Pharmacological augmentation of serotonin reuptake inhibitors in patients with obsessive-compulsive disorder: A network meta-analysis.

OBJECTIVES: The augmentation of serotonin reuptake inhibitors (SRIs) can be achieved by add-on therapy with different pharmacological agents in obsessive-compulsive disorder (OCD) for a better clinical outcome. This network meta-analysis (NMA) was conducted to evaluate and compare the effects of available augmentation agents for SRIs in OCD. METHOD: The data was extracted from 59 relevant clinical trials after a literature search on MEDLINE/PubMed, Scopus, Cochrane databases and clinical trial registries. PRISMA guidelines were followed in data extraction, analysis and reporting. Random effects Bayesian NMA was done to pool the effects across the interventions for the change in Yale-Brown Obsessive-Compulsive Scale (YBOCS) scoring from baseline to the end of the study. Network graph was built, consistency model was run, node splitting analysis was performed, treatments were ranked as per SUCRA score and meta-regression was done for refractoriness to SRIs and duration of augmentation therapy as the predictor variables. RESULTS: The drugs showing significant reduction in YBOCS scoring were pregabalin (MD:-8.1;95% CrI: -16, -0.43), memantine (MD:-6.2;95% CrI: -9.9, -2.3), lamotrigine (MD:-6;95% CrI: -12, -0.47), ondansetron (MD:-5.7;95% CrI: -11, -0.67), granisetron (MD:-5.6;95% CrI: -11, -0.44), aripiprazole (MD:-5.4;95% CrI:-9.1, -1.6), risperidone (MD:-3.3;95% CrI: -6.4, -0.20) and topiramate (MD:-5.3;95% CrI: -9.6, -0.97). The node-split analysis showed that direct and indirect pooled effect sizes for all comparisons were comparable. Meta-regression showed a statistically non-significant association between YBOCS score reduction with the duration of augmentation therapy, but significant with SRI-refractory status. Finally, the results were sorted based on certainty of evidence. CONCLUSION: Memantine was found to be most effective augmentation agent for SRIs in OCD, followed by lamotrigine, ondansetron and granisetron with moderate certainty of evidence. The augmentation agents showed better symptom reduction in patients with SRI-refractory OCD in comparison to non-refractory OCD. PROSPERO REGISTRATION: CRD42022360110.

Effect of Colchicine in Reducing Inflammatory Biomarkers and Cardiovascular Risk in Coronary Artery Disease: A Meta-analysis of Clinical Trials.

BACKGROUND: Colchicine's role in reducing inflammation and cardiovascular adverse events despite standard care in coronary artery disease (CAD) is controversial. STUDY QUESTION: Can colchicine reduce inflammation [high-sensitivity C-reactive protein (hs-CRP)] in CAD? DATA SOURCES: PubMed, Cochrane Library, and Trial registries. STUDY DESIGN: The meta-analysis included 15 studies using add-on colchicine in patients with CAD. The outcomes evaluated were hs-CRP, white blood cell and neutrophil count, a composite end point of major cardiovascular events, myocardial infarction (MI), cardiovascular and all-cause mortality, and gastrointestinal adverse events. The analysis was performed using a random-effects model to calculate pooled mean difference and odds ratio (OR). RESULTS: The meta-analysis revealed a mean reduction of 0.36 mg/L in hs-CRP levels [95% confidence interval (CI): -0.51 to -0.20] with add-on colchicine. The mean white blood cell reduction of 371.75 per µL (95% CI: -544.27 to -199.24) and the mean neutrophil reduction also favored the add-on colchicine group. There was a reduction in composite end point of major cardiovascular events [OR, 0.65 (95% CI: 0.51-0.83)] and MI [OR, 0.77 (95% CI: 0.63-0.95)] with add-on colchicine therapy. There was no reduction in cardiovascular/overall mortality. Gastrointestinal adverse events were less with low-dose colchicine than those with high dose. CONCLUSION: Add-on colchicine has reduced the inflammation in CAD as implicated by a decrease in inflammatory markers. It has also lowered the incidence of MI but not mortality. With this present trend, the authors recommend further trials to validate the effectiveness of add-on colchicine in the secondary prevention of CAD.

