Assessing generalizability of an AI-based visual test for cervical cancer screening.

A number of challenges hinder artificial intelligence (AI) models from effective clinical translation. Foremost among these challenges is the lack of generalizability, which is defined as the ability of a model to perform well on datasets that have different characteristics from the training data. We recently investigated the development of an AI pipeline on digital images of the cervix, utilizing a multi-heterogeneous dataset of 9,462 women (17,013 images) and a multi-stage model selection and optimization approach, to generate a diagnostic classifier able to classify images of the cervix into "normal", "indeterminate" and "precancer/cancer" (denoted as "precancer+") categories. In this work, we investigate the performance of this multiclass classifier on external data not utilized in training and internal validation, to assess the generalizability of the classifier when moving to new settings. We assessed both the classification performance and repeatability of our classifier model across the two axes of heterogeneity present in our dataset: image capture device and geography, utilizing both out-of-the-box inference and retraining with external data. Our results demonstrate that device-level heterogeneity affects our model performance more than geography-level heterogeneity. Classification performance of our model is strong on images from a new geography without retraining, while incremental retraining with inclusion of images from a new device progressively improves classification performance on that device up to a point of saturation. Repeatability of our model is relatively unaffected by data heterogeneity and remains strong throughout. Our work supports the need for optimized retraining approaches that address data heterogeneity (e.g., when moving to a new device) to facilitate effective use of AI models in new settings.

Superior metabolic improvement of polycystic ovary syndrome traits after GLP1-based multi-agonist therapy.

Polycystic ovary syndrome (PCOS) is a heterogeneous condition, defined by oligo-/anovulation, hyper-androgenism and/or polycystic ovaries. Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes, which severely compromise the clinical course of affected women. Yet, therapeutic options remain mostly symptomatic and of limited efficacy for the metabolic and reproductive alterations of PCOS. We report here the hormonal, metabolic and gonadal responses to the glucagon-like peptide-1 (GLP1)-based multi-agonists, GLP1/Estrogen (GLP1/E), GLP1/gastric inhibitory peptide (GLP1/GIP) and GLP1/GIP/Glucagon, in two mouse PCOS models, with variable penetrance of metabolic and reproductive traits, and their comparison with metformin. Our data illustrate the superior efficacy of GLP1/E vs. other multi-agonists and metformin in the management of metabolic complications of PCOS; GLP1/E ameliorates also ovarian cyclicity in an ovulatory model of PCOS, without direct estrogenic uterotrophic effects. In keeping with GLP1-mediated brain targeting, quantitative proteomics reveals changes in common and distinct hypothalamic pathways in response to GLP1/E between the two PCOS models, as basis for differential efficiency. Altogether, our data set the basis for the use of GLP1-based multi-agonists, and particularly GLP1/E, in the personalized management of PCOS.

Association of depressive symptoms with incidence and mortality rates of COVID-19 over 2 years among healthcare workers in 20 countries: multi-country serial cross-sectional study.

