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Treatment-resistant depression (TRD) is a severe form of major depressive disorder (MDD) with substantial public health impact and poor treatment outcome. Treatment outcome in MDD is significantly heritable, but genome-wide association studies have failed to identify replicable common marker alleles, suggesting a potential role for uncommon variants. Here we investigated the hypothesis that uncommon, putatively functional genetic variants are associated with TRD. Whole-exome sequencing data was obtained from 182 TRD cases and 2021 psychiatrically healthy controls. After quality control, the remaining 149 TRD cases and 1976 controls were analyzed with tests designed to detect excess burdens of uncommon variants. At the gene level, 5 genes, ZNF248 , PRKRA , PYHIN1 , SLC7A8 , and STK19 each carried exome-wide significant excess burdens of variants in TRD cases (q < 0.05). Analysis of 41 pre-selected gene sets suggested an excess of uncommon, functional variants among genes involved in lithium response. Among the genes identified in previous TRD studies, ZDHHC3 was also significant in this sample after multiple test correction. ZNF248 and STK19 are involved in transcriptional regulation, PHYIN1 and PRKRA are involved in immune response, SLC7A8 is associated with thyroid hormone transporter activity, and ZDHHC3 regulates synaptic clustering of GABA and glutamate receptors. These results implicate uncommon, functional alleles in TRD and suggest promising novel targets for future research.

ObjectiveTo evaluate the effect of colchicine and high-intensity rosuvastatin in addition to standard of care on the progression of COVID-19 disease in hospitalised patients.DesignA pragmatic, open-label, multicentre, randomised controlled trial conducted from October 2020 to September 2021. Follow-up was conducted at 30 and 60 days. The electronic medical record was used at all stages of the trial including screening, enrolment, randomisation, event ascertainment and follow-up.SettingFour centres in the Yale New Haven Health System.ParticipantsNon-critically ill hospitalised patients with COVID-19.InterventionsPatients were randomised 1:1 to either colchicine plus high-intensity rosuvastatin in addition to standard of care versus standard of care alone. Assigned treatment was continued for the duration of index hospitalisation or 30 days, whichever was shorter.Primary and secondary outcome measuresThe prespecified primary endpoint was progression to severe COVID-19 disease (new high-flow or non-invasive ventilation, mechanical ventilation, need for vasopressors, renal replacement therapy or extracorporeal membrane oxygenation, or death) or arterial/venous thromboembolic events (ischaemic stroke, myocardial infarction, deep venous thrombosis or pulmonary embolism) evaluated at 30 days.ResultsAmong the 250 patients randomised in this trial (125 to each arm), the median age was 61 years, 44% were women, 15% were Black and 26% were Hispanic/Latino. As part of the standard of care, patients received remdesivir (87%), dexamethasone (92%), tocilizumab (18%), baricitinib (2%), prophylactic/therapeutic anticoagulation (98%) and aspirin (91%). The trial was terminated early by the data and safety monitoring board for futility. No patients were lost to follow-up due to electronic medical record follow-up. There was no significant difference in the primary endpoint at 30 days between the active arm and standard of care arm (15.2% vs 8.8%, respectively, p=0.17).ConclusionsIn this small, open-label, randomised trial of non-critically ill hospitalised patients with COVID-19, the combination of colchicine and rosuvastatin in addition to standard of care did not appear to reduce the risk of progression of COVID-19 disease or thromboembolic events, although the trial was underpowered due to a lower-than-expected event rate. The trial leveraged the power of electronic medical records for efficiency and improved follow-up and demonstrates the utility of incorporating electronic medical records into future trials.Trial registrationNCT04472611.

