State-dependent signaling by Cav1.2 regulates hair follicle stem cell function.

The signals regulating stem cell activation during tissue regeneration remain poorly understood. We investigated the baldness associated with mutations in the voltage-gated calcium channel (VGCC) Cav1.2 underlying Timothy syndrome (TS). While hair follicle stem cells express Cav1.2, they lack detectable voltage-dependent calcium currents. Cav1.2(TS) acts in a dominant-negative manner to markedly delay anagen, while L-type channel blockers act through Cav1.2 to induce anagen and overcome the TS phenotype. Cav1.2 regulates production of the bulge-derived BMP inhibitor follistatin-like1 (Fstl1), derepressing stem cell quiescence. Our findings show how channels act in nonexcitable tissues to regulate stem cells and may lead to novel therapeutics for tissue regeneration.

Cell Therapy Clinical Trials for Stress Urinary Incontinence: Current Status and Perspectives.

Stress urinary incontinence (SUI) affects 200 million people worldwide. Standard therapies often provide symptomatic relief, but without targeting the underlying etiology, and show tremendous patient-to-patient variability, limited success and complications associated with the procedures. We review in this article the latest clinical trials performed to treat SUI using cell-based therapies. These therapies, despite typically including only a small number of patients and short term evaluation of results, have proven to be feasible and safe. However, there is not yet a consensus for the best cell source to be used to treat SUI and not all patients may be suitable for these therapies. Therefore, more clinical trials should be promoted recruiting large number of patients and evaluating long term results.

[Successful oral desensitization to levothyroxine. Report of one case]. / Desensibilización a levotiroxina. Caso clínico.

We report a 39-year-old female who underwent a total thyroidectomy as treatment for a thyroid papillary cancer. She suffered several episodes of mild angioedema in lips and tongue, after using different commercial Levothyroxine formulations, with and without excipients. Given the need to use this drug, the patient was admitted in our hospital and we proceeded to desensitize her with oral Levothyroxine. The patient fasted throughout the whole procedure, was properly monitored and had an adequate peripheral venous access. On the first day of the procedure, a 15-step protocol was performed, first administering placebo and then, compounded formulations of Levothyroxine starting from 0.01 ug, followed by doubling doses every 15 minutes until the cumulative dose of 111.95 ug was completed, corresponding to the daily dose of Levothyroxine her endocrinologist prescribed (112 ug). The patient was monitored at baseline, between each dose and up to 3 hours after the procedure was completed. There were no incidents such as urticaria, angioedema, or others. On the second day, the patient received a single-full dose of 112 ug on an empty stomach. The medication was successfully tolerated and she was discharged. Thereafter, she tolerates daily Levothyroxine.

Impact of inappropriate antifungal therapy according to current susceptibility breakpoints on Candida bloodstream infection mortality, a retrospective analysis.

BACKGROUND: The mortality of Candida Bloodstream Infection (CBSI) remains high. Antifungal susceptibility breakpoints were recently updated for Candida species, the impact remains unknown. In this study we evaluated the impact of inappropriate antifungal treatment according to recent breakpoints on 30-day mortality of CBSI. METHODS: From June 2008 to July 2014, data on CBSI episodes from two tertiary-care centers, treated > 72 h were analyzed. Antifungal therapy and 30-day mortality were registered. Inappropriate antifungal treatment according to current Clinical & Laboratory Standards Institute (CLSI) breakpoints was adjusted with 30-day mortality-related co-variates. RESULTS: One hundred forty-nine episodes of CBSI were analyzed. The most frequent species were: C. albicans (40%), C. tropicalis (23%) and C. glabrata complex (20%). According to the 2012 CLSI, 10.7% received inappropriate treatment. The 30-day mortality was 38%; severe sepsis [Odds ratio (OR) 3.4; 95% CI 1.3-8.4], cirrhosis (OR 36; 95% CI 12.2-605), early central venous catheter removal (OR 0.23; 95% CI 0.08-0.66) and previous antifungal therapy (OR 0.15; 95%CI 0.03-0.62), were associated with 30-day mortality by multivariate analysis. Inappropriate antifungal treatment was not (OR 0.19; 95% CI 0.03-1.2). CONCLUSIONS: Appropriate antifungal therapy according to CLSI 2012 did not have an impact on mortality. Mortality of CBSI remains high due to disease severity and comorbidities; early antifungal therapy and catheter removal may reduce it.