BACKGROUND: Long-term deterioration in the mental health of healthcare workers (HCWs) has been reported during and after the COVID-19 pandemic. Determining the impact of COVID-19 incidence and mortality rates on the mental health of HCWs is essential to prepare for potential new pandemics. This study aimed to investigate the association of COVID-19 incidence and mortality rates with depressive symptoms over 2 years among HCWs in 20 countries during and after the COVID-19 pandemic. METHODS: This was a multi-country serial cross-sectional study using data from the first and second survey waves of the COVID-19 HEalth caRe wOrkErS (HEROES) global study. The HEROES study prospectively collected data from HCWs at various health facilities. The target population included HCWs with both clinical and non-clinical roles. In most countries, healthcare centers were recruited based on convenience sampling. As an independent variable, daily COVID-19 incidence and mortality rates were calculated using confirmed cases and deaths reported by Johns Hopkins University. These rates represent the average for the 7 days preceding the participants' response date. The primary outcome was depressive symptoms, assessed by the Patient Health Questionnaire-9. A multilevel linear mixed model (LMM) was conducted to investigate the association of depressive symptoms with the average incidence and mortality rates. RESULTS: A total of 32,223 responses from the participants who responded to all measures used in this study on either the first or second survey, and on both the first and second surveys in 20 countries were included in the analysis. The mean age was 40.1 (SD = 11.1), and 23,619 responses (73.3%) were from females. The 9323 responses (28.9%) were nurses and 9119 (28.3%) were physicians. LMM showed that the incidence rate was significantly and positively associated with depressive symptoms (coefficient = 0.008, standard error 0.003, p = 0.003). The mortality rate was significantly and positively associated with depressive symptoms (coefficient = 0.049, se = 0.020, p = 0.017). CONCLUSIONS: This is the first study to show an association between COVID-19 incidence and mortality rates with depressive symptoms among HCWs during the first 2 years of the outbreak in multiple countries. This study's findings indicate that additional mental health support for HCWs was needed when the COVID-19 incidence and mortality rates increase during and after the early phase of the pandemic, and these findings may apply to future pandemics. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04352634.

Air quality in a small city: criteria pollutants, volatile organic compounds, metals, and microbes.

This work presents a year-long integral study of air quality parameters in Ciudad Real, a small city in the center of Spain, and its influence on the nearby national park, Las Tablas de Daimiel. The study covers meteorological parameters and criteria pollutants such as O3, NO, NO2, SO2, and PM10. Additionally, for each month, a 1-week campaign was performed sampling air in sorbent tubes with 8-h time resolution to analyze anthropogenic volatile organic compounds and the effects of seasons, daytime, and working-weekend days. During these campaigns, 24-h PM2.5 samples were also collected to measure the load of bacteria and fungi, as well as the trace concentrations of elements.The city and the national park NOx profiles showed that emissions from the town had a non-perceivable effect on the protected area. PM10 levels in Ciudad Real were influenced by Saharan intrusions, as was the national park; however, Ciudad Real had a higher contribution from anthropogenic sources. Ozone levels were lower in the city during the cold season due to the higher concentration of NOx and have not changed significantly in the last decade.The VOCs with higher average concentrations were toluene, m,p-xylene, benzene, methylene chloride, and o-xylene, with traffic being the main source of these pollutants in the city. For benzene and carbon tetrachloride levels, weak carcinogenic risks were estimated. In PM2.5, the most abundant metals were Na, Zn, Mg, Ca, Al, Fe, and K. The carcinogenic and non-carcinogenic risks estimated from the levels of the studied metals were negligible. Bacterial and fungal counts positively correlated with the concentration of PM2.5. Microbial community composition showed seasonal variability, with the dominance of human pathogenic bacteria which correlated with certain pollutants such as SO2. Bacillus and Cutibacterium were the most abundant genera.

Cardiac events occurring after allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide. Study conducted on behalf of the GETH-TC.

This multicenter study investigates the incidence and predictors of cardiac events (CE) following allo-HCT with PTCY in 453 AML patients. CE occurred in 57 (12.3%) patients within a median of 52 days (IQR: 13-289), with day 100 and 5-year cumulative incidences of 7.7% and 13.5%. Early (first 100 days) and late CE occurred at rates of 7.7% and 4.8%. The most prevalent CE were heart failure (n = 18, 31.6%), pericardial complications (n = 16, 28.1%), and arrhythmia (n = 14, 24.6%). The proportions of patients older than 55 years (64.9% vs. 46.1%, P = 0.010), with hypertension (36.8% vs. 18.4%, P = 0.001) and dyslipidemia (28.1% vs. 11.1%, P = 0.001) were higher in patients with CE. Patients undergoing haplo-HCT trend to have more CE (68.4% vs. 56.8%, P = 0.083). The multivariate regression analysis revealed that only hypertension (HR 1.88, P = 0.036) and dyslipidemia (HR 2.20, P = 0.018) were predictors for CE, with no differences according to donor type (haplo-HCT vs. others: HR 1.33, P = 0.323). Among the 57 patients with CE, the mortality rate was 12.2%. Notably, the diagnosis of CE negatively impacted NRM (HR 2.57, P = 0.011) and OS (HR 1.80, P = 0.009), underscoring necessity of aggressively treating cardiovascular risk factors, and implementing post-transplant cardiac monitoring protocols to prevent these complications.