Perioperative mortality and morbidity of hip fractures among COVID-19 infected and non-infected patients: A systematic review and meta-analysis.

PURPOSE: Hip fractures among elderly patients are surgical emergencies. During COVID-19 pandemic time, many such patients could not be operated at early time because of the limitation of the medical resources, the risk of infection and redirection of medical attention to a severe infective health problem. METHODS: A search of electronic databases (PubMed, Medline, CINAHL, EMBASE and the Cochrane Central Register of Controlled Trials) with the keywords "COVID", "COVID-19″, "SARS-COV-2", "Corona", "pandemic", "hip fracture", "trochanteric fracture" and "neck femur fracture" revealed 64 studies evaluating treatment of hip fracture in elderly patients during COVID-19 pandemic time. The 30-day mortality rate, inpatient mortality rate, critical care/special care need, readmission rate and complications rate in both groups were evaluated. Data were analyzed using Review Manager (RevMan) V.5.3. RESULTS: After screening, 7 studies were identified that described the mortality and morbidity in hip fractures in both COVID-19 infected (COVID-19 +) and non-infected (COVID-19 -) patients. There were significantly increased risks of 30-day mortality (32.23% COVID-19 + death vs. 8.85% COVID-19 - death) and inpatient mortality (29.33% vs. 2.62%) among COVID-19 + patients with odds ratio (OR) of 4.84 (95% CI: 3.13 - 7.47, p < 0.001) and 15.12 (95% CI: 6.12 - 37.37, p < 0.001), respectively. The COVID-19 + patients needed more critical care admission (OR = 5.08, 95% CI: 1.49 - 17.30, p < 0.009) and they remain admitted for a longer time in hospital (mean difference = 3.6, 95% CI: 1.74 - 5.45, p < 0.001); but there was no difference in readmission rate between these 2 groups. The risks of overall complications (OR = 17.22), development of pneumonia (OR = 22.25), and acute respiratory distress syndrome/acute respiratory failure (OR = 32.96) were significantly high among COVID-19 + patients compared to COVID-19 - patients. CONCLUSIONS: There are increased risks of the 30-day mortality, inpatient mortality and critical care admission among hip fracture patients who are COVID-19 +. The chances of developing pneumonia and acute respiratory failure are more in COVID-19 + patients than in COVID-19 ‒ patients.

Abatacept-based Graft-Versus-Host Disease Prophylaxis in Haplo-identical Hematopoietic Cell Transplant in a High-risk Cohort.

BACKGROUND: There is insufficient guidance in using posttransplant cyclophosphamide in patients with organ dysfunctions. Abatacept (Aba), a T cell costimulation blockade, has recently been shown to prevent severe acute graft-versus-host disease (GVHD). OBSERVATION: We report adding Aba as GVHD prophylaxis in 4 pediatrics patients who received haplo-hematopoietic cell transplantation. Two patients had grade 2 acute GVHD and 2 had mild chronic GVHD. All 4 patients are alive with full donor chimerism, and 3 are off immunosuppressants. CONCLUSION: An Aba-based regimen can result in reliable engraftment and acceptable GVHD when concerns of organ dysfunction prevents the use of posttransplant cyclophosphamide in haplo-hematopoietic cell transplantation.

CAMPAREE: a robust and configurable RNA expression simulator.