Left ventricular (LV) dysfunction is associated with poor clinical outcomes in acute respiratory failure (ARF). This study evaluates the efficacy of LV strain in detecting LV dysfunction in ARF patients requiring invasive mechanical ventilation (IMV) compared to conventionally measured left ventricular ejection fraction (LVEF). ARF patients requiring IMV who had echocardiography performed during MICU admission were included. LV global longitudinal strain (LVGLS) and LVEF were measured retrospectively using speckle tracking (STE) and traditional transthoracic echocardiography (TTE), respectively, by investigators blinded to the status of IMV and clinical data. The cohort was divided into three groups: TTE during IMV (TTE-IMV), before IMV (TTE-bIMV), and after IMV (TTE-aIMV). Multivariable regression models, adjusted for illness severity score, chronic cardiac disease, acute respiratory failure etiology, body mass index, chronic obstructive pulmonary disease, and obstructive sleep apnea, evaluated associations between LV function parameters and the presence of IMV. Among 376 patients, TTE-IMV, TTE-bIMV, and TTE-aIMV groups constituted 223, 68, and 85 patients, respectively. The median age was 65 years (IQR: 56–74), with 53.2% male participants. Adjusted models showed significantly higher LVGLS in groups not on IMV at the time of TTE (TTE-bIMV: β = 4.19, 95% CI 2.31 to 6.08, p < 0.001; TTE-aIMV: β = 3.79, 95% CI 2.03 to 5.55, p < 0.001), while no significant differences in LVEF were observed across groups. In a subgroup analysis of patients with LVEF ≥55%, the significant difference in LVGLS among the groups remained (TTE-bIMV: β = 4.18, 95% CI 2.22 to 6.15, p < 0.001; TTE-aIMV: β = 3.45, 95% CI 1.50 to 5.40, p < 0.001), but was no longer present in those with LVEF < 55%. This suggests an association between IMV and lower LVGLS in ARF patients requiring IMV, indicating that LVGLS may be a more sensitive marker for detecting subclinical LV dysfunction compared to LVEF in this population. Future studies should track and assess serial echocardiography data in the same cohort of patients pre-, during, and post-IMV in order to validate these findings and prognosticate STE-detected LV dysfunction in ARF patients requiring IMV.

Right ventricular (RV) dysfunction is associated with poor prognosis in acute respiratory failure (ARF). Our study evaluates the efficacy of RV strain in detecting RV dysfunction in ARF patients requiring invasive mechanical ventilation (IMV) compared to tricuspid annular plane systolic excursion (TAPSE). In this retrospective study involving 376 patients diagnosed with ARF and requiring IMV, we extracted clinical and outcome data from patient records. RV global longitudinal strain (RVGLS), free wall longitudinal strain (FWLS), and TAPSE were measured retrospectively using speckle tracking echocardiography (STE) and traditional echocardiography, respectively. We divided the cohort into three groups: TTE during IMV (TTE-IMV, 223 patients), before IMV (TTE-bIMV, 68 patients), and after IMV (TTE-aIMV, 85 patients). Multivariable regression analysis, adjusted for covariates, revealed significantly higher RVGLS and FWLS in the groups not on IMV at the time of TTE compared to the TTE-IMV group. Specifically, the TTE-bIMV group showed higher RVGLS (β = 7.28, 95% CI 5.07, 9.48) and FWLS (β = 5.83, 95% CI 3.36, 8.31), while the TTE-aIMV group exhibited higher RVGLS (β = 9.39, 95% CI 6.10, 12.69) and FWLS (β = 7.54, 95% CI 4.83, 10.24). TAPSE did not reveal any significant differences across the groups. Our study suggests an association between IMV and lower RVGLS and FWLS in ARF patients, indicating that IMV itself may contribute to RV dysfunction. RVGLS and FWLS appear to be more sensitive than TAPSE in detecting changes in RV function that were previously subclinical in patients on IMV. Prospective studies with TTE before, during, and after IMV are necessary to assess the primary driver of RV dysfunction and to prognosticate STE-detected RV dysfunction in this population.