Accuracy of supervised measurement of fetal weight in a residency program.

OBJECTIVES: To evaluate the accuracy of ultrasound estimates of fetal weight made by residents. METHODS: A cross-sectional study was conducted on consecutive pregnancies attended in an obstetric ward. All participants provided their consent to participate. Inclusion criteria were singleton pregnancies with ultrasound evaluation and delivery within 14 days. Congenital abnormalities and stillbirths were excluded. Ultrasound scans were performed by two residents, one observer per subject, following standardized methodology and supervised by senior staff. Fetal weight was calculated using the four-parameter Hadlock 1985 formula. Birth weight was measured using a standard clinical scale. Bland-Altman and mixed-effects analyses were performed. RESULTS: In a 6-month period, 95 gestations were recruited at 30-41 weeks, and birth weights ranged from 1200 to 4080 g. The bias between methods was -28 g (CI95%, -74 to 18) with 95% limits of agreement of ±440 g. The 95% deviation between methods was of ±16%. Parity had the most significant effect on the bias between methods; operator and maternal weight had no significant effect. CONCLUSIONS: Supervised measurement of fetal weight by residents demonstrated high accuracy. Parity bias may be associated with visceral fat deposition independent of maternal weight gain. A methodology for medical evaluation is presented.

Rectal thionamide administration in the setting of thyroid storm: a case report and review of the literature.

Summary: Thyroid storm is a clinical diagnosis characterized by life-threatening multisystemic organ involvement in the setting of uncontrolled hyperthyroidism. Current estimates suggest a mortality rate of up to 30%. Treatment often consists of the administration of thionamide medications, iodine solution(s), corticosteroids, and beta-blockers; in extreme circumstances, both plasmapheresis and thyroidectomy are subsequent therapeutic options. Thionamides are typically administered orally, with the intent of preventing further thyroid hormone synthesis; however, in the literature, there are instances whereby oral access cannot be obtained, and alternative routes of administration are required. We present a case of a patient who presented with a thyroid storm due to lack of adherence to methimazole. During admission, he was found to have significant abdominal pain and ultimately a duodenal perforation requiring strict nil-per-os (NPO) status, due to which he was unable to receive oral thionamides. Due to the lack of availability of intravenous formulations of thionamides in the United States, this patient was treated with an enema compound of propylthiouracil for a total of five per rectum (PR) doses. He would later develop hepatocellular injury, requiring discontinuation and eventual transition to oral methimazole. The literature pertaining to alternative-route thionamide administration is scant, and therefore this case report and literature review is written to provide an up-to-date review and further educate all levels of clinicians about this infrequent (but emergent) situation. Learning points: Thyroid storm is a clinical diagnosis for which urgent recognition is required to prevent untoward mortality. Treatment for thyroid storm requires prompt administration of thionamides, iodine, corticosteroids, and beta-blockers. In extreme circumstances, treatment considerations include plasmapheresis and thyroidectomy. Infrequently, patients with a thyroid storm may not be able to tolerate oral medications, for which alternative routes of access are required. Currently, available alternatives include intravenous methimazole (in Europe and Japan), as well as both enema and suppository preparations of propylthiouracil and methimazole.

UNAM-HIMFG Bacterial Lysate Activates the Immune Response and Inhibits Colonization of Bladder of Balb/c Mice Infected with the Uropathogenic CFT073 Escherichia coli Strain.

