Tag: pubmed

Sci Rep. 2022 Sep 28;12(1):16203. doi: 10.1038/s41598-022-20500-4.

ABSTRACT

BRCA1 (Breast Cancer 1, early onset) is linked to breast and ovarian cancer predisposition. Still, the risks conferred by a significant portion of BRCA1 variants identified in the population remains unknown. Most of these variants of uncertain significance are missense alterations. However, the functional implications of small in-frame deletions and/or insertions (indels) are also difficult to predict. Our group has previously evaluated the functional impact of 347 missense variants using an extensively validated transcriptional activity assay. Here we show a systematic assessment of 30 naturally occurring in-frame indels located at the C-terminal region of BRCA1. We identified positions sensitive and tolerant to alterations, expanding the knowledge of structural determinants of BRCA1 function. We further designed and assessed the impact of four single codon deletions in the tBRCT linker region and six nonsense variants at the C-terminus end of BRCA1. Amino acid substitutions, deletions or insertions in the disordered region do not significantly impact activity and are not likely to constitute pathogenic alleles. On the other hand, a sizeable fraction of in-frame indels at the BRCT domain significantly impact function. We then use a Bayesian integrative statistical model to derive the probability of pathogenicity for each variant. Our data highlights the importance of assessing the impact of small in-frame indels in BRCA1 to improve risk assessment and clinical decisions for carriers.

PMID:36171434 | DOI:10.1038/s41598-022-20500-4

Pharmacogenomics J. 2022 Sep 28. doi: 10.1038/s41397-022-00289-1. Online ahead of print.

ABSTRACT

Available drugs have been used as an urgent attempt through clinical trials to minimize severe cases of hospitalizations with Coronavirus disease (COVID-19), however, there are limited data on common pharmacogenomics affecting concomitant medications response in patients with comorbidities. To identify the genomic determinants that influence COVID-19 susceptibility, we use a computational, statistical, and network biology approach to analyze relationships of ineffective concomitant medication with an adverse effect on patients. We statistically construct a pharmacogenetic/biomarker network with significant drug-gene interactions originating from gene-disease associations. Investigation of the predicted pharmacogenes encompassing the gene-disease-gene pharmacogenomics (PGx) network suggests that these genes could play a significant role in COVID-19 clinical manifestation due to their association with autoimmune, metabolic, neurological, cardiovascular, and degenerative disorders, some of which have been reported to be crucial comorbidities in a COVID-19 patient.

PMID:36171417 | DOI:10.1038/s41397-022-00289-1

Eur J Nucl Med Mol Imaging. 2022 Sep 29. doi: 10.1007/s00259-022-05984-6. Online ahead of print.

ABSTRACT

PURPOSE: We aimed to evaluate whether [⁶⁸ Ga]Ga-FAPI-04 PET/CT could characterize the early stages of cardiac fibrosis in pressure overload heart failure.

METHODS: Sprague-Dawley rats underwent abdominal aortic constriction (AAC) (n = 12) and sham surgery (n = 10). All rats were scanned with [⁶⁸ Ga]Ga-FAPI-04 PET/CT at 2, 4, and 8 weeks after surgery. The expression of fibroblast activation protein (FAP) in the myocardium was detected by immunohistochemistry. [⁶⁸ Ga]Ga-FAPI-04 PET signal and FAP expression were compared between two groups.

RESULTS: Compared with the sham group, the AAC group presented with decreased ejection fraction (EF) and fractional shortening (FS) and increased left ventricular internal dimensions in diastole (LVIDd) and systole (LVIDs) at 4 and 8 weeks (all p < 0.01). The AAC group showed higher [⁶⁸ Ga]Ga-FAPI-04 accumulation in the heart than the sham group at 2, 4, and 8 weeks, and FAPI increased significantly from 2 to 8 weeks (all p < 0.001). Immunohistochemistry confirmed the higher density of the FAP⁺ area in the AAC group. The intensity of the [⁶⁸ Ga]Ga-FAPI-04 correlated with the density of the FAP⁺ area (p < 0.001). The expression of the [⁶⁸ Ga]Ga-FAPI-04 at 4 weeks correlated with the deterioration of cardiac function at 8 weeks (EF: R = – 0.87; FS: R = – 0.72; LVIDd: R = 0.77; LVIDs: R = 0.79; all p < 0.001). The AAC group also showed an increased [⁶⁸ Ga]Ga-FAPI-04 signal in the liver, peaking at 4 weeks and then declining. Cardiac and liver PET signals correlated at 4 weeks in the AAC group (R = 0.69, p = 0.0010), suggesting an early fibrotic link between organs. A combination of the [⁶⁸ Ga]Ga-FAPI-04 intensity in the heart and liver at 4 weeks better predicted the deterioration of cardiac function at 8 weeks.