IGFBP-3 Interacts with the Vitamin D Receptor in Insulin Signaling Associated with Obesity in Visceral Adipose Tissue.

Adipose tissue has traditionally only been considered as an energy storage organ. Nevertheless, the importance of this tissue in systemic physiology and, especially, in systemic inflammation has been highlighted in recent years. Adipose tissue expresses proteins related to vitamin D (VD) metabolism, and it has been proposed that it can act as a VD storage tissue. The active form of VD, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is able to modify adipocyte and adipose tissue physiology via the VD receptor (VDR), decreasing the expression of pro-inflammatory cytokines in adipose tissue. Moreover, VD deficiency and VDR has been reported to be associated with obesity and diabetes. However, the results of the different studies are not conclusive. Insulin growth binding proteins (IGFBPs) have been identified in adipose tissue, but their roles are poorly understood. Therefore, the objective of this study was to analyze the plasma levels of VD and the gene expression of VDR in the adipose tissue of subjects with morbid obesity (MO) and with different degrees of insulin resistance (IR), as well as the functionality of direct interaction between IGFBP-3 and VDR, which could explain its inhibitory role in adipogenesis. Our results show a novel role of the VD system in the regulation and activation of IGFBP-3 in visceral adipose tissue (VAT) of patients with MO, as a new and alternative mechanism proposed in the insulin signaling associated with obesity.

PDE5A Polymorphisms Influence on Sildenafil Treatment Success.

INTRODUCTION: Diabetes and cardiovascular disease are risk factors for erectile dysfunction (ED). Selective inhibitors of the type 5 phosphodiesterase are the first option for treating ED. However, it is unknown why there are patients with low response to this treatment. Polymorphisms in the PDE5A gene may influence the response to PDE5 inhibitors treatment. AIM: The aim of this study is to analyze the relationship between PDE5A polymorphisms, diabetes, and the efficacy of sildenafil treatment. METHODS: A Spanish prospective cohort of 170 Caucasian male patients diagnosed with ED and ischemic heart disease treated with angioplasty was studied. MAIN OUTCOME MEASURES: ED was evaluated according to the 5-item version of the International Index for Erectile Function before and after treatment with sildenafil 50 mg. The gene sequence of the PDE5A gene was analyzed for the presence of rs12646525 and rs3806808 polymorphisms. Glucose and glycosylated hemoglobin levels were measured in blood serum samples. The relationship between treatment response, genotype, and glycemic status was analyzed. RESULTS: Patients with G-allele of rs3806808 polymorphism showed a worse response to the treatment compared to TT-homozygote patients. Nondiabetic G-allele carriers showed a worse treatment response than TT-homozygotes patients. These differences were not seen in diabetic patients. There were no significant differences in treatment response according to the rs12646525 polymorphism in total population or according to the glycemic status. Logistic regression analysis showed that nondiabetic carriers of the major allele of both the rs12646525 and rs3806808 polymorphism had a significantly higher likelihood to respond to the treatment than diabetic patients carriers of the minor allele (P < .05). CONCLUSION: The response to sildenafil treatment depends on polymorphisms in the PDE5A gene and the glycemic status of the patients.

Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome.

