-
American Journal of Human Genetics May 2024
PubMed: 38701747
DOI: 10.1016/j.ajhg.2024.04.008 -
The Journal of Clinical Investigation May 2024The gut microbiota is an integral part of the human metaorganism that is required to shape physiologic host immune responses including host defense against pathogens....
The gut microbiota is an integral part of the human metaorganism that is required to shape physiologic host immune responses including host defense against pathogens. Disease-associated gut dysbiosis has been characterized by blooms of pathobionts, which are bacterial species that can drive disease under certain conditions. Pathobionts like Enterobacteriaceae often bloom during flares of inflammatory bowel disease (IBD) and are causally linked with IBD in murine models. In this issue of the JCI, Hecht and colleagues investigated how simple carbohydrates are causally linked to the bloom of the gut pathobiont Klebsiella pneumoniae, which belong to the Enterobacteriaceae family. Notably, the presence of fiber reduced the dissemination of K. pneumoniae into the blood and liver in a colitis model. Their findings provide a diet-related mechanism for gut dysbiosis, which has implications in the management of IBD and other conditions in which gut dysbiosis is an underlying factor.
Topics: Humans; Dysbiosis; Animals; Gastrointestinal Microbiome; Klebsiella pneumoniae; Inflammatory Bowel Diseases; Mice; Dietary Carbohydrates; Klebsiella Infections; Colitis; Dietary Fiber
PubMed: 38690730
DOI: 10.1172/JCI180001 -
BMJ Open Apr 2024We aimed to assess the healthcare costs and impact on the economy at large arising from emergency medical services (EMS) treated non-traumatic shock.
OBJECTIVES
We aimed to assess the healthcare costs and impact on the economy at large arising from emergency medical services (EMS) treated non-traumatic shock.
DESIGN
We conducted a population-based cohort study, where EMS-treated patients were individually linked to hospital-wide and state-wide administrative datasets. Direct healthcare costs (Australian dollars, AUD) were estimated for each element of care using a casemix funding method. The impact on productivity was assessed using a Markov state-transition model with a 3-year horizon.
SETTING
Patients older than 18 years of age with shock not related to trauma who received care by EMS (1 January 2015-30 June 2019) in Victoria, Australia were included in the analysis.
PRIMARY AND SECONDARY OUTCOME MEASURES
The primary outcome assessed was the total healthcare expenditure. Secondary outcomes included healthcare expenditure stratified by shock aetiology, years of life lived (YLL), productivity-adjusted life-years (PALYs) and productivity losses.
RESULTS
A total of 21 334 patients (mean age 65.9 (±19.1) years, and 9641 (45.2%) females were treated by EMS with non-traumatic shock with an average healthcare-related cost of $A11 031 per episode of care and total cost of $A280 million. Annual costs remained stable throughout the study period, but average costs per episode of care increased (P=0.05). Among patients who survived to hospital, the average cost per episode of care was stratified by aetiology with cardiogenic shock costing $A24 382, $A21 254 for septic shock, $A19 915 for hypovolaemic shock and $A28 057 for obstructive shock. Modelling demonstrated that over a 3-year horizon the cohort lost 24 355 YLLs and 5059 PALYs. Lost human capital due to premature mortality led to productivity-related losses of $A374 million. When extrapolated to the entire Australian population, productivity losses approached $A1.5 billion ($A326 million annually).
CONCLUSION
The direct healthcare costs and indirect loss of productivity among patients with non-traumatic shock are high. Targeted public health measures that seek to reduce the incidence of shock and improve systems of care are needed to reduce the financial burden of this syndrome.
Topics: Humans; Female; Male; Victoria; Aged; Health Care Costs; Middle Aged; Emergency Medical Services; Cost of Illness; Aged, 80 and over; Shock; Cohort Studies; Adult; Quality-Adjusted Life Years; Health Expenditures
PubMed: 38684259
DOI: 10.1136/bmjopen-2023-078435 -
BioRxiv : the Preprint Server For... Apr 2024Bloom Syndrome helicase (Blm) is a RecQ family helicase involved in DNA repair, cell-cycle progression, and development. Pathogenic variants in human cause the...