CONCLUSIONS: The activated fibroblasts in the heart and liver after pressure overload can be monitored by [⁶⁸ Ga]Ga-FAPI-04 PET/CT, which reveals an early fibrotic link in cardio-liver interactions and could better predict nonischemic heart failure prognosis.

PMID:36171409 | DOI:10.1007/s00259-022-05984-6

Sci Rep. 2022 Sep 28;12(1):16219. doi: 10.1038/s41598-022-20584-y.

ABSTRACT

Carbon monoxide poisoning may damage the brain and adrenal glands, but it is unclear whether it is associated with adrenal insufficiency. We identified all COP patients diagnosed between 1999 and 2012 in Taiwan using the Nationwide Poisoning Database and selected a reference cohort (participants without COP) from the same database by exact matching of age and index date at a 1:2 ratio. Participants with a history of adrenal insufficiency or steroid use of more than 14 days were excluded. We followed up participants until 2013 and compared the risk of developing adrenal insufficiency between the two cohorts. The 21,842 COP patients had a higher risk for adrenal insufficiency than the 43,684 reference participants (adjusted hazard ratio [AHR] = 2.5; 95% confidence interval [CI]: 1.8-3.5) after adjustment for sex and underlying comorbidities (liver disease, thyroid disease, mental disorder). The risk continued to elevate even after 1 year (AHR = 2.1; 95% CI: 1.4-3.4). The COP patients who had acute respiratory failure had an even higher risk for adrenal insufficiency than those without acute respiratory failure, which may indicate a dose-response relationship. Stratified analyses showed that female patients had an elevated risk (AHR = 3.5; 95% CI: 2.1-6.0), but not male patients. Younger patients (< 50 years) had higher risks, and the AHR reached statistical significance in the age groups 20-34 (AHR = 5.5; 95% CI: 1.5-20.6) and 35-49 (AHR = 4.9; 95% CI: 2.3-10.6) years old. The risk for developing adrenal insufficiency elevated after COP, especially in female and younger patients. Carbon monoxide is the most common gaseous agent causing acute intoxication worldwide. Results of the current study call for monitoring adrenal function of patients with COP.

PMID:36171402 | DOI:10.1038/s41598-022-20584-y

Sci Rep. 2022 Sep 28;12(1):16207. doi: 10.1038/s41598-022-20550-8.

ABSTRACT

In studies evaluating the association between body mass index (BMI) and risk of tuberculosis (TB), the data for the underweight population has been limited and results were conflicting. Our study aimed to evaluate whether being underweight increases the risk of TB using a nationwide representative sample from the Republic of Korea. A large population-based cohort study of over ten million subjects who participated in the health screening in 2010 was performed using the Korean National Health Insurance database 2010-2017. We evaluated the incidence and risk of TB by BMI category (kg/m²) for Asians using a multivariable Cox regression model, adjusting for age, sex, smoking, alcohol consumption, regular exercise, low-income state, and underlying hypertension, diabetes mellitus, and dyslipidemia. To evaluate the association between BMI and TB risk, the underweight population was further subdivided according to the degree of thinness. During 70,063,154.3 person-years of follow-up, 52,615 of 11,135,332 individuals developed active TB with an incidence of 0.75 per 1000 person-years. Overall, there was a log-linear inverse relationship between TB incidence and BMI, within the BMI range of 15-30 kg/m² (R² = 0.95). The estimated adjusted hazard ratio (HR) for incident TB in the underweight population (BMI < 18.5) was 2.08 (95% confidence intervals, CI 2.02-2.15), overweight (23 ≤ BMI < 25) was 0.56 (0.55-0.58) and obese (BMI ≥ 25) was 0.40 (0.39-0.41) relative to the normal weight population. Among the underweight population, TB risk increased as the degree of thinness increased (adjusted HR = 1.98, 1.91-2.05; 2.50, 2.33-2.68; and 2.83, 2.55-3.15, for mild, moderate and severe thinness, respectively) (p for trend < 0.001). We found a significant inverse relationship between BMI and TB incidence, which was especially profound in the underweight population. Public health strategies to screen TB more actively in the underweight population and improve their weight status may help reduce the burden of TB.

PMID:36171396 | DOI:10.1038/s41598-022-20550-8

Sci Rep. 2022 Sep 28;12(1):16202. doi: 10.1038/s41598-022-20319-z.