BACKGROUND: Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases. METHODS: The DNA of eight patients affected by MAS [all of whom presenting with Sjögren's syndrome (SS)], four patients affected by SS alone and 38 unaffected individuals, were subject to WES. Filters to identify novel and rare functional (pathogenic-deleterious) homozygous and/or compound heterozygous variants in these patients and controls were applied. Bioinformatics tools such as the Human gene connectome as well as pathway and network analysis were applied to test overrepresentation of genes harbouring these variants in critical pathways and networks involved in autoimmunity. RESULTS: Eleven novel and rare functional variants were identified in cases but not in controls, harboured in: MACF1, KIAA0754, DUSP12, ICA1, CELA1, LRP1/STAT6, GRIN3B, ANKLE1, TMEM161A, and FKRP. These were subsequently subject to network analysis and their functional relatedness to genes already associated with autoimmunity was evaluated. Notably, the LRP1/STAT6 novel mutation was homozygous in one MAS affected patient and heterozygous in another. LRP1/STAT6 disclosed the strongest plausibility for autoimmunity. LRP1/STAT6 are involved in extracellular and intracellular anti-inflammatory pathways that play key roles in maintaining the homeostasis of the immune system. Further; networks, pathways, and interaction analyses showed that LRP1 is functionally related to the HLA-B and IL10 genes and it has a substantial impact within immunological pathways and/or reaction to bacterial and other foreign proteins (phagocytosis, regulation of phospholipase A2 activity, negative regulation of apoptosis and response to lipopolysaccharides). Further, ICA1 and STAT6 were also closely related to AIRE and IRF5, two very well known autoimmunity genes. CONCLUSIONS: Novel and rare exonic mutations that may account for autoimmunity were identified. Among those, the LRP1/STAT6 novel mutation has the strongest case for being categorised as potentially causative of MAS given the presence of intriguing patterns of functional interaction with other major genes shaping autoimmunity.

Partial proteasome inhibitors induce hair follicle growth by stabilizing ß-catenin.

The activation of tissue stem cells from their quiescent state represents the initial step in the complex process of organ regeneration and tissue repair. While the identity and location of tissue stem cells are becoming known, how key regulators control the balance of activation and quiescence remains mysterious. The vertebrate hair is an ideal model system where hair cycling between growth and resting phases is precisely regulated by morphogen signaling pathways, but how these events are coordinated to promote orderly signaling in a spatial and temporal manner remains unclear. Here, we show that hair cycle timing depends on regulated stability of signaling substrates by the ubiquitin-proteasome system. Topical application of partial proteasomal inhibitors (PaPIs) inhibits epidermal and dermal proteasome activity throughout the hair cycle. PaPIs prevent the destruction of the key anagen signal ß-catenin, resulting in more rapid hair growth and dramatically shortened telogen. We show that PaPIs induce excess ß-catenin, act similarly to the GSK3ß antagonist LiCl, and antagonize Dickopf-related protein-mediated inhibition of anagen. PaPIs thus represent a novel class of hair growth agents that act through transiently modifying the balance of stem cell activation and quiescence pathways.

[Association between family functionality and mild cognitive impairment in the family with the elderly]. / Asociación entre funcionalidad familiar y deterioro cognitivo leve en la familia con adulto mayor.

AIM: To determine the association between family functionality and mild cognitive impairment in the family with the elderly. METHODOLOGY: Analytical cross-sectional design in families with geriatric patients. A family with a geriatric patient was considered when at least one of its members was over 60years of age. The comparison groups were the family with a geriatric patient without cognitive impairment and the family with a geriatric patient with mild cognitive impairment determined with the MoCA instrument. Family functionality was evaluated with the family APGAR instrument, which identifies three categories: family functionality, moderate family dysfunction, and severe family dysfunction. Statistical analysis included Chi square and Mann-Whitney test. RESULTS: In the family with a geriatric patient, in the group without cognitive impairment the prevalence of family functionality is 89.7% and in the group with mild cognitive impairment the prevalence of family functionality is 59.3% (MW=4.87, P<.000). CONCLUSION: There is an association between family functionality and mild cognitive impairment.

Favourable effect of clavulanic acid on the minimum inhibitory concentrations of cefixime and ceftibuten in ESBL-producing Escherichia coli and Klebsiella pneumoniae.