BACKGROUND: The accurate interpretation of RNA-Seq data presents a moving target as scientists continue to introduce new experimental techniques and analysis algorithms. Simulated datasets are an invaluable tool to accurately assess the performance of RNA-Seq analysis methods. However, existing RNA-Seq simulators focus on modeling the technical biases and artifacts of sequencing, rather than on simulating the original RNA samples. A first step in simulating RNA-Seq is to simulate RNA. RESULTS: To fill this need, we developed the Configurable And Modular Program Allowing RNA Expression Emulation (CAMPAREE), a simulator using empirical data to simulate diploid RNA samples at the level of individual molecules. We demonstrated CAMPAREE's use for generating idealized coverage plots from real data, and for adding the ability to generate allele-specific data to existing RNA-Seq simulators that do not natively support this feature. CONCLUSIONS: Separating input sample modeling from library preparation/sequencing offers added flexibility for both users and developers to mix-and-match different sample and sequencing simulators to suit their specific needs. Furthermore, the ability to maintain sample and sequencing simulators independently provides greater agility to incorporate new biological findings about transcriptomics and new developments in sequencing technologies. Additionally, by simulating at the level of individual molecules, CAMPAREE has the potential to model molecules transcribed from the same genes as a heterogeneous population of transcripts with different states of degradation and processing (splicing, editing, etc.). CAMPAREE was developed in Python, is open source, and freely available at https://github.com/itmat/CAMPAREE .

Type 2 innate lymphoid cells from Id1 transgenic mice alleviate skin manifestations of graft-versus-host disease.

BACKGROUND: Acute graft-versus-host disease (aGVHD) is one of the most common causes of morbidity for patients undergoing allogeneic stem cell transplantation. There is preliminary evidence that activated Group 2 innate lymphoid cells (ILC2s) from wild type (WT) mice reduces the lethality of aGVHD and is effective in treating lower gastrointestinal (GI) tract manifestations of aGVHD. This raises the prospect that ILC2s may be used for cell-based therapy of aGVHD but vigorous investigation is necessary to assess their impacts on different aspects of aGVHD. Genetically engineered mice which either express Id1 protein (Id1tg/tg), an inhibitor of E protein transcription factors or have E protein genes knocked out (dKO) in the thymus produce massive numbers of ILC2s, thus allowing extensive evaluation of ILC2s. We investigated whether these ILC2s have protective effects in aGVHD as WT ILC2s do using an established mouse model of aGVHD. RESULTS: bone marrow transplant was performed by irradiating BALB/c strain of recipient mice and transplanting with bone marrow and T cells from the MHC-disparate C57BL/6 strain. We isolated ILC2s from Id1tg/tg and dKO mice and co-transplanted them to study their effects. Our results confirm that activated ILC2s have a protective role in aGVHD, but the effects varied depending on the origin of ILC2s. Co-transplantation of ILC2s from Id1tg/tg mice were beneficial in aGVHD and are especially helpful in ameliorating the skin manifestations of aGVHD. However, ILC2s from dKO mice were less effective at the protection and behaved differently depending on if the cells were isolated from dKO mice were pre-treated with IL-25 in vivo. CONCLUSION: These findings support the notion that thymus-derived ILC2s from Id1tg/tg mice are protective against aGVHD, with a significant improvement of skin lesions and they behave differently from dKO mice in the setting of aGVHD.

Modeling the viral load dependence of residence times of virus-laden droplets from COVID-19-infected subjects in indoor environments.

In the ongoing COVID-19 pandemic situation, exposure assessment and control strategies for aerosol transmission path are feebly understood. A recent study pointed out that Poissonian fluctuations in viral loading of airborne droplets significantly modifies the size spectrum of the virus-laden droplets (termed as "virusol") (Anand and Mayya, 2020). Herein we develop the theory of residence time of the virusols, as contrasted with complete droplet system in indoor air using a comprehensive "Falling-to-Mixing-Plate-out" model that considers all the important processes namely, indoor dispersion of the emitted puff, droplet evaporation, gravitational settling, and plate out mechanisms at indoor surfaces. This model fills the existing gap between Wells falling drop model (Wells, 1934) and the stirred chamber models (Lai and Nazarofff, 2000). The analytical solutions are obtained for both 1-D and 3-D problems for non-evaporating falling droplets, used mainly for benchmarking the numerical formulation. The effect of various parameters is examined in detail. Significantly, the mean residence time of virusols is found to increase nonlinearly with the viral load in the ejecta, ranging from about 100 to 150 s at low viral loads (<104 /ml) to about 1100-1250 s at high viral loads (>1011 /ml). The implications are discussed.