Background To compare image quality, lesion detection and patient comfort of 3T prostate MRI using a combined rigid two-channel phased-array endorectal coil and an external phased-array coil (ERC-PAC) compared to external PAC acquisition in the same patients. Methods Thirty three men (mean age 65.3y) with suspected ( n  = 15) or biopsy-proven prostate cancer (PCa, n  = 18) were prospectively enrolled in this exploratory study. 3T prostate MRI including T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) was performed using an ERC-PAC versus PAC alone, in random order. Image quality, lesion detection and characterization (biparametric PI-RADSv2.1) were evaluated by 2 independent observers. Estimated signal-to-noise ratio (eSNR) was measured in identified lesions and the peripheral zone (PZ). Patient comfort was assessed using a questionnaire. Data were compared between sequences and acquisitions. Inter/intra-observer agreement for PI-RADS scores was evaluated. Results Twenty four prostate lesions (22 PCa) were identified in 20/33 men. Superior image quality was found for ERC-PAC compared to PAC for T2WI for one observer (Obs.1, p  < 0.03) and high b-value DWI for both observers ( p  < 0.05). The sensitivity of PI-RADS for lesion detection for ERC-PAC and PAC acquisitions was 79.2 and 75% for Obs.1, and 79.1 and 66.7%, for Obs.2, without significant difference for each observer (McNemar p -values ≥0.08). Inter−/intra-observer agreement for PI-RADS scores was moderate-to-substantial (kappa = 0.52–0.84). Higher eSNR was observed for lesions and PZ for T2WI and PZ for DWI using ERC-PAC ( p  < 0.013). Most patients (21/33) reported discomfort at ERC insertion. Conclusion Despite improved image quality and eSNR using the rigid ERC-PAC combination, no significant improvement in lesion detection was observed, therefore not supporting the routine use of ERC for prostate MRI.

Two patients, aged 48 and 45 years, were treated for symptomatic uterine fibroids with not only embolization of both uterine but also both ovarian arteries. Note was made of other collateral arterial supply via branches of the superior mesenteric artery (SMA). The two identified SMA branches were embolized for the first patient, but no embolization was deemed necessary for the other patient.

Sir, Despite the popularity of free flaps and microsurgery, the pedicled transverse rectus abdominis myocutaneous (TRAM) flap remains a common autologous alternative for breast reconstruction. [2] The rounded facet of the rigid steel wands stretches blood vessels to the point of rupture. [3] The conventional method with the bipolar cautery requires additional diathermic haemostasis, and this is dependent on the surgeon's field of vision that may be concealed by the structure of the tunnel. Financial...

Background With various changes implemented such as perioperative antibiotics for tangential excision, this retrospective study reviews the infection profile of burn patients at Singapore’s only centralized burns unit. Worldwide, the appearance of multidrug-resistant (MDR) strains of Acinetobacter baumannii ( A. baumannii ) continues to worsen patient outcomes. This study also surveys the role of blood cultures in burns at our unit. Methods Four hundred fifty-two burn patients admitted to the unit between 2011 and 2013, and with cultures performed, were included in the study. The yields of various cultures were evaluated and 2684 samples were amassed, of which 984 (36.7 %) were positive. Patient variables for predictors of MDR A. baumannii infection acquisition and bacteremia were evaluated through multivariate analyses. Results Pseuodomonas aeruginosa ( P. aeruginosa ) (67 patients) was the most common organism in those with total body surface area (TBSA) burn <20 % while MDR A. baumannii ( 39 patients) was most prevalent in those with TBSA burn ≥20 %. We found a yield of 1.1 % positive blood cultures for TBSA burn <20 % and a yield of 18.6 % positive cultures in TBSA burn ≥20 %. The median time between surgery and bacteremia was 6.5 days (range -18 to 68 days, interquartile range 4.5); 2.9 and 8.8 % of bacteremic episodes occurred within 24 and 48 h, respectively. This is a decrease from a predeceasing study (45.3 % for 24 h and 60 % for 48 h). Multivariate analysis revealed that length of hospital stay and TBSA burn ≥20 % were predictors of MDR A. baumannii infection and positive blood cultures. Conclusions MDR A. baumannii infection burdens patient management, especially in those with TBSA burn ≥20 % and longer hospital stay. Prophylactic antibiotics may reduce perioperative bacteremia, but their role in MDR infections needs to be evaluated. The role of blood cultures in TBSA burn <20 % needs reconsideration.