OBJECTIVES: The use of cephalosporins combined with clavulanate for the treatment of ESBL-harbouring Enterobacteriaceae has been scarcely described. We aimed to describe the effect of different concentrations of clavulanate in the MIC of cefixime and ceftibuten of ESBL-producing Escherichia coli and Klebsiella pneumoniae. METHODS: ESBL-producing E. coli and K. pneumoniae isolates were studied. Fixed concentrations of cefixime and ceftibuten (ranges of 32-0.25 and 64-0.5 ng/ml, respectively) were used. Combinations of cefixime/clavulanate and ceftibuten/clavulanate in different ratios (1:0, 1:1, 2:1, 4:1, 8:1, 16:1, 32:1) were tested. MIC were determined by broth microdilution. RESULTS: A total of 6 ESBL-producing E. coli, 6 ESBL-producing K. pneumoniae and 2 control E. coli were tested. When different quantities of clavulanate were added to cefixime and ceftibuten, greater than two-fold decreases in the MIC were observed. When testing the 1:1 cefixime/clavulanate ratio, 10/12 isolates were susceptible. When the ratios 2:1, 4:1, 8:1, and 16:1 were tested, susceptibility was noted for 9/12, 8/12, 4/12, and 5/12 isolates, respectively. Only 2/12 K. pneumoniae isolates were susceptible when the ratio 32:1 was tested. When testing ceftibuten/clavulanate, all isolates remained susceptible across all experiments. CONCLUSIONS: Clavulanic acid has a favourable effect in reducing the MIC of cefixime and ceftibuten in isolates of ESBL-producing E. coli and K. pneumoniae. Combining clavulanate with ceftibuten or cefixime could be a useful treatment strategy.

Hepatocellular carcinoma arising in a telangiectatic hepatocellular adenoma.

Telangiectatic hepatocellular adenoma is a rare, recently recognized subtype of benign liver tumor that may very rarely undergo transformation into hepatocellular carcinoma. We report an unusual case of a 75-year-old woman with no history of oral contraceptive use that underwent malignant transformation of a telangiectactic hepatocellular adenoma. No risk factors for adenoma development were identified in this otherwise healthy woman. Radiological characteristics, gross features and histopathology are herein described. In conclusion, telangiectatic hepatocellular adenoma can undergo malignant transformation. Further studies are needed to better clarify the factors associated with malignant progression.

Sex Surveys in Europe: Reflections on over Four Decades of Sexual Behavior and Sexual Health Surveillance.

Sexual expression is fundamental to human existence and an important topic of enquiry in its own right. Understanding sexual behavior is also essential to establish effective sexual health prevention activities (e.g., education), services and policies, and to assess the progress of policies and action plans. Questions on sexual health are rarely included in general health surveys, and therefore dedicated population studies are required. Many countries lack both funding and sociopolitical support to conduct such surveys. A tradition of periodic population sexual health surveys exists in Europe but the methods used (e.g., in questionnaire construction, recruiting methods or interview format) vary from one survey to another. This is because the researchers within each country are confronted with conceptual, methodological, sociocultural and budgetary challenges, for which they find different solutions. These differences limit comparison across countries and pooling of estimates, but the variation in approaches provides a rich source of learning on population survey research. In this review, survey leads from 11 European countries discuss how their surveys evolved during the past four decades in response to sociohistorical and political context, and the challenges they encountered. The review discusses the solutions they identified and shows that it is possible to create well designed surveys which collect high quality data on a range of aspects of sexual health, despite the sensitivity of the topic. Herewith, we hope to support the research community in their perennial quest for political support and funding, and ongoing drive to advance methodology in future national sex surveys.

Frequency of microsatellite instability (MSI) in upper tract urothelial carcinoma: comparison of the Bethesda panel and the Idylla MSI assay in a consecutively collected, multi-institutional cohort.

AIMS: Upper tract urothelial carcinoma (UTUC) is a rare malignancy with a poor prognosis which occurs sporadically or in few cases results from a genetic disorder called Lynch syndrome. Recently, examination of microsatellite instability (MSI) has gained importance as a biomarker: MSI tumours are associated with a better response to immunomodulative therapies. Limited data are known about the prevalence of MSI in UTUC. New detection methods using the fully automated Idylla MSI Assay facilitate analysis of increased patient numbers. METHODS: We investigated the frequency of MSI in a multi-institutional cohort of 243 consecutively collected UTUC samples using standard methodology (Bethesda panel), along with immunohistochemistry of mismatch repair (MMR) proteins. The same tumour cohort was retested using the Idylla MSI Assay by Biocartis. RESULTS: Using standard methodology, 230/243 tumours were detected as microsatellite stable (MSS), 4/243 tumours as MSI and 9/243 samples as invalid. In comparison, the Idylla MSI Assay identified four additional tumours as MSS, equalling 234/243 tumours; 4/243 were classified as MSI and only 5/243 cases as invalid. At the immunohistochemical level, MSI results were supported in all available cases with a loss in MMR proteins. The overall concordance between the standard and the Idylla MSI Assay was 98.35%. Time to result differed between 3 hours for Idylla MSI Assay and 2 days with the standard methodology. CONCLUSION: Our data indicate a low incidence rate of MSI tumours in patients with UTUC. Furthermore, our findings highlight that Idylla MSI Assay can be applied as an alternative method of MSI analysis for UTUC.

