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The COVID-19 pandemic has presented significant challenges in clinical management, and intensive care units (ICUs) worldwide have become epicenters of high-stakes treatment decisions. Among these, corticosteroid therapy has risen as a pivotal, yet controversial, treatment modality. In Saudi Arabia, where unique demographic and health system characteristics intersect, understanding the specific effects of corticosteroids on ICU patient outcomes is not just critical but a pressing necessity in tailoring effective COVID-19 management strategies. This study aims to elucidate the effects of corticosteroid therapy on the outcomes of severe COVID-19 patients in Saudi Arabian ICUs, providing critical insights into treatment efficacy and guiding future clinical practices. In this cohort study, we meticulously reviewed the medical records of 1085 severe COVID-19 patients admitted to Saudi Arabian ICUs. Our analysis focused on demographic details, ICU outcomes, and the extent and implications of corticosteroid therapy. The study employed comprehensive methods for data collection, evaluation criteria, and statistical analysis, ensuring a thorough understanding of the impact of corticosteroids in this context. The study encompassed 1085 patients, predominantly male (74.5%, N=806), with an average age of 56 and a mean BMI of 30.07. A significant portion (72.3%, N=784) received corticosteroid therapy. These patients generally experienced longer ICU (mean 23 days) and hospital stays (mean 16 days), along with higher rates of microbiological cure (72.3%, N=648) and increased ICU discharge likelihood. Conversely, corticosteroid recipients showed higher mortality rates at ICU discharge. The statistical analysis confirmed the significance of these findings, reinforcing their importance in managing COVID-19 in ICUs. The research highlights the intricate dynamics of corticosteroid use in treating severe COVID-19 cases in ICUs. While associated with prolonged ICU stays and increased mortality, corticosteroids also correlate with higher microbiological cure rates and discharge likelihood. These insights call for careful deliberation in applying corticosteroid therapy, with implications for enhancing clinical protocols and guiding future research in severe COVID-19 treatment.

Type 1 diabetes mellitus (T1DM) is increasingly prevalent among Saudi Arabian youth, particularly in the Jazan region. This chronic condition necessitates lifelong insulin therapy and poses significant daily management challenges for affected adolescents. Despite the high incidence rates, there is a notable lack of research into how T1DM impacts the health-related quality of life (HRQoL) of these individuals. This study aimed to assess HRQoL and its demographic correlates in T1DM patients in the Jazan region of Saudi Arabia. In this cross-sectional study, 236 T1DM patients completed the Pediatric Quality of Life Inventory Diabetes Module 3.0 (PedsQL DM). The HRQoL across domains of diabetes symptoms, treatment barriers, adherence, worry, and communication was compared by gender, nationality, age, education, residence, and healthcare follow-up using t-tests and ANOVA. Multivariate regression identified predictors of overall HRQoL. Most respondents were female (51.3%), 42.8% were between the ages of seven and 12 years, and 94.5% were Saudi nationals. Males reported better HRQoL than females, with fewer symptoms, treatment barriers, and better communication (all p<0.05). Non-Saudis had better treatment adherence, communication, and overall HRQoL than Saudis (all p<0.05). Older children (13-18 years) reported lower treatment barriers than younger children (three to six years) (p<0.05). Those with intermediate education had lower treatment barriers than those with preliminary education (p = 0.038). Only the female gender (-0.171, p = 0.009) independently predicted poorer overall HRQoL. This study revealed disparities in HRQoL among T1DM children and adolescents. Males, non-Saudis, older children, and those with more education had better HRQoL. Females were at particular risk for poorer outcomes. Targeted interventions are needed to address this region's demographic disparities in diabetes-related HRQoL.