ABSTRACT

We aimed to identify prognostic factors of cancer-specific survival (CSS) in non-metastatic castration-resistant prostate cancer (M0CRPC) patients. The final analysis of this retrospective cohort included 82 patients who were diagnosed as M0CRPC between 1998 and 2018 at the University of Tokyo Hospital. CRPC was defined as prostate-specific antigen (PSA) progression (increased PSA ≥ 25% and ≥ 2 ng/mL above the nadir or detection of a metastatic lesion). The median value of age and PSA at the time of CRPC were 76 (range 55-94) years and 2.84 (range 2.04-22.5) ng/mL, respectively. The median follow-up time from CRPC diagnosis was 38 (range 3-188) months. The prognostic factors of CSS were ‘PSA doubling time (PSADT) ≤ 3 months’, ‘time to CRPC diagnosis from the start of androgen deprivation therapy (TTCRPC) ≤ 12 months’, of which TTCRPC was a novel risk factor of CSS. In the multivariate analysis, ‘PSADT ≤ 3 months’ and TTCRPC ≤ 12 months’ remained as statistically significant predictors of CSS. Novel risk stratification was developed based on the number of these risk factors. The high-risk group showed a hazard ratio of 4.416 (95% confidence interval 1.701-11.47, C-index = 0.727).

PMID:36171391 | DOI:10.1038/s41598-022-20319-z

World J Surg. 2022 Sep 28. doi: 10.1007/s00268-022-06763-y. Online ahead of print.

ABSTRACT

BACKGROUND: Major abdominal emergency surgery (MAES) has a high risk of postoperative mortality and a high complication rate. The aim of this study was to evaluate whether the implementation of a perioperative care bundle reduced long-term mortality and the Comprehensive Complication Index (CCI) after MAES.

METHODS: This study was a single-centre retrospective cohort study. Data in the intervention group were collected prospectively and compared with a historical cohort from the same centre. It includes adult patients undergoing MAES. We implemented a care bundle under the name Abdominal Surgery Acute Protocol (ASAP). We initiated fast-track initiatives and standardised optimised care in before, during and after surgery. Data were analysed using survival analysis and multiple regression.

RESULTS: We included 120 patients in the intervention cohort and 258 in the historical cohort. The one-year mortality rate was 21.7% in the intervention cohort compared to 28.3% in the standard care cohort. Adjusted odds ratio of one-year mortality 0.81 (CI95% 0.41-1.56). The 30-day mortality was lowered from 19.0 to 6.7% (p = 0.003). The CCI in the intervention cohort was 8.7 (IQR 0-34) compared to 21 (IQR 0-36) in the control cohort (p = 0.932) The length of stay increased by two days (p = 0.021). Most cases had 71-80% protocol compliance.

CONCLUSION: Implementing bundle care in major abdominal emergency surgery lowered the 30-day postoperative mortality. The difference in mortality was preserved over time although not significant after one year. The changes in the Comprehensive Complication Index were not statistically significant.

PMID:36171351 | DOI:10.1007/s00268-022-06763-y

Psychiatr Danub. 2022 Sep;34(Suppl 8):256-261.

ABSTRACT

BACKGROUND: Up to 45% of ischemic strokes are cryptogenic, which is an impediment to proposing preventative measures. In this investigation we aimed to study underlying heart arrhythmias in patients with cryptogenic stroke, taking into consideration the context of the COVID-19 pandemic and stressful lockdown conditions.

SUBJECTS AND METHODS: In this cross-sectional study we observed 52 patients with cryptogenic stroke >1 month after acute presentation, and a control group consisting of 88 patients without stroke. All patients undewent the laboratory and instrumental investigation consisting of the following: lipid spectrum; hemostasiograms; hemoglobin A1c; transthoracic or/and transesophageal echocardiography; 24-hours monitoring of ECG; computer tomography or magnetic resonance imaging of the brain. We studied the hemodynamics of the common carotid arteries using Doppler ultrasound imaging and digital sphygmography (SG).

RESULTS: The groups were indentical with respect to the preponderance of study parameters (sex, age, comorbidities, instrumental and laboratory data). The ischemic stroke group had a statistically significant difference in the prevalence of the first type of extrasystolic arrhythmia according to our gradation of extrasystoles, which are ventricular systoles of extrasystolic contraction appearing before the transmitral blood flow peak (peak E in echocardiography). We observed that earlier ventricular systoles of extrasystole in the cardiac cycle predicted for greater growth of hemodynamic and kinetic parameters. Calculating the indices of a four-field table established the significant relationship between the moment of appearance of extrasystolic ventricular contraction in the cardiac cycle and the risk for cryptogenic stroke (normalized value of the Pearson coefficient (C`) of the two paramaters was 0.318).

CONCLUSIONS: Extrasystolic arrhythmia appeared as an additional risk factor of earlier stroke. The most dangerous type of arrhythmia was when the ventricular contraction of the extrasystole appeared before the transmitral blood flow peak in the cardiac cycle. This observation could present a risk-marker for brain-related cardiovascular complications such as stroke, which might be patients suffering from different internal diseases, especially in the context of environmental stress conditions of the current pandemic and its related lockdown measures.