Urinary tract infections (UTIs) represent a clinical and epidemiological problem of worldwide impact that affects the economy and the emotional state of the patient. Control of the condition is complicated due to multidrug resistance of pathogens associated with the disease. Considering the difficulty in carrying out effective treatment with antimicrobials, it is necessary to propose alternatives that improve the clinical status of the patients. With this purpose, in a previous study, the safety and immunostimulant capacity of a polyvalent lysate designated UNAM-HIMFG prepared with different bacteria isolated during a prospective study of chronic urinary tract infection (CUTI) was evaluated. In this work, using an animal model, results are presented on the immunostimulant and protective activity of the polyvalent UNAM-HIMFG lysate to define its potential use in the control and treatment of CUTI. Female Balb/c mice were infected through the urethra with Escherichia coli CFT073 (UPEC O6:K2:H1) strain; urine samples were collected before the infection and every week for up to 60 days. Once the animals were colonized, sublingual doses of UNAM-HIMFG lysate were administrated. The colonization of the bladder and kidneys was evaluated by culture, and their alterations were assessed using histopathological analysis. On the other hand, the immunostimulant activity of the compound was analyzed by qPCR of spleen mRNA. Uninfected animals receiving UNAM-HIMFG lysate and infected animals administered with the physiological saline solution were used as controls. During this study, the clinical status and evolution of the animals were evaluated. At ninety-six hours after infection, the presence of CFT073 was identified in the urine of infected animals, and then, sublingual administration of UNAM-HIMFG lysate was started every week for 60 days. The urine culture of mice treated with UNAM-HIMFG lysate showed the presence of bacteria for three weeks post-treatment; in contrast, in the untreated animals, positive cultures were observed until the 60th day of this study. The histological analysis of bladder samples from untreated animals showed the presence of chronic inflammation and bacteria in the submucosa, while tissues from mice treated with UNAM-HIMFG lysate did not show alterations. The same analysis of kidney samples of the two groups (treated and untreated) did not present alterations. Immunostimulant activity assays of UNAM-HIMFG lysate showed overexpression of TNF-α and IL-10. Results suggest that the lysate activates the expression of cytokines that inhibit the growth of inoculated bacteria and control the inflammation responsible for tissue damage. In conclusion, UNAM-HIMFG lysate is effective for the treatment and control of CUTIs without the use of antimicrobials.

Diet Impacts on Gene Expression in Healthy Colon Tissue: Insights from the BarcUVa-Seq Study.

(1) Introduction: The global rise of gastrointestinal diseases, including colorectal cancer and inflammatory bowel diseases, highlights the need to understand their causes. Diet is a common risk factor and a crucial regulator of gene expression, with alterations observed in both conditions. This study aims to elucidate the specific biological mechanisms through which diet influences the risk of bowel diseases. (2) Methods: We analyzed data from 436 participants from the BarcUVa-Seq population-based cross-sectional study utilizing gene expression profiles (RNA-Seq) from frozen colonic mucosal biopsies and dietary information from a semi-quantitative food frequency questionnaire. Dietary variables were evaluated based on two dietary patterns and as individual variables. Differential expression gene (DEG) analysis was performed for each dietary factor using edgeR. Protein-protein interaction (PPI) analysis was conducted with STRINGdb v11 for food groups with more than 10 statistically significant DEGs, followed by Reactome-based enrichment analysis for the resulting networks. (3) Results: Our findings reveal that food intake, specifically the consumption of blue fish, alcohol, and potatoes, significantly influences gene expression in the colon of individuals without tumor pathology, particularly in pathways related to DNA repair, immune system function, and protein glycosylation. (4) Discussion: These results demonstrate how these dietary components may influence human metabolic processes and affect the risk of bowel diseases.

Evaluation of inflammatory biomarkers and their association with anti-SARS-CoV-2 antibody titers in healthcare workers vaccinated with BNT162B2.