Bloom Syndrome helicase (Blm) is a RecQ family helicase involved in DNA repair, cell-cycle progression, and development. Pathogenic variants in human cause the autosomal recessive disorder Bloom Syndrome, characterized by predisposition to numerous types of cancer. Prior studies of mutants lacking helicase activity or protein have shown sensitivity to DNA damaging agents, defects in repairing DNA double-strand breaks (DSBs), female sterility, and improper segregation of chromosomes in meiosis. Blm orthologs have a well conserved and highly structured RecQ helicase domain, but more than half of the protein, particularly in the N-terminus, is predicted to be unstructured. Because this region is poorly conserved across multicellular organisms, we compared closely related species to identify regions of conservation, potentially indicating important functions. We deleted two of these -conserved regions in using CRISPR/Cas9 gene editing and assessed the effects on different Blm functions. Each deletion had distinct effects on different Blm activities. Deletion of either conserved region 1 (CR1) or conserved region 2 (CR2) compromised DSB repair through synthesis-dependent strand annealing and resulted in increased mitotic crossovers. In contrast, CR2 is critical for embryonic development but CR1 is not as important. CR1 deletion allows for proficient meiotic chromosome segregation but does lead to defects in meiotic crossover designation and patterning. Finally, deletion of CR2 does not lead to significant meiotic defects, indicating that while each region has overlapping functions, there are discreet roles facilitated by each. These results provide novel insights into functions of the N-terminal disordered region of Blm.
PubMed: 38659896
DOI: 10.1101/2024.04.12.589165 -
International Journal of Molecular... Apr 2024We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders... (Review)
Review
We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders (OPMD) to undergo malignant transformation to oral squamous cell carcinoma (OSCC). Defects in the homologous recombination/Fanconi anemia (HR/FA), but not in the non-homologous end joining, causes the DNA repair pathway to appear to be consistent with features of familial conditions that are predisposed to OSCC (FA, Bloom's syndrome, Ataxia Telangiectasia); this is true for OSCC that occurs in young patients, sometimes with little/no exposure to classical risk factors. Even in Dyskeratosis Congenita, a disorder of the telomerase complex that is also predisposed to OSCC, attempts at maintaining telomere length involve a pathway with shared HR genes. Defects in the HR/FA pathway therefore appear to be pivotal in conditions that are predisposed to OSCC. There is also some evidence that abnormalities in the HR/FA pathway are associated with malignant transformation of sporadic cases OPMD and OSCC. We provide data showing overexpression of HR/FA genes in a cell-cycle-dependent manner in a series of OPMD-derived immortal keratinocyte cell lines compared to their mortal counterparts. The observations in this study argue strongly for an important role of the HA/FA DNA repair pathway in the development of OSCC.
Topics: Humans; Mouth Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Fanconi Anemia; Head and Neck Neoplasms; DNA
PubMed: 38612901
DOI: 10.3390/ijms25074092 -
The World Journal of Men's Health Apr 2024Non-obstructive azoospermia (NOA) is a common, but complex problem, with multiple therapeutic options and a lack of clear guidelines. Hence, there is considerable...
Global Practice Patterns and Variations in the Medical and Surgical Management of Non-Obstructive Azoospermia: Results of a World-Wide Survey, Guidelines and Expert Recommendations.
PURPOSE
Non-obstructive azoospermia (NOA) is a common, but complex problem, with multiple therapeutic options and a lack of clear guidelines. Hence, there is considerable controversy and marked variation in the management of NOA. This survey evaluates contemporary global practices related to medical and surgical management for patients with NOA.
MATERIALS AND METHODS
A 56-question online survey covering various aspects of the evaluation and management of NOA was sent to specialists around the globe. This paper analyzes the results of the second half of the survey dealing with the management of NOA. Results have been compared to current guidelines, and expert recommendations have been provided using a Delphi process.