The prevalence of asthma among children has been on the rise worldwide, leading to significant morbidity and mortality. Our study was conducted to determine the prevalence of asthma and its related risk factors among school-age children in the Jazan Region, Saudi Arabia. The study was a cross-sectional prospective study that used Phase I ISAAC protocol and was conducted from March to June 2023. The sample size was calculated to be 1600 among school-age children in the Jazan Region Saudi Arabia. This study complies with the Declaration of Helsinki. Data was analyzed using SPSS version 23.0, Descriptive statistics were calculated for study variables, and appropriate tests of significance were performed to determine statistical significance. The total study population was 1368 the majority of them, 96.6% (n=1321), were Saudi nationals, and most of them lived in rural areas (70.6%, n=966). The prevalence of life-long wheezing, wheezing in the last 12 months, and exercise-induced wheezing was 28.0%, 29.2%, and 30.9%, respectively. Risk factors such as having indoor plants, having a pet, and a smoker in the household were reported by 48.0%, 24.6%, and 36.4% of participants, respectively. Living near an industrial area was determined as a risk factor in 98 (7.2%) of the children. Asthma-related symptoms were strongly correlated with all risk factors based on the chi-square test, and some risk factors based on multivariate linear regression. The prevalence of asthma among children in the Jazan Region is higher than previously reported, and the reported risk factors are significantly correlated with symptoms of asthma.

Whereas significant anti-tumor responses are observed in most BRAF V600E -mutant melanoma patients exposed to MAPK-targeting agents, resistance almost invariably develops. Here, we show that in therapy-responsive cells BRAF inhibition induces downregulation of the processing of Sterol Regulator Element Binding (SREBP-1) and thereby lipogenesis. Irrespective of the escape mechanism, therapy-resistant cells invariably restore this process to promote lipid saturation and protect melanoma from ROS-induced damage and lipid peroxidation. Importantly, pharmacological SREBP-1 inhibition sensitizes BRAF V600E -mutant therapy-resistant melanoma to BRAF V600E inhibitors both in vitro and in a pre-clinical PDX in vivo model. Together, these data indicate that targeting SREBP-1-induced lipogenesis may offer a new avenue to overcome acquisition of resistance to BRAF-targeted therapy. This work also provides evidence that targeting vulnerabilities downstream of oncogenic signaling offers new possibilities in overcoming resistance to targeted therapies. Melanoma patients harbouring BRAF V600E mutation generally develop resistance to targeted therapy. In this study, the authors demonstrate that SREBP-1-mediated induction of lipid biosynthesis contributes to therapy resistance in BRAF mutant melanoma.

Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12–15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, leaving patients with limited options. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer is not known. Here, we show that a subgroup of resistant tumors decreases phosphoglycerate dehydrogenase (PHGDH) expression at relapse after platinum-based chemotherapy. Mechanistically, we observe that this phenomenon is accompanied by a specific oxidized nicotinamide adenine dinucleotide (NAD + ) regenerating phenotype, which helps tumor cells in sustaining Poly (ADP-ribose) polymerase (PARP) activity under platinum treatment. Our findings reveal metabolic vulnerabilities with clinical implications for a subset of platinum resistant ovarian cancers. Metabolic reprogramming is associated with cancer development and therapy resistance. Here, the authors show that downregulation of the serine biosynthesis enzyme PHGDH in a fraction of patients is associated with relapse in platinum-treated ovarian cancers and to NAD + and PARP activity upregulation.

Most tumours have an aberrantly activated lipid metabolism 1 , 2 that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation 3 . This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we show that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers. In several human and mouse cancer cell lines and carcinomas, a sapienate biosynthesis pathway underpins metabolic plasticity by allowing these cells to bypass stearoyl-CoA desaturase-dependent fatty acid desaturation.

Studies indicate that individuals with chronic conditions and specific baseline characteristics may not mount a robust humoral antibody response to SARS-CoV-2 vaccines. In this paper, we used data from the Texas Coronavirus Antibody REsponse Survey (Texas CARES), a longitudinal state-wide seroprevalence program that has enrolled more than 90,000 participants, to evaluate the role of chronic diseases as the potential risk factors of non-response to SARS-CoV-2 vaccines in a large epidemiologic cohort. A participant needed to complete an online survey and a blood draw to test for SARS-CoV-2 circulating plasma antibodies at four-time points spaced at least three months apart. Chronic disease predictors of vaccine non-response are evaluated using logistic regression with non-response as the outcome and each chronic disease + age as the predictors. As of April 24, 2023, 18,240 participants met the inclusion criteria; 0.58% (N = 105) of these are non-responders. Adjusting for age, our results show that participants with self-reported immunocompromised status, kidney disease, cancer, and \"other\" non-specified comorbidity were 15.43, 5.11, 2.59, and 3.13 times more likely to fail to mount a complete response to a vaccine, respectively. Furthermore, having two or more chronic diseases doubled the prevalence of non-response. Consistent with smaller targeted studies, a large epidemiologic cohort bears the same conclusion and demonstrates immunocompromised, cancer, kidney disease, and the number of diseases are associated with vaccine non-response. This study suggests that those individuals, with chronic diseases with the potential to affect their immune system response, may need increased doses or repeated doses of COVID-19 vaccines to develop a protective antibody level.

