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BioRxiv : the Preprint Server For... Jun 2024DNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly...
DNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly occurs through homologous recombination (HR) and non-homologous end joining (NHEJ). In HR-deficient cells, DNA polymerase theta (Polθ) becomes critical for DSB repair via microhomology-mediated end joining (MMEJ), also termed theta-mediated end joining (TMEJ). Thus, Polθ is synthetically lethal with BRCA1/2 and other HR factors, underscoring its potential as a therapeutic target in HR-deficient cancers. However, the molecular mechanisms governing Polθ-mediated MMEJ remain poorly understood. Here we present a series of cryo-electron microscopy structures of the Polθ helicase domain (Polθ-hel) in complex with DNA containing 3'-overhang. The structures reveal the sequential conformations adopted by Polθ-hel during the critical phases of DNA binding, microhomology searching, and microhomology annealing. The stepwise conformational changes within the Polθ-hel subdomains and its functional dimeric state are pivotal for aligning the 3'-overhangs, facilitating the microhomology search and subsequent annealing necessary for DSB repair via MMEJ. Our findings illustrate the essential molecular switches within Polθ-hel that orchestrate the MMEJ process in DSB repair, laying the groundwork for the development of targeted therapies against the Polθ-hel.
PubMed: 38895274
DOI: 10.1101/2024.06.07.597860 -
The Israel Medical Association Journal... Jun 2024Diabetic ketoacidosis (DKA) is an acute metabolic, life-threatening complication of diabetes mellitus with a mortality rate that now stand at less than 1%. Although...
BACKGROUND
Diabetic ketoacidosis (DKA) is an acute metabolic, life-threatening complication of diabetes mellitus with a mortality rate that now stand at less than 1%. Although mortality is coupled with the etiology of DKA, literature on the influence of DKA etiology on patient outcome is scarce.
OBJECTIVES
To study different triggers for DKA and their effect on outcomes.
METHODS
We conducted a retrospective study that include 385 DKA patients from 2004 to 2017. The study compared demographics, clinical presentation, and mortality rates by different precipitating factors.
RESULTS
Patients with DKA due to infections had a higher risk to develop in-hospital mortality after controlling for age and sex (odds ratio 4.40, 95% confidence interval 1.35-14.30), had a higher Charlson Comorbidity Index score, a higher risk of being mechanical ventilated (14% vs. 3%, P < 0.01), and a longer duration of hospitalization (5 days vs. 3 days, P < 0.001).
CONCLUSIONS
It is crucial to find the triggers that precipitate DKA and start the treatment as early as possible in addition to the metabolic aspect of the treatment especially when the trigger is an infectious disease.
Topics: Humans; Diabetic Ketoacidosis; Male; Female; Retrospective Studies; Prognosis; Middle Aged; Hospital Mortality; Adult; Risk Factors; Length of Stay; Precipitating Factors; Respiration, Artificial; Infections; Israel; Aged
PubMed: 38884305
DOI: No ID Found -
Cureus May 2024A myasthenic crisis denotes a severe exacerbation of myasthenia gravis, leading a patient to enter a life-threatening state due to progressing muscle weakness that...
A myasthenic crisis denotes a severe exacerbation of myasthenia gravis, leading a patient to enter a life-threatening state due to progressing muscle weakness that ultimately results in respiratory failure. A crisis can require intubation, mechanical ventilation, and additional critical care to prevent further decompensation and potentially death. Numerous well-documented precipitating factors exist, such as infections, surgery, stress, and various medications. We present the case of a 43-year-old woman recently diagnosed with myasthenia gravis who has experienced two myasthenic crises since diagnosis without evident triggers such as surgery, changes in medication, or infection. Following an unremarkable initial diagnostic test and continued treatment for the crisis, we sought additional information from the patient's family member at the bedside. We were informed that two weeks prior to both times of crisis with intubation, the patient had dyed her hair blue. The common chemical component in the two different hair dyes used was methylisothiazolinone, which is suspected to have contributed to the exacerbation of the patient's myasthenia gravis. As more evidence for new precipitating factors of myasthenic crises develops, it is crucial for physicians to quickly identify signs and symptoms of a crisis so appropriate intervention can occur in a time-sensitive manner. In addition, myasthenia gravis patients should be made aware to be cautious of precipitating factors of a crisis, including but not limited to new beauty products.