RESULTS
Participants from 49 countries submitted 336 valid responses. Hormonal therapy for 3 to 6 months was suggested before surgical sperm retrieval (SSR) by 29.6% and 23.6% of participants for normogonadotropic hypogonadism and hypergonadotropic hypogonadism respectively. The SSR rate was reported as 50.0% by 26.0% to 50.0% of participants. Interestingly, 46.0% reported successful SSR in <10% of men with Klinefelter syndrome and 41.3% routinely recommended preimplantation genetic testing. Varicocele repair prior to SSR is recommended by 57.7%. Half of the respondents (57.4%) reported using ultrasound to identify the most vascularized areas in the testis for SSR. One-third proceed directly to microdissection testicular sperm extraction (mTESE) in every case of NOA while others use a staged approach. After a failed conventional TESE, 23.8% wait for 3 months, while 33.1% wait for 6 months before proceeding to mTESE. The cut-off of follicle-stimulating hormone for positive SSR was reported to be 12-19 IU/mL by 22.5% of participants and 20-40 IU/mL by 27.8%, while 31.8% reported no upper limit.
CONCLUSIONS
This is the largest survey to date on the real-world medical and surgical management of NOA by reproductive experts. It demonstrates a diverse practice pattern and highlights the need for evidence-based international consensus guidelines.
PubMed: 38606867
DOI: 10.5534/wjmh.230339 -
Antioxidants (Basel, Switzerland) Feb 2024Obesity and metabolic dysfunction have been shown to be associated with overproduction of reactive oxygen species (ROS) in the gastrointestinal (GI) tract, which...
Obesity and metabolic dysfunction have been shown to be associated with overproduction of reactive oxygen species (ROS) in the gastrointestinal (GI) tract, which contributes to dysbiosis or imbalances in the gut microbiota. Recently, the reversal of dysbiosis has been observed as a result of dietary supplementation with antioxidative compounds including polyphenols. Likewise, dietary polyphenols have been associated with scavenging of GI ROS, leading to the hypothesis that radical scavenging in the GI tract is a potential mechanism for the reversal of dysbiosis. The objective of this study was to investigate the relationship between GI ROS, dietary antioxidants and beneficial gut bacterium . The results of this study demonstrated to be a discriminant microorganism between lean ( = 7) and obese ( = 7) mice. The relative abundance of was also found to have a significant negative correlation with extracellular ROS in the GI tract as measured using fluorescent probe hydroindocyanine green. The ability of the dietary antioxidants ascorbic acid, β-carotene and grape polyphenols to scavenge GI ROS was evaluated in tandem with their ability to support bloom in lean mice ( = 20). While the relationship between GI ROS and relative abundance of was conserved in lean mice, only grape polyphenols stimulated the bloom of . Analysis of fecal antioxidant capacity and differences in the bioavailability of the antioxidants of interest suggested that the poor bioavailability of grape polyphenols contributes to their superior radical scavenging activity and support of in comparison to the other compounds tested. These findings demonstrate the utility of the GI redox environment as a modifiable therapeutic target in the treatment of chronic inflammatory diseases like metabolic syndrome.
PubMed: 38539838
DOI: 10.3390/antiox13030304 -
Pharmacopsychiatry May 2024Up to now, it is unclear whether different medicinal (MC) strains are differently efficacious across different medical conditions. In this study, the effectiveness of...
BACKGROUND
Up to now, it is unclear whether different medicinal (MC) strains are differently efficacious across different medical conditions. In this study, the effectiveness of different MC strains was compared depending on the disease to be treated.
METHODS
This was an online survey conducted in Germany between June 2020 and August 2020. Patients were allowed to participate only if they received a -based treatment from pharmacies in the form of flowers prescribed by a physician.
RESULTS
The survey was completed by n=1,028 participants. Most participants (58%) have used MC for more than 1 year, on average, 5.9 different strains. (pure tetrahydrocannabinol to pure cannabidiol [THC:CBD]=22:<1) was the most frequently prescribed strain, followed by (THC:CBD=19:<1) and (THC:CBD=22:1). The most frequent conditions MC was prescribed for were different pain disorders, psychiatric and neurological diseases, and gastrointestinal symptoms. Overall, the mean patient-reported effectiveness was 80.1% (range, 0-100%). A regression model revealed no association between the patient-reported effectiveness and the variety. Furthermore, no influence of the disease on the choice of the MC strain was detected. On average, 2.1 side effects were reported (most commonly dry mouth (19.5%), increased appetite (17.1%), and tiredness (13.0%)). However, 29% of participants did not report any side effects. Only 398 participants (38.7%) indicated that costs for MC were covered by their health insurance.