ObjectiveAcute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity.DesignFollowing phenotypic characterisation, we performed RNA sequencing on CD14+CD16− monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an in vitro model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function.ResultsMonocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14+CD16− monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of in vitro generated- as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores.ConclusionIn ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes partially revives their function, opening up new options for therapeutic targeting in these patients.

Background One of the key limitations of targeted cancer therapies is the rapid onset of therapy resistance. Taking BRAF-mutant melanoma as paradigm, we previously identified the lipogenic regulator SREBP-1 as a central mediator of resistance to MAPK-targeted therapy. Reasoning that lipogenesis-mediated alterations in membrane lipid poly-unsaturation lie at the basis of therapy resistance, we targeted fatty acid synthase (FASN) as key player in this pathway to evoke an exquisite vulnerability to clinical inducers of reactive oxygen species (ROS), thereby rationalizing a novel clinically actionable combination therapy to overcome therapy resistance. Methods Using gene expression analysis and mass spectrometry-based lipidomics of BRAF-mutant melanoma cell lines, melanoma PDX and clinical data sets, we explored the association of FASN expression with membrane lipid poly-unsaturation and therapy-resistance. Next, we treated therapy-resistant models with a preclinical FASN inhibitor TVB-3664 and a panel of ROS inducers and performed ROS analysis, lipid peroxidation tests and real-time cell proliferation assays. Finally, we explored the combination of MAPK inhibitors, TVB-3664 and arsenic trioxide (ATO, as a clinically used ROS-inducer) in Mel006 BRAF mutant PDX as a gold model of therapy resistance and assessed the effect on tumor growth, survival and systemic toxicity. Results We found that FASN expression is consistently increased upon the onset of therapy resistance in clinical melanoma samples, in cell lines and in Mel006 PDX and is associated with decreased lipid poly-unsaturation. Forcing lipid poly-unsaturation in therapy-resistant models by combining MAPK inhibition with FASN inhibition attenuated cell proliferation and rendered cells exquisitely sensitive to a host of ROS inducers. In particular, the triple combination of MAPK inhibition, FASN inhibition, and the clinical ROS-inducing compound ATO dramatically increased survival of Mel006 PDX models from 15 to 72% with no associated signs of toxicity. Conclusions We conclude that under MAPK inhibition the direct pharmacological inhibition of FASN evokes an exquisite vulnerability to inducers of ROS by increasing membrane lipid poly-unsaturation. The exploitation of this vulnerability by combining MAPK and/or FASN inhibitors with inducers of ROS greatly delays the onset of therapy resistance and increases survival. Our work identifies a clinically actionable combinatorial treatment for therapy-resistant cancer.

Accurate estimates of natural and/or vaccine-induced antibodies to SARS-CoV-2 are difficult to obtain. Although model-based estimates of seroprevalence have been proposed, they require inputting unknown parameters including viral reproduction number, longevity of immune response, and other dynamic factors. In contrast to a model-based approach, the current study presents a data-driven detailed statistical procedure for estimating total seroprevalence (defined as antibodies from natural infection or from full vaccination) in a region using prospectively collected serological data and state-level vaccination data. Specifically, we conducted a longitudinal statewide serological survey with 88,605 participants 5 years or older with 3 prospective blood draws beginning September 30, 2020. Along with state vaccination data, as of October 31, 2021, the estimated percentage of those 5 years or older with naturally occurring antibodies to SARS-CoV-2 in Texas is 35.0% (95% CI = (33.1%, 36.9%)). This is 3× higher than, state-confirmed COVID-19 cases (11.83%) for all ages. The percentage with naturally occurring or vaccine-induced antibodies (total seroprevalence) is 77.42%. This methodology is integral to pandemic preparedness as accurate estimates of seroprevalence can inform policy-making decisions relevant to SARS-CoV-2.