Meta-analysis of the efficacy of a single stage laparoscopic management versus two-stage endoscopic management of symptomatic gallstones with common bile duct stones.

Background. The optimal treatment of gallstones with associated common bile duct stones in the laparoscopic era is controversial. Various reviews and decision based algorithms have been published, but the superior treatment modality is unclear. Therefore, a metaanalysis was conducted to compare the two most commonly used treatment strategies. Methods. A systematic review was conducted to compare single stage laparoscopic cholecystectomy with common bile duct exploration versus a combined endoscopic and laparoscopic treatment. Eligible studies were identified using a search of Medline, Embase, Cochrane and Science Citation Index Expanded databases. Appropriately selected articles were independently reviewed and data was extracted and cross referenced. A meta-analysis was conducted of the pooled trial data to determine difference in outcomes. Results. A total of seven randomized trials were identified with 746 patients with 366 in the laparoscopic only treatment group and 380 in the combined endoscopic and laparoscopic treatment arms. There was no significant difference in successful bile duct clearance between the two groups (OR 1.23; 95% CI 0.55 to 2.75, P = 0.61). There was no statistical difference in morbidity (RR 1.23; 95% CI 0.92 to 1.66; P = 0.17), mortality (RD -0.00; 95% CI -0.02 to 0.01, P = 0.59) or length of hospital stay (MD -0.31; 95% CI -1.68 to 1.06, P = 0.66). However, there was a statistically significant difference in the duration of procedure in favour of the single stage laparoscopic treatment (MD -6.83; 95% CI -9.59 to -4.07, P \u3c 0.00001). Conclusion. Both the laparoscopic alone or the combined endoscopic and laparoscopic treatment approaches show comparative efficacy in management of symptomatic gallstones with associated choledocholithiasis

Meta-analiza učinkovitosti laparoskopskog liječenja u jednom aktu u usporedbi s endoskopskim liječenjem simptomatskih žučnih kamenaca i žučnih kamenaca u glavnom žučovodu u više akata

Background The optimal treatment of gallstones with associated common bile duct stones in the laparoscopic era is controversial. Various reviews and decision based algorithms have been published, but the superior treatment modality is unclear. Therefore, a meta-analysis was conducted to compare the two most commonly used treatment strategies. Methods A systematic review was conducted to compare single stage laparoscopic cholecystectomy with common bile duct exploration versus a combined endoscopic and laparoscopic treatment. Eligible studies were identified using a search of Medline, Embase, Cochrane and Science Citation Index Expanded databases. Appropriately selected articles were independently reviewed and data was extracted and cross referenced. A meta-analysis was conducted of the pooled trial data to determine difference in outcomes. Results A total of seven randomized trials were identified with 746 patients with 366 in the laparoscopic only treatment group and 380 in the combined endoscopic and laparoscopic treatment arms. There was no significant difference in successful bile duct clearance between the two groups (OR 1.23; 95% CI 0.55 to 2.75, P = 0.61). There was no statistical difference in morbidity (RR 1.23; 95% CI 0.92 to 1.66; P = 0.17), mortality (RD -0.00; 95% CI -0.02 to 0.01, P = 0.59) or length of hospital stay (MD -0.31; 95% CI -1.68 to 1.06, P = 0.66). However, there was a statistically significant difference in the duration of procedure in favour of the single stage laparoscopic treatment (MD -6.83; 95% CI -9.59 to -4.07, P < 0.00001). Conclusion Both the laparoscopic alone or the combined endoscopic and laparoscopic treatment approaches show comparative efficacy in management of symptomatic gallstones with associated choledocholithiasis.Pozadina Optimalno liječenje žučnih kamenaca uz prateće žučne kamence u glavnom žučovodu u eri laparoskopske kirurgije je kontroverzno. Objavljeni su razni pregledni radovi i algoritmi odlučivanja, no pitanje odluke o odabiru preporučenog načina liječenja ostaje neriješeno. S ciljem usporedbe dva najčešće korištena načina liječenja provedena je meta-analiza. Metode Sistematsko istraživanje provedeno je kako bi se usporedila kolecistektomija s eksploracijom glavnog žučovoda u jednom aktu u odnosu na kombinirano endoskopsko i laparoskopsko liječenje. Dostupne studije nađene su pomoću sljedećih baza podataka: Medline, Embase, Cochrane i Science Citation Index Expanded. Probrani relevantni radovi zasebno su pregledani, a podaci izdvojeni i međusobno uspoređeni. Provedena je meta-analiza svih prikupljenih podataka da bi se odredila razlika u ishodima. Rezultati Pronađeno je sveukupno sedam randomiziranih studija sa 746 pacijenata od kojih je 366 u skupini liječenoj isključivo laparoskopski te 380 liječenih kombinirano endoskopski i laparoskopski. Nije utvrđena značajna razlika u uspješnom čišćenju žučnih vodova između dvije skupine (OR 1,23; 95% CI 0,55 do 2,75, P = 0,61). Nije nađena značajna razlika u morbiditetu (RR 1,23; 95% CI 0,92 do 1,66; P = 0,17), smrtnosti (RD -0,00; 95% CI -0.02 do 0,01, P = 0,59) ili trajanju hospitalizacije (MD -0,31; 95% CI -1,68 to 1,06, P = 0,66). Međutim, postojala je statistički značajna razlika u trajanju zahvata (MD -6,83; 95% CI -9,59 do -4,07, P < 0,00001). Zaključak Laparoskopski ili kombinirani endoskopski i laparoskopski pristup liječenju pokazuje značajnu učinkovitost u liječenju simptomatskih žučnih kamenaca s pratećom koledoholitijazom

An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models

Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Impairment of Auditory-Motor Timing and Compensatory Reorganization after Ventral Premotor Cortex Stimulation

Integrating auditory and motor information often requires precise timing as in speech and music. In humans, the position of the ventral premotor cortex (PMv) in the dorsal auditory stream renders this area a node for auditory-motor integration. Yet, it remains unknown whether the PMv is critical for auditory-motor timing and which activity increases help to preserve task performance following its disruption. 16 healthy volunteers participated in two sessions with fMRI measured at baseline and following rTMS (rTMS) of either the left PMv or a control region. Subjects synchronized left or right finger tapping to sub-second beat rates of auditory rhythms in the experimental task, and produced self-paced tapping during spectrally matched auditory stimuli in the control task. Left PMv rTMS impaired auditory-motor synchronization accuracy in the first sub-block following stimulation (p<0.01, Bonferroni corrected), but spared motor timing and attention to task. Task-related activity increased in the homologue right PMv, but did not predict the behavioral effect of rTMS. In contrast, anterior midline cerebellum revealed most pronounced activity increase in less impaired subjects. The present findings suggest a critical role of the left PMv in feed-forward computations enabling accurate auditory-motor timing, which can be compensated by activity modulations in the cerebellum, but not in the homologue region contralateral to stimulation

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570