Fungal Infections in the ICU during the COVID-19 Pandemic in Mexico.

Background: Invasive Fungal Infections (IFI) are emergent complications of COVID-19. In this study, we aim to describe the prevalence, related factors, and outcomes of IFI in critical COVID-19 patients. Methods: We conducted a nested case-control study of all COVID-19 patients in the intensive care unit (ICU) who developed any IFI and matched age and sex controls for comparison (1:1) to evaluate IFI-related factors. Descriptive and comparative analyses were made, and the risk factors for IFI were compared versus controls. Results: We found an overall IFI prevalence of 9.3% in COVID-19 patients in the ICU, 5.6% in COVID-19-associated pulmonary aspergillosis (CAPA), and 2.5% in invasive candidiasis (IC). IFI patients had higher SOFA scores, increased frequency of vasopressor use, myocardial injury, and more empirical antibiotic use. CAPA was classified as possible in 68% and 32% as probable by ECMM/ISHAM consensus criteria, and 57.5% of mortality was found. Candidemia was more frequent for C. parapsilosis Fluconazole resistant outbreak early in the pandemic, with a mortality of 28%. Factors related to IFI in multivariable analysis were SOFA score > 2 (aOR 5.1, 95% CI 1.5-16.8, p = 0.007) and empiric antibiotics for COVID-19 (aOR 30, 95% CI 10.2-87.6, p = <0.01). Conclusions: We found a 9.3% prevalence of IFIs in critically ill patients with COVID-19 in a single center in Mexico; factors related to IFI were associated with higher SOFA scores and empiric antibiotic use for COVID-19. CAPA is the most frequent type of IFI. We did not find a mortality difference.

Risk Factors Associated with the Development of Hospital-Acquired Infections in Hospitalized Patients with Severe COVID-19.

Recognition of risk factors for hospital-acquired infections (HAI) in patients with COVID-19 is warranted. We aimed to describe factors associated with the development of HAI in patients with severe COVID-19. We conducted a retrospective cohort study including all adult patients admitted with severe COVID-19 between March 2020 and November 2020. The primary outcome was HAI development. Bivariate and multiple logistic regression models were constructed. Among 1540 patients, HAI occurred in 221 (14%). A total of 299 episodes of HAI were registered. The most common HAI were hospital-acquired/ventilation-associated pneumonia (173 episodes) and primary bloodstream infection (66 episodes). Death occurred in 387 (35%) patients and was more frequent in patients with HAI (38% vs. 23%, p < 0.01). Early mechanical ventilation (aOR 18.78, 95% CI 12.56-28.07), chronic kidney disease (aOR 3.41, 95% CI 1.4-8.27), use of corticosteroids (aOR 2.95, 95% CI 1.92-4.53) and tocilizumab (aOR 2.68, 95% CI 1.38-5.22), age ≥ 60 years (aOR 1.91, 95% CI 1.27-2.88), male sex (aOR 1.52, 95% CI 1.03-2.24), and obesity (aOR 1.49, 95% CI 1.03-2.15) were associated with HAI. In patients with severe COVID-19, mechanical ventilation within the first 24 h upon admission, chronic kidney disease, use of corticosteroids, use of tocilizumab, age ≥ 60 years, male sex, and obesity were associated with a higher risk of HAI.

Predictors of Mortality in Patients with Infections Due to Carbapenem-Resistant Gram-Negative Bacteria.

