Molecular basis of microhomology-mediated end-joining by purified full-length Polθ

DNA polymerase θ (Polθ) is a unique polymerase-helicase fusion protein that promotes microhomology-mediated end-joining (MMEJ) of DNA double-strand breaks (DSBs). How full-length human Polθ performs MMEJ at the molecular level remains unknown. Using a biochemical approach, we find that the helicase is essential for Polθ MMEJ of long ssDNA overhangs which model resected DSBs. Remarkably, Polθ MMEJ of ssDNA overhangs requires polymerase-helicase attachment, but not the disordered central domain, and occurs independently of helicase ATPase activity. Using single-particle microscopy and biophysical methods, we find that polymerase-helicase attachment promotes multimeric gel-like Polθ complexes that facilitate DNA accumulation, DNA synapsis, and MMEJ. We further find that the central domain regulates Polθ multimerization and governs its DNA substrate requirements for MMEJ. These studies identify unexpected functions for the helicase and central domain and demonstrate the importance of polymerase-helicase tethering in MMEJ and the structural organization of Polθ

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

The etiology and autopsy findings in Colchicine intoxication-related deaths

Colchicine is a drug which has a very narrow therapeutic range. This drug has been commonly used for Familial Mediterranean Fever (FMF), Behcets disease, gout arthritis and acute pseudo gout attacks. In this study, the investigation reports and autopsy reports written by the Council of Forensic Medicine of Ankara between the years 2010-2014 were retrospectively analyzed to find out presence in the cases related to colchicine. Six cases were identified as colchicine intoxication, while three of them used colchicine for medical purpose. In four cases, colchicine was found to have been used for suicidal purpose. Among these four cases, two used colchicine for treatment. In all of our cases, colchicine was detected in bile specimen. Alveolar pulmonary edema and petechial hemorrhage were observed in the lung in all cases. Colchicine was detected in blood in four of the cases. In two cases, the concentration was found to be in therapeutic ranges (0,012 mg/L and 0,018 mg/L), while the other two, in lethal levels (0.099 mg/L and 0,264 mg/L). The most frequent histopathological finding is alveolar pulmonary edema in colchicine intoxication autopsies. Colchicine is widely used alkaloid drugs with narrow therapeutic ranges. More than 0.8 mg / kg in the acute high dose has usually fatal effects. The deaths resulted from colchicine intoxication are mainly suicide-oriented. Similar to other suicides with medicines, they are common among women. In our cases, colchicine was used for intention of suicide in four incidents (66, 66%). [Med-Science 2016; 5(4.000): 990-3

Predictive value of the international prostate symptom score for positive prostate needle biopsy in the low-intermediate rostate-specific antigen range

Purpose: Serum prostate-specific antigen (PSA) has a restricted predictive value for prostate cancer in the low-intermediate PSA range (2.5 - 10 ng/ ml). Our aim was to determine the predictive value of the International Prostate Symptom Score (IPSS) for positive prostate needle biopsy (PNB) in patients who underwent transrectal ultrasound (TRUS)- guided prostate biopsy with a low-intermediate PSA level. Patients and Methods: Between 2001 and 2004, the data of 389 consecutive patients applying for any urologic complaint to our department and who underwent TRUS- guided prostate biopsy due to an elevated serum PSA and/ or abnormal digital rectal examination (DRE) were retrospectively analyzed. A total of 158 eligible patients with a low- intermediate PSA level were included in the study. The patient's age, PSA, free PSA, free/ total PSA, prostate volume, PSA density (PSAD), pre- biopsy IPSS were compared in the positive and negative biopsy groups. Results: Fifty- eight of 158 patients (37%) who underwent TRUS- guided prostate biopsy had positive PNBs. Forty- eight patients (30%) had abnormal DREs. In the positive PNB group, the mean age was older and PSAD was higher, but the means of the prostate volumes and total IPSS were lower (p < 0.05). Multivariate analysis demonstrated that age and IPSS were independent predictors of a positive PNB ( p < 0.05). The odds ratio of mild IPSS for positive PNB controlled for age was 3.0 (95% CI 1.5 - 6.7). Receiver- operating characteristics analysis revealed a mild IPSS (AUC = 0.640) and was a considerable predictor for positive PNB as well as PSAD (AUC = 0.648). The sensitivity and specifi city of IPSS with a cutoff value of 7.5 points were 31 and 87% for prediction of prostate cancer detection. Conclusion: In the low- intermediate PSA range, mild IPSS may be a predictive factor for positive PNB with a similar specifi city of PSAD. Copyright (c) 2005 S. Karger AG, Basel

Novel biomarker-based score (SAD-60) for predicting mortality in patients with COVID-19 pneumonia: a multicenter retrospective cohort of 1013 patients

Background: The aim was to explore a novel risk score to predict mortality in hospitalized patients with COVID-19 pneumonia. Methods: This was a retrospective, multicenter study. Results: A total of 1013 patients with COVID-19 were included. The mean age was 60.5 +/- 14.4 years, and 581 (57.4%) patients were male. In-hospital death occurred in 124 (12.2%) patients. Multivariate analysis revealed peripheral capillary oxygen saturation (SpO2), albumin, D-dimer and age as independent predictors. The mortality score model was given the acronym SAD-60, representing SpO2, Albumin, D-dimer, age >= 60 years. The SAD-60 score (0.776) had the highest area under the curve compared with CURB-65 (0.753), NEWS2 (0.686) and qSOFA (0.628) scores. Conclusion: The SAD-60 score has a promising predictive capacity for mortality in hospitalized patients with COVID-19

Paclitaxel plus Doxorubicin Chemotherapy as Second-Line Therapy in Patients with Advanced Urothelial Carcinoma Pretreated with Platinum plus Gemcitabine Chemotherapy

Background: We retrospectively evaluated the efficacy and toxicity of paclitaxel plus doxorubicin as a second-line treatment in patients with urothelial carcinoma, who had not responded to a prior platinum plus gemcitabine combination. Patients and Methods: All patients received intravenous infusions of paclitaxel (175 mg/m(2)/h) and doxorubicin (50 mg/m(2)/30 min) on day 1. Chemotherapy courses were repeated every 21 days. Results: The median follow-up duration was 13.5 months (range 2.8-22.4 months). Complete and partial responses were observed in 2 (5.6%) and 10 (27.8%) patients, respectively. Median overall survival was 8.9 months (95% confidence interval (CI): 6.2-11.6). Median time to progression was 3.8 months (95% CI: 2.7-4.8). The most common hematologic toxicities were neutropenia (n = 21, 58.3%), thrombocytopenia (n = 10, 27.8%), and anemia (n = 9, 25%). The most common non-hematologic toxicities consisted of fatigue (n = 15, 41.7%), nausea/vomiting (n = 13, 36.1%), peripheral neuropathy (n = 11, 30.6%), and mucositis (n = 6, 16.7%). Dose reductions by 25-35% were performed in 6 (16.7%) patients because of grade 3/4 toxicity. Anthracycline-related heart failure did not occur. Conclusion: 3-weekly courses of cyclic paclitaxel plus doxorubicin were found to be effective and tolerable in patients with urothelial carcinoma, who had not responded to prior platinum- and gemcitabine-based chemotherapy

Bevacizumab plus irinotecan in recurrent or progressive malign glioma: a multicenter study of the Anatolian Society of Medical Oncology (ASMO)

The overall prognosis for recurrent malignant glioma (MG) is extremely poor, and treatment options are limited. We evaluated our multicenter retrospective experience for patients with recurrent MG administering bevacizumab and irinotecan in combination therapy