CONCLUSIONS
Patients self-reported very good efficacy and tolerability of MC. There was no evidence suggesting that specific MC strains are superior depending on the disease to be treated.
Topics: Humans; Germany; Male; Medical Marijuana; Female; Adult; Middle Aged; Prospective Studies; Aged; Young Adult; Cannabidiol; Surveys and Questionnaires; Adolescent; Dronabinol; Cannabis; Treatment Outcome
PubMed: 38471525
DOI: 10.1055/a-2261-2269 -
Open Heart Mar 2024Coronary CT angiography (CCTA) permits both qualitative and quantitative analysis of atherosclerotic plaque and may be a suitable risk modifier in assessing patients at...
OBJECTIVE
Coronary CT angiography (CCTA) permits both qualitative and quantitative analysis of atherosclerotic plaque and may be a suitable risk modifier in assessing patients at intermediate risk of atherosclerotic cardiovascular disease. We sought to determine the association of plaque components with long-term major adverse cardiovascular events (MACEs) in asymptomatic intermediate-risk patients, compared with conventional coronary artery calcium (CAC) score.
METHODS
100 intermediate-risk patients underwent double-blinded CCTA. Follow-up was conducted at 10 years and data were cross-referenced with the National Death Index. The primary outcome was MACE, which was a composite of death, acute coronary syndrome (ACS), revascularisation and stroke.
RESULTS
The median time from CCTA to follow-up was 9.5 years. 83 patients completed follow-up interview and mortality data were available on all 100 patients. MACE occurred in 17 (20.5%) patients, which included 2 (2%) deaths, 8 (10%) ACS, 3 (4%) strokes and 5 (6%) revascularisation procedures. 47 (57%) patients had mixed plaque, which was predictive of MACE (OR 4.68 (95% CI 1.19 to 18.5) p=0.028). The burden of non-calcified and mixed plaque, defined by non-calcified plaque segment stenosis score, was also a predictor of long-term MACE (OR 1.59 (95% CI 1.18 to 2.13) p=0.002). Neither calcified plaque (OR 3.92 (95% CI 0.80 to 19.3)) nor CAC score (OR 1.01 (95% CI 0.999 to 1.02)) was associated with long-term MACE.
CONCLUSION
The presence and burden of mixed plaque on CCTA is associated with an increased risk of long-term MACE among asymptomatic intermediate-risk patients and is a superior predictor to CAC score.
Topics: Humans; Plaque, Atherosclerotic; Computed Tomography Angiography; Prognosis; Coronary Angiography; Tomography, X-Ray Computed; Atherosclerosis; Acute Coronary Syndrome
PubMed: 38458771
DOI: 10.1136/openhrt-2024-002609 -
Translational Oncology May 2024Cancer management in Africa faces diverse challenges due to limited resources, health system challenges, and other matters. Identifying hereditary cancer syndromic cases...
Cancer management in Africa faces diverse challenges due to limited resources, health system challenges, and other matters. Identifying hereditary cancer syndromic cases is crucial to improve clinical management and preventive care in these settings. This study aims to explore the clinicopathological features and genetic factors associated with hereditary cancer in Tunisia, a North African country with a rising cancer burden MATERIALS AND METHODS: Clinicopathological features and personal/family history of cancer were explored in 521 patients. Genetic analysis using Sanger and next-generation sequencing was performed for a set of patients RESULTS: Hereditary breast and ovarian cancer syndrome was the most frequent cluster in which 36 BRCA mutations were identified. We described a subgroup of patients with likely ''breast cancer-only syndrome'' among this cluster. Two cases of Li-Fraumeni syndrome with distinct TP53 mutations namely c.638G>A and c.733G>A have been identified. Genetic investigation also allowed the identification of a new BLM homozygous mutation (c.3254dupT) in one patient with multiple primary cancers. Phenotype-genotype correlation suggests the diagnosis of Bloom syndrome. A recurrent MUTYH mutation (c.1143_1144dup) was identified in three patients with different phenotypes CONCLUSION: Our study calls for comprehensive genetic education and the implementation of genetic screening in Tunisia and other African countries health systems, to reduce the burden of hereditary diseases and improve cancer outcomes in resource-stratified settings.
PubMed: 38387387
DOI: 10.1016/j.tranon.2024.101912