PubMed: 38868287
DOI: 10.7759/cureus.60186 -
Central Pontine Myelinolysis: A Rare and Life-Threatening Adverse Effect of Clobazam and Quetiapine.Cureus May 2024Central pontine myelinolysis (CPM) is a rare neurological disorder characterized by demyelination within the central portion of the pons. While hyponatremia is a...
Central pontine myelinolysis (CPM) is a rare neurological disorder characterized by demyelination within the central portion of the pons. While hyponatremia is a well-known precipitating factor, other etiologies, including medication use, have been reported. We present a case of a 69-year-old male with a history of obsessive-compulsive disorder, stroke, and type 2 diabetes mellitus who developed confusion, altered sensorium, and weakness in all four limbs. An MRI brain imaging revealed characteristic findings suggestive of CPM. Despite normal serum sodium levels, discontinuation of clobazam and quetiapine, medications taken by the patient, led to clinical improvement. This case underscores the importance of considering medication-induced CPM in the differential diagnosis of patients presenting with neurological symptoms, even in the absence of electrolyte abnormalities.
PubMed: 38854288
DOI: 10.7759/cureus.60007 -
Industrial Psychiatry Journal 2024There is a dearth of research on risk factors of delirium among elderly inpatients in nonintensive low resource settings.
BACKGROUND
There is a dearth of research on risk factors of delirium among elderly inpatients in nonintensive low resource settings.
AIM
To determine the risk factors of delirium in elderly inpatients in a nonintensive care unit setting.
MATERIALS AND METHODS
Sixty two elderly patients with delirium (cases) and 62 patients without delirium (controls) were administered a semi-structured proforma with socio-demographic variables and putative predisposing and precipitating risk factors and the Vellore screening instrument for dementia.
RESULTS
On univariate analysis, factors such as past cognitive impairment, history of nocturnal confusion and delirium, diminished daily living activities, severe medical illness, history of psychiatric illness, presence of dementia, infection, fever above 100F, abnormal electrolytes abnormal RFT, leukocytes in urine, hypoxia, anticholinergics and benzodiazepines, emergency admission, use of physical restraints, bladder catheterization, more than routine investigations, intensive care unit admission, surgery, and duration of hospital stay more than 10 days were found to be significantly associated with delirium. On multivariate analysis with binary logistic regression, bladder catheterization (odds ratio [OR] = 13.85; confidence interval [CI] = 1.44-133.14), abnormal electrolytes (OR = 5.12; CI = 1.11-23.69), and hypoxia (OR = 75.52; CI = 4.64-1.134E3) were detected to be independently associated with delirium.
CONCLUSION
Acute modifiable rather than long-term factors were risk factors for delirium among the elderly. An awareness of modifiable risk factors has the potential of developing targeted interventions for the early mitigation of delirium.
PubMed: 38853788
DOI: 10.4103/ipj.ipj_16_23 -
Biomedicine & Pharmacotherapy =... Jul 2024Intracranial atherosclerotic stenosis (ICAS) is a pathological condition characterized by progressive narrowing or complete blockage of intracranial blood vessels caused... (Review)
Review
Intracranial atherosclerotic stenosis (ICAS) is a pathological condition characterized by progressive narrowing or complete blockage of intracranial blood vessels caused by plaque formation. This condition leads to reduced blood flow to the brain, resulting in cerebral ischemia and hypoxia. Ischemic stroke (IS) resulting from ICAS poses a significant global public health challenge, especially among East Asian populations. However, the underlying causes of the notable variations in prevalence among diverse populations, as well as the most effective strategies for preventing and treating the rupture and blockage of intracranial plaques, remain incompletely comprehended. Rupture of plaques, bleeding, and thrombosis serve as precipitating factors in the pathogenesis of luminal obstruction in intracranial arteries. Pericytes play a crucial role in the structure and function of blood vessels and face significant challenges in regulating the Vasa Vasorum (VV)and preventing intraplaque hemorrhage (IPH). This review aims to explore innovative therapeutic strategies that target the pathophysiological mechanisms of vulnerable plaques by modulating pericyte biological function. It also discusses the potential applications of pericytes in central nervous system (CNS) diseases and their prospects as a therapeutic intervention in the field of biological tissue engineering regeneration.
