimean-Congo Hemorrhagic Fever, Spain, 2013-2021.

Crimean-Congo hemorrhagic fever (CCHF) is a viral infectious disease for which distribution of the main vector, Hyalomma spp. ticks, is expanding. We analyzed all 10 cases of CCHF diagnosed in Spain during 2013-2021; case-patient median age was 56.5 years, and 7 were men. We identified CCHF virus genotypes III and V. Six case-patients acquired the infection in urban areas. Sixty percent of patients were infected in summer and 40% in spring. Two patients met criteria for hemophagocytic syndrome. Seven patients survived. The epidemiologic pattern of CCHF in Spain is based on occasional cases with an elevated mortality rate. Genotype III and, to a less extent also genotype V, CCHF circulates in humans in a common geographic area in Spain. Those data suggest that the expansion pathways are complex and may change over time. Physicians should remain alert to the possibility of new CCHF cases.