TEVAR for complicated and uncomplicated type B aortic dissection-Systematic review and meta-analysis.

BACKGROUND: Type B aortic dissection (TBAD), is defined as a dissection involving the aorta distal to left subclavian artery with the ascending aorta and the aortic arch not affected. TBAD is classified due to the time frame and presence of complications. Complicated TBAD (co-TBAD) patients have a greater mortality rate than uncomplicated TBAD (un-TBAD) and thoracic endovascular aortic repair (TEVAR) is considered the gold-standard intervention for these clinical challenges. METHODS: We undertook a systematic review of the literature regarding TEVAR intervention in co-TBAD and un-TBAD. A comprehensive search was undertaken across four major databases and was evaluated and assessed until June 2020. RESULTS: A total of 16,104 patients were included in the study (7772 patients co-TBAD and 8352 un-TBAD). A significantly higher proportion of comorbidities were seen in co-TBAD patients compared with un-TBAD. Acute dissection was more frequent in the co-TBAD group (73.55% vs. 66.91%), while chronic dissection was more common in un-TBAD patients (33.8% vs. 70.73%). Postprocedure stroke was higher in co-TBAD (5.85% vs. 3.92%; p < .01), while postprocedural renal failure was higher in un-TBAD patients (7.23 vs. 11.38%; p < .01). No difference was observed in in-hospital mortality however the 30 days mortality was higher in the co-TBAD group. One-year survival was higher in the uncomplicated group but this difference was not observed in the 5-year survival. CONCLUSION: In our analysis we can appreciate that despite significantly higher comorbidities in the co-TBAD cohort, there was no difference in in-hospital mortality between the two groups and the 5-year survival did not have any difference.

Effect of intra-operative high inspired fraction of oxygen on postoperative nausea and vomiting in children undergoing surgery: A prospective randomised double-blind study.

BACKGROUND: Administration of high inspired fraction of oxygen (FiO2) during anaesthesia has been proposed to decrease postoperative nausea and vomiting (PONV) in adults but has not been extensively studied in children. OBJECTIVES: The primary objective of this study was to evaluate the effect of 80% FiO2 on the incidence of PONV in children undergoing surgery. DESIGN: Prospective, randomised, study. SETTING: Single-centre, teaching hospital. PATIENTS: Children of either gender in the age group of 5 to 15 years scheduled for elective surgeries were assessed for eligibility. Emergency surgeries; patients receiving supplemental oxygen pre-operatively or on mechanical ventilation; sepsis; bowel obstruction or ischaemia; poor nutritional status; anaemia (Hb <8 g%) or surgeries lasting less than 1 h or greater than 4 h were excluded from the study. INTERVENTIONS: After induction of anaesthesia, children were randomised to receive either 30 or 80% oxygen in air, till the end of surgery. MAIN OUTCOME MEASURES: Incidence of PONV within 24 h; surgical site infections (SSI)s; serum serotonin and TNF-α levels and the incidence of postoperative pulmonary complications (PPC)s were studied. RESULTS: The overall 24 h incidence of PONV was not different between the low and high FiO2 groups [24 vs. 23%; P = 0.84; odds ratio (OR) 0.92; 95% confidence interval (CI), 0.44 to 2.06]. The incidence of SSIs (15 vs. 12%; P = 0.61; OR 0.77; 95% CI, 0.28 to 2.10) and PPCs (12 vs. 8%; P = 0.38; OR 0.59; 95% CI, 0.18 to 1.92) were not significant between the low and high FiO2 groups, respectively. Intragroup and intergroup comparisons of serum serotonin and TNF-α showed no significant difference either at baseline or at the end of surgery. CONCLUSION: High intra-operative FiO2 of 80% does not provide additional protection against PONV in children. TRIAL REGISTRATION: The study was registered with Clinical Trials Registry of India (CTRI) with trial registration no: CTRI/2018/07/014974.