Topics: Pericytes; Humans; Animals; Intracranial Arteriosclerosis; Vasa Vasorum; Cerebral Arteries
PubMed: 38850658
DOI: 10.1016/j.biopha.2024.116870 -
The International Journal of Angiology... Jun 2024Venous thromboembolism (VTE) is a very frequent cardiovascular entity that encompasses deep vein thrombosis and pulmonary embolism (PE). This last entity represents a... (Review)
Review
Venous thromboembolism (VTE) is a very frequent cardiovascular entity that encompasses deep vein thrombosis and pulmonary embolism (PE). This last entity represents a major cause of cardiovascular morbidity and mortality. The incidence of PE and the rate of PE-related morbidity significantly increase with age, race, and underlying medical conditions, such as malignancy. Given the recent advances in diagnostic strategies and algorithms, patients can be risk assessed and treated promptly to avoid disease progression. Anticoagulation is the mainstay of treatment for acute PE that is not hemodynamically unstable. Direct oral anticoagulants, such as apixaban, rivaroxaban, or edoxaban, are currently the preferred agents for the treatment of patients who present with acute PE or for long-term treatment. Treatment duration should be continued for at least 3 months, and all patients should be assessed for extended duration of therapy based on the precipitating factors that led to the development of the VTE. Novel anticoagulant agents targeting factor XI/XIa are currently being investigated in phases 2 and 3 clinical trials, representing an attractive option in anticoagulation therapies in patients with VTE. For hemodynamically unstable patients, systemic thrombolysis is the treatment of choice, and it may also be of benefit-in reduced dose-for patients with intermediate to high risk who are at risk of hemodynamic collapse.
PubMed: 38846991
DOI: 10.1055/s-0044-1782537 -
International Journal of... Jun 2024Sleep quality often deteriorates with age, and insomnia among the elderly increases the risks of both physical and psychiatric disorders. To elucidate the mechanisms and...
Sleep quality often deteriorates with age, and insomnia among the elderly increases the risks of both physical and psychiatric disorders. To elucidate the mechanisms and identify useful diagnostic biomarkers for insomnia in the elderly, the current study investigated the associations of waking brain activity patterns with susceptibility to stress-induced insomnia (sleep reactivity) and dysfunctional beliefs about sleep, major factors precipitating and maintaining insomnia, respectively. Forty-five participants aged 60 years or older with insomnia completed self-reported measures assessing depression, anxiety, sleep quality, dysfunctional beliefs about sleep, and sleep reactivity. Participants were then examined by quantitative electroencephalography (qEEG) during wakefulness, and spectral analysis was conducted to examine associations of regional frequency band power with these insomnia-precipitating and -maintaining factors. Dysfunctional beliefs about sleep were significantly correlated with higher beta/high-beta frequency band powers, while sleep reactivity was correlated with higher theta and delta frequency band powers. These findings suggest that sleep reactivity of older adults is associated with widespread cortical deactivation leading to poor stress coping, while their dysfunctional beliefs about sleep are associated with hyperactivation which is related to cognitive processes. These associations suggest that cognitive inflexibility and maladaptive stress-coping contribute to insomnia among the elderly.
PubMed: 38844053
DOI: 10.1016/j.ijpsycho.2024.112373 -
BMC Gastroenterology Jun 2024Type C hepatitis B-related acute-on-chronic liver failure (HBV-ACLF), which is based on decompensated cirrhosis, has different laboratory tests, precipitating events,...