Introduction: Vaccine-induced immunity against COVID-19 generates antibody and lymphocyte responses. However, variability in antibody titers has been observed after vaccination, and the determinants of a better response should be studied. The main objective of this investigation was to analyze the inflammatory biomarker response induced in healthcare workers vaccinated with BNT162b2, and its association with anti-Spike (a SARS-CoV-2 antigen) antibodies measured throughout a 1-year follow-up. Methods: Anti-spike antibodies and 92 biomarkers were analyzed in serum, along with socio-demographic and clinical variables collected by interview or exploration. Results: In our study, four biomarkers (ADA, IL-17C, CCL25 and CD8α) increased their expression after the first vaccine dose; and 8 others (uPA, IL-18R1, EN-RAGE, CASP-8, MCP-2, TNFß, CD5 and CXCL10) decreased their expression. Age, body mass index (BMI), smoking, alcohol consumption, and prevalent diseases were associated with some of these biomarkers. Furthermore, higher baseline levels of T-cell surface glycoprotein CD6 and hepatocyte growth factor (HGF) were associated with lower mean antibody titers at follow-up, while levels of monocyte chemotactic protein 2 (MCP-2) had a positive association with antibody levels. Age and BMI were positively related to baseline levels of MCP-2 (ß=0.02, 95%CI 0.00-0.04, p=0.036) and HGF (ß=0.03, 95%CI 0.00-0.06, p=0.039), respectively. Conclusion: Our findings indicate that primary BNT162b2 vaccination had a positive effect on the levels of several biomarkers related to T cell function, and a negative one on some others related to cancer or inflammatory processes. In addition, a higher level of MCP-2 and lower levels of HGF and CD6 were found to be associated with higher anti-Spike antibody titer following vaccination.

Capacitation of ram spermatozoa promotes changes in energy metabolism and aquaporin 3 and is affected by individual testosterone variations.

BACKGROUND: Recently, the metabolic pathways involved in energy production and the role of aquaglyceroporins in capacitation-associated events have been studied in humans and mice. However, little is known about these in ram spermatozoa. OBJECTIVE: The present study investigated bioenergetic and aquaglyceroporin 3 variations during in vitro capacitation of ram spermatozoa. In addition, differences in testosterone levels between males were examined to determine their influence on capacitation-like changes. MATERIALS AND METHODS: Spermatozoa obtained from nine rams (ejaculates = 36) were incubated for 180 min in three different media (control, capacitating, and aquaglyceroporin-inhibitor media) at 38.5°C. At 0 and 180 min of incubation in each medium, sperm viability, kinetics, chlortetracycline patterns, adenosine triphosphate concentration, lactate excretion (final subproduct of glycolysis), and immunolocalization of aquaporin 3 were evaluated. RESULTS: The increment of the capacitated spermatozoa-chlortetracycline pattern and the hyperactivated-like movement characterized by the highest curvilinear velocity and amplitude of lateral head displacement and the lowest linearity was only recorded after 180 min in the capacitating medium. At this time and conditions, adenosine triphosphate content and lactate excretion decreased, whereas the aquaglyceroporin 3 location in the midpiece and principal piece increased compared to 0 min. Such changes were not observed in the control medium over time. Incubation in the aquaglyceroporin-inhibitor medium for 180 min reduced drastically sperm motility and adenosine triphosphate content compared to the other media. Testosterone analysis revealed a significant individual variability, which was also present in all sperm parameters evaluated. Furthermore, testosterone was negatively correlated with adenosine triphosphate content but positively correlated with lactate excretion levels, sperm viability, motility, capacitated sperm-chlortetracycline pattern, and aquaglyceroporin 3 immunolabeling in the midpiece and principal piece. CONCLUSION: Despite individual differences, capacitation of ram spermatozoa increases adenosine triphosphate consumption, energy metabolism, and aquaglyceroporin 3 location in the midpiece and principal piece, which seems to be related to the acquisition of hyperactivated-like motility. Furthermore, testosterone levels may serve as a valuable tool to select those males with a greater sperm metabolism rate and fertilizing capacity.

Improvement in antibacterial use in intensive care units from Argentina: A quality improvement collaborative process evaluation using Normalization Process Theory.