Joint awareness after unicompartmental knee arthroplasty and total knee arthroplasty: a systematic review and meta-analysis of cohort studies.

PURPOSE: The purpose of this systematic review and meta-analysis is to evaluate the joint awareness after unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA). It was hypothesized that patients with UKA could better forget about their artificial joint in comparison to TKA. METHODS: A search of major literature databases and bibliographic details revealed 105 studies evaluating forgotten joint score in UKA and TKA. Seven studies found eligible for this review were assessed for risk of bias and quality of evidence using the Newcastle-Ottawa Scale. The forgotten joint score (FJS-12) was assessed at 6 months, 1 year, and 2 years. RESULTS: The mean FJS-12 at 2 years was 82.35 in the UKA group and 74.05 in the TKA group. Forest plot analysis of five studies (n = 930 patients) revealed a mean difference of 7.65 (95% CI: 3.72, 11.57, p = 0.0001; I2 = 89% with p < 0.0001) in FJS-12 at 2 years. Further sensitivity analysis lowered I2 heterogeneity to 31% after exclusion of the study by Blevin et al. (MD 5.88, 95%CI: 3.10, 8.66, p < 0.0001). A similar trend of differences in FJS-12 between the groups was observed at 6 months (MD 32.49, 95% CI: 17.55, 47.43, p < 0.0001) and at 1 year (MD 25.62, 95% CI: 4.26, 46.98, p = 0.02). CONCLUSIONS: UKA patients can better forget about their artificial joint compared to TKA patients. LEVEL OF EVIDENCE: III.

Myocardial Protection in Adult Cardiac Surgery With del Nido Versus Blood Cardioplegia: A Systematic Review and Meta-Analysis.

BACKGROUND: Myocardial protection in adult cardiac surgery is commonly achieved with either multidose blood cardioplegia or single-dose del Nido crystalloid cardioplegia. AIM: The aim of this systematic review and meta-analysis was to compare the outcomes of del Nido cardioplegia versus blood cardioplegia in adult cardiac surgery. METHOD: All English-language articles were searched in MEDLINE (PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar up to March 2020, to identify randomised control trials, prospective observational studies, and retrospective analyses (with or without propensity matching) reporting any or all of the primary and secondary endpoints. The primary endpoint was all-cause mortality. Secondary endpoints included cardiopulmonary bypass (CPB) and aortic cross-clamp (AoX) time; cardioplegia volume; need for defibrillation after AoX release; intraoperative glucose; postoperative myocardial enzyme release; postoperative left ventricular ejection fraction (LVEF); incidence of postoperative acute kidney injury (AKI), atrial fibrillation (AF), stroke, and low cardiac output syndrome (LCOS); postoperative blood transfusion; duration of mechanical ventilation; and length of intensive care unit (ICU) and hospital stay. RESULTS: Twenty-nine (29) studies were included. There was no difference in the primary outcome of mortality between the two groups (odds ratio [OR], 1.18; 95% confidence interval [CI], 0.82-1.72 [p=0.37]). del Nido cardioplegia was associated with significantly shorter CPB (mean difference [MD], -7.42 minutes; 95% CI, -12.53 to -2.31 [p=0.004]) and AoX times (MD, -6.39 minutes; 95% CI, -10.30 to -2.48 [p=0.001]), and lower cardioplegia volumes. Significantly fewer patients required defibrillation after AoX release in the del Nido group. Intraoperative glucose homeostasis was better preserved in the del Nido group. Postoperative cardiac troponin T release and the number of patients needing transfusions were less in the del Nido group. No differences were seen in postoperative LVEF, or in the incidence of AKI, stroke, AF, and LCOS. Duration of mechanical ventilation, and length of ICU and hospital stay were similar. CONCLUSIONS: Although this meta-analysis failed to find any mortality benefits with del Nido cardioplegia, significant benefits were seen in a number of intraoperative and postoperative variables. del Nido cardioplegia is a safe and favourable alternative to blood cardioplegia in adult cardiac surgery.