BACKGROUND
Type C hepatitis B-related acute-on-chronic liver failure (HBV-ACLF), which is based on decompensated cirrhosis, has different laboratory tests, precipitating events, organ failure and clinical outcomes. The predictors of prognosis for type C HBV-ACLF patients are different from those for other subgroups. This study aimed to construct a novel, short-term prognostic score that applied serological indicators of hepatic regeneration and noninvasive assessment of liver fibrosis to predict outcomes in patients with type C HBV-ACLF.
METHOD
Patients with type C HBV-ACLF were observed for 90 days. Demographic information, clinical examination, and laboratory test results of the enrolled patients were collected. Univariate and multivariate logistic regression were performed to identify independent prognostic factors and develop a novel prognostic scoring system. A receiver operating characteristic (ROC) curve was used to analyse the performance of the model.
RESULTS
A total of 224 patients with type C HBV-ACLF were finally included. The overall survival rate within 90 days was 47.77%. Age, total bilirubin (TBil), international normalized ratio (INR), alpha-fetoprotein (AFP), white blood cell (WBC), serum sodium (Na), and aspartate aminotransferase/platelet ratio index (APRI) were found to be independent prognostic factors. According to the results of the logistic regression analysis, a new prognostic model (named the A3Twin score) was established. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) was 0.851 [95% CI (0.801-0.901)], the sensitivity was 78.8%, and the specificity was 71.8%, which were significantly higher than those of the MELD, IMELD, MELD-Na, TACIA and COSSH-ACLF II scores (all P < 0.001). Patients with lower A3Twin scores (<-9.07) survived longer.
CONCLUSIONS
A new prognostic scoring system for patients with type C HBV-ACLF based on seven routine indices was established in our study and can accurately predict short-term mortality and might be used to guide clinical management.
Topics: Humans; Male; Female; alpha-Fetoproteins; Acute-On-Chronic Liver Failure; Retrospective Studies; Middle Aged; Prognosis; Adult; Biomarkers; Aspartate Aminotransferases; ROC Curve; Platelet Count; Hepatitis B, Chronic; Liver Cirrhosis; Survival Rate; Predictive Value of Tests; Logistic Models
PubMed: 38834942
DOI: 10.1186/s12876-024-03276-x -
Epilepsia Open Jun 2024Epilepsy surgery may be a curative therapy for patients with drug-resistant epilepsies when focal lesions or foci are identified. Genetic testing is not yet routinely...
Epilepsy surgery may be a curative therapy for patients with drug-resistant epilepsies when focal lesions or foci are identified. Genetic testing is not yet routinely included in many presurgical evaluation programs although recent evidence support that finding a germline genetic mutation could help to better delineate the patient candidacy to surgery and provide valuable information on the expected surgery outcome. In this study, we report nine patients presenting drug-resistant focal epilepsy enrolled in presurgical evaluation. We show how the identification of genetic pathogenic variant in epilepsy known genes led to the interruption of the presurgical work-up and ruled out surgery in 7 of them. We observed that the co-existence of some recurrent clinical characteristics as early seizures' onset, frequent precipitating factors including fever, and developmental delay or intellectual disability may be useful markers for germline genetic pathogenic variants. In this group, genetic assessment should be mandatory during presurgical work up, mainly in patients with negative magnetic resonance imaging (MRI) or doubtful structural lesions. The integration of next generation targeted sequencing into the presurgical evaluation can improve the selection of candidates for resective surgery and fosters a personalized medicine approach with a better outcome. PLAINE LANGUAGE ABSTRACT: Genetic testing is not yet systematically included in the pre-surgical assessment of patients with drug-resistant focal epilepsies. In this study, through the description of nine patients, we underline how the integration of genomics into the presurgical work up can help in evaluating the patient candidacy to surgery and provide valuable information on expected surgery outcome.
PubMed: 38829689
DOI: 10.1002/epi4.12964