PMID:36170739

Psychiatr Danub. 2022 Sep;34(Suppl 8):238-245.

ABSTRACT

BACKGROUND: The stigmatization by healthcare professionals (HP) of patients suffering from mental disorders is an important problem that interferes with the delivery of medical assistance. Social distancing by HP is an integral part of stigmatization, which differs between various mental disorders, as well as between psychiatrists (PSY) versus nonpsychiatrist healthcare professionals (NPHP).

SUBJECTS AND METHODS: The study included 141 HP: PSY (n=20; 36.2±4.2 y.o.) and NPHP (n=121; 25.9±2.2 y.o.). The NPHP group included general practitioners (GP)/physicians (n=29; 20.6%), surgeons (n=19; 13.5%), obstetrician-gynecologists (n=26; 18.4%), neurologists (n=11; 7.8%), pediatricians (n=6; 4.3%), and other subspecialists (including urologists, tuberculosis specialists, ophthalmologists and dermatologists) (n=30; 21.3%). The modified Bogardus Social Distance Self-Assessment Scale (BSDS) was used to evaluate the indicators of social distance phenomena. The assessment was performed by HP for the following groups of patients with the following mental disorders: alcohol use disorder, bipolar disorder, depression, drug addiction, epilepsy, mental retardation, personality disorder, schizophrenia. All statistical calculations were performed using IBM SPSS-27 software (IBM Corp. 2021, licensed to Samara State Medical University). P-value ≤0.05 was determined as significant for the between-group (PSY vs NPHP) comparisons using a nonparametric Mann-Whitney U-test.

RESULTS: Our data analysis showed that HP achieved varying social distance scores for patients depending on the type of mental disorder, but with common trends among PSY and NPHPs. The mean (SD) scores of social distance ranged from 3.65(1.50) for depression to 5.25 (1.74) for drug addiction in the PSY, versus 3.44 (1.69), 6.19 (1.37) in NPHP, respectively. As compared to PSY, mean BSDS total scores were greater in the NPHP group, notably in the obstetricians-gynecologist – 6.27(1.40), and GP – 6.62 (0.90) groups, with similar trends of differing attitudes appeared among pediatricians – 7.00 (0.01) – regarding drug addiction, whereas the neurologists demonstrated a tendency towards lower social distance in relation to patients with depression – 2.27 (1.68), and epilepsy – 2.82 (1.47).

CONCLUSIONS: Social distance measures by PSY and NPHP groups in contemporary Russia were highest in relation to patients with drug addiction, and lowest scores for depression and epilepsy. Stigmatization among HPs seems to influence health care delivery to certain categories of patients, which calls for further investigation. Higher social distance scores for patients with drug addiction might be related to higher stigma and lack of compassion toward these patients. Conversely, lower scores of social distance and corresponding emotional acceptance of people with depression by HP might interfere in the timely diagnosis and availability of appropriate care at an early stage amenable to treatment. This might reflect the cultural context of depressive mentality in Russia, or elevated prevalence of depressive states among HP. We propose interventions aiming to destigmatize mental disorders by targeting particular subgroups of vulnerable patients and also certain representatives of HP community.

PMID:36170737

Psychiatr Danub. 2022 Sep;34(Suppl 8):220-230.

ABSTRACT

The impact of diagnostic delay in mental health is significant in terms of neurocognitive impairment, comorbidities, prognostic and socio-economical cost. For this reason, diagnostical research in psychiatry and the classification methods are continuously questioned. The network theory of mental disorders aims at contributing to the improvement of psychiatric diagnosis and considers mental disorders as the results of complex sets of interactions among symptoms instead of being their common cause. In this study, we use network theory and its associate statistical methods, namely Gaussian Graphical Models, centrality, and cluster analysis, to estimate respectively the interactions among symptoms from different disorders, their relative importance, and how they overlap, in a sample of psychiatric inpatients. The community detection found nine clusters with their interactions. Many are closely related to DSM criteria but some of them share symptoms from both diagnostics. One central symptom of the construct is Insomnia. There was a significant difference in the sum scores for psychotic symptoms, but not for bipolar symptoms, across psychotic and bipolar patients. This study needs however to be replicated in a bigger sample of different patients. Computing Bayesian Network to assess causalities in the network and adding other variables (such as biomarkers or therapeutic responses) could contribute to a more personalized diagnostic. How symptoms connect to each other in a specific time frame would define a person phenotype. Network analysis allows for investigating connections, identifying which symptoms are relatively important to the self-determination of disorders as well as how network nodes predict each other and arise in communities. For instance, in psychotic and mood disorders, sleep related symptoms or altered speech features and the importance of their communities in the probable transfer of symptomatology.

PMID:36170734