INTRODUCTION: Infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) are a significant cause of mortality and represent a serious challenge to health systems. The early identification of mortality predictors could guide appropriate treatment and follow-up. We aimed to identify the factors associated with 90-day all-cause mortality in patients with CR-GNB infections. METHODS: We conducted a cohort study from 1 January 2019 to 30 April 2022. The primary outcome was death from any cause during the first 90 days after the date of the first CR-GNB-positive culture. Secondary outcomes included infection relapse, invasive mechanical ventilation during follow-up, need for additional source control, acute kidney injury, Clostridioides difficile infection, and all-cause hospital admission after initial discharge. Bivariate and multivariate Cox-proportional hazards models were constructed to identify the factors independently associated with 90-day all-cause mortality. RESULTS: A total of 225 patients with CR-GNB infections were included. Death occurred in 76 (34%) cases. The most-reported comorbidities were immunosuppression (43%), arterial hypertension (35%), and COVID-19 (25%). The median length of stay in survivors was 18 days (IQR 10-34). Mechanical ventilation and ICU admission after diagnosis occurred in 8% and 11% of cases, respectively. Both infection relapse and rehospitalisation occurred in 18% of cases. C. difficile infection was diagnosed in 4% of cases. Acute kidney injury was documented in 22% of patients. Mechanical ventilation after diagnosis, ICU admission after diagnosis, and acute kidney injury in the first ten days of appropriate treatment were more frequently reported among non-survivors. In the multivariate analysis, age (HR 1.19 (95%CI 1.00-1.83)), immunosuppression (HR 1.84 (95%CI 1.06-3.18)), and septic shock at diagnosis (HR 2.40 (95% 1.41-4.08)) had an independent association with death during the first 90 days after the CR-GNB infection diagnosis. Receiving antibiogram-guided appropriate treatment was independently associated with a lower risk of death (HR 0.25 (95%CI 0.14-0.46)). CONCLUSIONS: The presence of advanced age, immunosuppression, septic shock at diagnosis, and inappropriate treatment are associated with higher 90-day all-cause mortality in hospitalised patients with infections due to CR-GNB. Recognition of the risk factors for adverse outcomes could further assist in patient care and the design of interventional studies that address the severe and widespread problem that is carbapenem resistance.

Validity and Reliability of the Spanish Version of Fear of COVID-19 Scale in Colombian Physicians.

The Fear COVID-19 Scale (FCV-19S) is a tool that assesses fears related to COVID-19. The objective was to know the validity and reliability of the FCV-19S in Colombian physicians. Five hundred thirty-one physicians aged between 21 and 69 years participated (M = 30.0, SD = 9.4). Internal consistency was estimated with Kuder-Richardson and McDonald's omega coefficients. The one-dimensional structure was corroborated with confirmatory factor analysis and goodness of fit coefficients. The FCV-19S showed Kuder-Richardson's coefficient of 0.16 and McDonald's omega of 0.42. The five-item version (FCV-19S-5), without items 3 and 7, showed Kuder-Richardson's coefficient of 0.67 and McDonald's omega of 0.68. In conclusion, the FCV-19S presented a poor psychometric performance in Colombian doctors, and the FCV-19S-5 showed acceptable internal consistency and dimensionality.

Popliteal artery pseudoaneurysm caused by non-penetrating trauma in a patient with hereditary multiple osteochondromatosis.

Hereditary multiple osteochondromatosis is a genetic condition characterized by the appearance of numerous osteochondromas, which can cause pseudoaneurysms in rare cases. The following article describes a 15-year-old patient with a history of current massages as part of his gym routine, who arrived at the emergency department with 4 days of pain, and ecchymosis in the right popliteal region. Therefore, duplex ultrasonography and arteriography were performed, confirming the diagnosis of popliteal pseudoaneurysm, which was subsequently treated by open surgery, providing a satisfactory outcome.

Correction: In-hospital mortality from severe COVID-19 in a tertiary care center in Mexico City; causes of death, risk factors and the impact of hospital saturation.

[This corrects the article DOI: 10.1371/journal.pone.0245772.].