ObjectivesTo evaluate the diagnostic performance of contrast-enhanced CT vs. MRI with extracellular contrast agents (EC-MRI) vs. MRI with gadoxetic acid (EOB-MRI) for HCC detection in patients with liver cirrhosis using liver explant as the reference. The additional value of hepatobiliary phase (HBP) post Gadoxetic acid was also assessed.MethodsTwo-hundred seventy-seven consecutive patients who underwent liver transplantation over a 9 year period and imaging within 90 days of were retrospectively included. Imaging consisted in CT (n = 100), EC-MRI (n = 77) and EOB-MRI (n = 100), the latter subdivided into dynamic EOB-MRI and full EOB-MRI (dynamic+HBP). Three radiologists retrospectively categorized lesions ≥ 1 cm using the LI-RADSv2017 algorithm. Dynamic EOB-MRI was re-evaluated with the addition of HBP. Results were correlated with explant pathology.ResultsPathology demonstrated 265 HCCs (mean size 2.1 ± 1.4 cm) in 177 patients. Per-patient sensitivities were 86.3% for CT, 89.5% for EC-MRI, 92.8% for dynamic EOB-MRI and 95.2% for full EOB-MRI (pooled reader data), with a significant difference between CT and dynamic/full EOB-MRI (p = 0.032/0.002), and between EC-MRI and full EOB-MRI (p = 0.047). Per-lesion sensitivities for CT, EC-MRI, dynamic EOB-MRI and full EOB-MRI were 59.5%,78.5%,69.7% and 76.8%, respectively, with a significant difference between MRI groups and CT (p-range:0.001–0.04), and no difference between EC-MRI and dynamic EOB-MRI (p = 0.949). For HCCs 1–1.9 cm, sensitivities were 34.4%, 64.6%, 57.3% and 67.3%, respectively, with all MRI groups significantly superior to CT (p ≤ 0.01) and full EOB-MRI superior to dynamic EOB-MRI (p = 0.002).ConclusionsEOB-MRI outperforms CT and EC-MRI for per-patient HCC detection sensitivity, and is equivalent to EC-MRI for per-lesion sensitivity. MRI methods outperform CT for detection of HCCs 1–1.9 cm.Key points• MRI is superior to CT for HCC detection in patients with liver cirrhosis.• EOB-MRI outperforms CT and MRI using extracellular contrast agents (EC-MRI) for per-patient HCC detection sensitivity, and is equivalent to EC-MRI for per-lesion sensitivity.• The addition of hepatobiliary phase images improves HCC detection when using gadoxetic acid.

The purpose of this ethnographic case study was to examine the lives of teachers, students, community members, and culture bearers within a musical community located in South Central Louisiana. The geographic area of focus in this research was Vermilion Parish and its surrounding area, known as Acadiana, the heart of Creole and Cajun culture where Traditional Louisiana Music finds its origins. Participants’ intrinsic cultural understandings of Louisiana’s music and impact on school music programs was examined through ethnographic interview and observation. A resource pedagogy known as funds of knowledge was used as a theoretical framework meant to maintain participants’ intrinsic cultural understandings, behavior, language, and customs throughout data collection, analysis, and presentation of findings. The findings from this study describe the perceptions and experiences of members involved in the Lâche Pas program, an after school cultural education program that immerses students of the community in the art, music, and history surrounding Creole and Cajun culture. An intangible cultural heritagewas recognized where cultural knowledge is transmitted from generation to generation and recreated by communities and groups in response to their environment. Customs were seen as fluid, dynamic and dependent on the motivations and contexts of each generation. Educators, administrators, community musicians, and students were uniquely motivated to take part in preserving their endangered culture.