BACKGROUND: Healthcare-associated infections and antibiotic resistance worsen globally. Antibiotic stewardship programs (ASP) aim to optimise infection treatment and curb resistance, yet implementation hurdles persist. This study examined ASP challenges in ICUs. METHODS: This study employed a qualitative methodological design to evaluate the implementation process of an antibiotic stewardship program (ASP) in eight intensive care units (ICUs) across Argentina. Thirty-four semi-structured interviews with healthcare workers (HCWs) were conducted. Interviews were analysed guided by Normalisation Process Theory, examining coherence, cognitive participation, collective action, and reflexive monitoring constructs. RESULTS: Key challenges included insufficient human resources, lack of institutional support, and resistance to change, particularly among staff not initially involved in the study. Despite these challenges, the program saw partial success in improving ICU practices, particularly in antibiotic use and communication across departments. The main strategy implemented in this quality improvement collaborative was the use of improvement cycles, which served as the central component for driving change. However, participation in improvement cycles was inconsistent, and sustainability post-intervention remains uncertain due to workload pressures and the need for continuous education. Concerns about workload and communication barriers persisted. Many participants did not perceive training as a separate component, which led to low engagement. Resistance to change became evident during modifications to clinical guidelines. The intervention had a positive impact on various processes, including communication and record keeping. CONCLUSION: This study underscores the persistent challenges in implementing ASPs in healthcare, emphasising the need for enhanced collaboration, workforce capacity building, and evidence-based practices to overcome barriers and optimize antimicrobial use to improve patient outcomes.

Physiological properties of auditory neurons responding to omission deviants in the anesthetized rat.

The detection of novel, low probability events in the environment is critical for survival. To perform this vital task, our brain is continuously building and updating a model of the outside world; an extensively studied phenomenon commonly referred to as predictive coding. Predictive coding posits that the brain is continuously extracting regularities from the environment to generate predictions. These predictions are then used to supress neuronal responses to redundant information, filtering those inputs, which then automatically enhances the remaining, unexpected inputs. We have recently described the ability of auditory neurons to generate predictions about expected sensory inputs by detecting their absence in an oddball paradigm using omitted tones as deviants. Here, we studied the responses of individual neurons to omitted tones by presenting individual sequences of repetitive pure tones, using both random and periodic omissions, presented at both fast and slow rates in the inferior colliculus and auditory cortex neurons of anesthetized rats. Our goal was to determine whether feature-specific dependence of these predictions exists. Results showed that omitted tones could be detected at both high (8 Hz) and slow repetition rates (2 Hz), with detection being more robust at the non-lemniscal auditory pathway.

Biosynthesis of resolvin D1, resolvin D2, and RCTR1 from 7,8(S,S)-epoxytetraene in human neutrophils and macrophages.

While the acute inflammatory response to harmful stimuli is protective, unrestrained neutrophil swarming drives collateral tissue damage and inflammation. Biosynthesized from omega-3 essential polyunsaturated fatty acids, resolvins are a family of signaling molecules produced by immune cells within the resolution phase to orchestrate return to homeostasis. Understanding the mechanisms that govern biosynthesis of these potent molecules gives insight into stimulating endogenous resolution and offers fresh opportunities for preventing and treating excessive inflammation. In this report, using materials prepared by total synthesis and liquid chromatography and tandem mass spectrometry-based matching studies, we established the role of 7,8(S,S)-epoxytetraene intermediate in the biosynthesis of resolvin D1, resolvin D2, and the resolvin conjugate in tissue regeneration (RCTR1) by human phagocytes. We demonstrated that this 7,8(S,S)-epoxy-containing intermediate is directly converted to resolvin D2 by human M2-like macrophages and to resolvin D1 and RCTR1 by human macrophages, neutrophils, and peripheral blood mononuclear cells. In addition, both human recombinant soluble epoxide hydrolase (sEH) and the glutathione S-transferase leukotriene C4 synthase (LTC4S) each catalyze conversion of this epoxide to resolvin D1 and RCTR1, respectively. MS3 ion-trap scans and isotope incorporation of 18O from H218O with sEH indicated that the oxygen atom at C-8 in resolvin D1 is derived from water. Results from molecular docking simulations with biosynthetic precursor 17S-hydroperoxy-4,7,10,13,19-cis-15-trans-docosahexaenoic acid and the epoxy intermediate were consistent with 5-lipoxygenase production of resolvin D1. Together, these results give direct evidence for the role of resolvin 7,8(S,S)-epoxytetraene intermediate in the endogenous formation of resolution-phase mediators resolvin D1, resolvin D2, and RCTR1 by human phagocytes.

Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors.

Lung cancer is the leading cause of cancer mortality worldwide. KRAS oncogenes are responsible for at least a quarter of lung adenocarcinomas, the main subtype of lung cancer. After four decades of intense research, selective inhibitors of KRAS oncoproteins are finally reaching the clinic. Yet, their effect on overall survival is limited due to the rapid appearance of drug resistance, a likely consequence of the high intratumoral heterogeneity characteristic of these tumors. In this study, we have attempted to identify those functional alterations that result from KRAS oncoprotein expression during the earliest stages of tumor development. Such functional changes are likely to be maintained during the entire process of tumor progression regardless of additional co-occurring mutations. Single-cell RNA sequencing analysis of murine alveolar type 2 cells expressing a resident Kras oncogene revealed impairment of the type I interferon pathway, a feature maintained throughout tumor progression. This alteration was also present in advanced murine and human tumors harboring additional mutations in the p53 or LKB1 tumor suppressors. Restoration of type I interferon (IFN) signaling by IFN-ß or constitutive active stimulator of interferon genes (STING) expression had a profound influence on the tumor microenvironment, switching them from immunologically "cold" to immunologically "hot" tumors. Therefore, enhancement of the type I IFN pathway predisposes KRAS mutant lung tumors to immunotherapy treatments, regardless of co-occurring mutations in p53 or LKB1.

COVID-19 and menstrual-related disturbances: a Spanish retrospective observational study in formerly menstruating women.

Introduction: Four years after the start of the pandemic, there is limited evidence on the impact of COVID-19 on the women's health regardless of their reproductive status. Objective: The aim was to analyze the prevalence and associated factors of menstrual-related disturbances in formerly menstruating women following SARS-CoV-2 infection. Study design: A retrospective observational study of adult women in Spain was conducted during the month of December 2021 using an online survey (N = 17,512). The present analysis includes a subpopulation of SARS-CoV-2-infected and formerly menstruating women (n = 72). The collected data included general characteristics, medical history, and specific information on COVID-19. Chi-square and Mann-Whitney U-tests were performed. Bivariate logistic regression analysis was then performed to investigate possible associations between the occurrence of menstrual-related disturbances after SARS-CoV-2 infection. Results: 38.8% of participants experienced menstrual-related disturbances following COVID-19. Among these, unexpected vaginal bleeding (20.8%) was the most common event, followed by spotting (11.1%) ( Table 1). Other reported changes were in the length (shorter = 12.5%) and flow (heavier = 30.3%) of menstrual bleeding in comparison to their previous experience. Regression analysis revealed that being a perimenopausal woman [adjusted odds ratio (AOR) 4.721, CI 95%, 1.022-21.796, p = 0.047] and having a previous diagnosis of menorrhagia (AOR 5.824 CI 95%, 1.521-22.310, p = 0.010) were factors associated with the event. Conclusion: These findings could help health professionals provide their patients with up-to-date scientific information to empower them to actively manage their reproductive health, especially in societies where menstrual health is still taboo.

Systematic Review of Genetic Substrate Reduction Therapy in Lysosomal Storage Diseases: Opportunities, Challenges and Delivery Systems.

BACKGROUND: Genetic substrate reduction therapy (gSRT), which involves the use of nucleic acids to downregulate the genes involved in the biosynthesis of storage substances, has been investigated in the treatment of lysosomal storage diseases (LSDs). OBJECTIVE: To analyze the application of gSRT to the treatment of LSDs, identifying the silencing tools and delivery systems used, and the main challenges for its development and clinical translation, highlighting the contribution of nanotechnology to overcome them. METHODS: A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines was performed. PubMed, Scopus, and Web of Science databases were used for searching terms related to LSDs and gene-silencing strategies and tools. RESULTS: Fabry, Gaucher, and Pompe diseases and mucopolysaccharidoses I and III are the only LSDs for which gSRT has been studied, siRNA and lipid nanoparticles being the silencing strategy and the delivery system most frequently employed, respectively. Only in one recently published study was CRISPR/Cas9 applied to treat Fabry disease. Specific tissue targeting, availability of relevant cell and animal LSD models, and the rare disease condition are the main challenges with gSRT for the treatment of these diseases. Out of the 11 studies identified, only two gSRT studies were evaluated in animal models. CONCLUSIONS: Nucleic acid therapies are expanding the clinical tools and therapies currently available for LSDs. Recent advances in CRISPR/Cas9 technology and the growing impact of nanotechnology are expected to boost the clinical translation of gSRT in the near future, and not only for LSDs.

Cardiac Events after Allo-HCT in Patients with Acute Myeloid Leukemia. Study Conducted con Behalf of the GETH-TC.

This multicenter study sponsored by GETH-TC aimed to investigate the incidence and predictors of early (within the first 100 days) and late cardiac events (CE) (ECE and LCE) following allo-HCT in AML patients treated with anthracyclines, focusing on exploring the impact of PTCY on cardiac complications and the impact of CE on overall survival (OS) and non-relapse mortality (NRM). 1020 AML patients were included. PTCY was given to 450 (44.1%) adults. Overall, 94 (9.2) patients experienced CE and being arrythmias, pericardial complications, and heart failure the most prevalent ones. ECE occurred in 49 (4.8%) patients in a median of 13 days after allo-HCT, while LCE were diagnosed in 45 (4.4%) patients in a median of 3.6 years after transplant. Using PTCY increased the risk for ECE in multivariate analysis (HR 2.86, P=0.007), but did not not significantly affect the risk for LCE (HR 1.06, P=0.892). The impact of variables on outcomes revealed was investigated using multivariate regression analyses and revealed that the diagnosis of CE significantly decreased the likelihood of OS (HR 1.66, P=0.005) and increased the likelihood of NRM (HR 2.88, P<0.001). Furthermore, despite using PTCY increased the risk for ECE, its administration was found to be beneficial for OS (HR 0.71, P=0.026). The study suggests that while the incidence of CE was relatively low, it significantly impacted mortality. Standard doses of PTCY increased ECE risk but were associated with improved OS. Therefore, implementing protocols to prevent cardiac complications is recommended, considering the widespread adoption of PTCY in allo-HCT.

Antibiotic Nanoparticles-Loaded Wound Dressings Against Pseudomonas aeruginosa's Skin Infection: A Systematic Review.

Pseudomonas aeruginosa (P. aeruginosa) is a common nosocomial pathogen that can cause severe infections in critically ill patients. Due to its resistance to multiple drugs, it is challenging to treat, which can result in serious illness and death. Conventional treatments for infected wounds often involve the topical or systemic application of antibiotics, which can lead to systemic toxicity and the development of drug resistance. The combination of wound dressings that promote wound healing with nanoparticles (NPs) represents a revolutionary strategy for optimizing the safety and efficacy of antibiotics. This review assesses a systematic search to identify the latest approaches where the evaluation of wound dressings loaded with antibiotic NPs is conducted. The properties of NPs, the features of wound dressings, the antimicrobial activity and biocompatibility of the different strategies are analyzed. The results indicate that most research in this field is focused on dressings loaded with silver NPs (57.1%) or other inorganic materials (22.4%). Wound dressings loaded with polymeric NPs and carbon-based NPs represent 14.3% and 6.1% of the evaluated studies, respectively. Nevertheless, there are no clinical trials that have evaluated the efficacy of NPs-loaded wound dressings in patients. Further research is required to ensure the safety of these treatments and to translate the findings from the bench to the bedside.