Hemophagocytic lymphohistiocytosis in systemic mastocytosis treated with allogeneic bone marrow transplant: A case report.

Systemic mastocytosis is a rare entity in pediatrics, usually associated with mutations in the c-KIT gene. We describe a Caucasian female who presented with severe systemic mastocytosis with food allergies requiring prolonged total parenteral nutrition. Her course was further complicated by the onset of hemophagocytic lymphohistiocytosis, which responded poorly to conventional chemotherapy. She underwent an allogeneic hematopoietic stem cell transplant that resulted in resolution of all symptoms related to systemic mastocytosis and hemophagocytic lymphohistiocytosis. She is now disease-free and without any complications two years after the transplant.

IDH1 mutated acute myeloid leukemia in a child with metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria.

D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare metabolic disorder characterized by developmental delay, hypotonia, and bi-allelic mutations in D-2-hydroxyglutarate dehydrogenase (D2HGDH) or a single gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2). Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) is a type of D-2-HGA that has been previously reported in ten patients (OMIM 614875), three of whom had somatic mosaicism for R132 variants in isocitrate dehydrogenase 1 (IDH1). We describe a 3-year-old boy with MC-HGA who subsequently developed acute myeloid leukemia (AML) and was found to have an IDH1 R132C mutation in a leukemic bone marrow sample. Further testing revealed presence of somatic mosaicism for IDH1 R132C variant, suggesting an association of IDH1 in inducing myeloid leukemogenesis.

Infantile Epithelioid Sarcoma with Genomic Segmental Amplification of BIRC3/YAP1 as Double Minutes Plus Trisomy 2: A Case Report.

Introduction: Epithelioid sarcoma is a malignant mesenchymal tumor exhibiting epithelioid cytomorphology and epithelial phenotype. Its histogenesis is unknown, but its tumorigenesis may relate to inactivation of hSNF5/SMARCB1/INI1 tumor suppressor gene. This tumor typically affects young adults and older children, but it is uncommon in infants. Case Report: We describe a unique neoplasm in a 15-month-old infant presenting with a heel mass. The tumor was remarkable for retention of SMARCB1/INI1 expression. Conventional cytogenetic analysis revealed trisomy 2 and double minutes, and SNP array analysis confirmed the trisomy 2 and identified segmental amplification of chromosome 11 containing YAP1 and BIRC3; FISH testing proved that the double minutes consisted of BIRC3 and YAP1, potent oncogenes related to tumorigenesis of several types of tumors but not described in epithelioid sarcoma. Conclusion: Our findings expand the spectrum of cytogenetic alterations in this neoplasm, help in better understanding its tumorigenesis, and suggest potential therapeutic targets.

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms.

It is now well established that bacterial infections are often associated with biofilm phenotypes that demonstrate increased resistance to common antimicrobials. Further, due to the collective attrition of new antibiotic development programs by the pharmaceutical industries, drug repurposing is an attractive alternative. In this work, we screened 1,280 existing commercially available drugs in the Prestwick Chemical Library, some with previously unknown antimicrobial activity, against Staphylococcus aureus, one of the commonly encountered causative pathogens of burn and wound infections. From the primary screen of the entire Prestwick Chemical Library at a fixed concentration of 10 µM, 104 drugs were found to be effective against planktonic S. aureus strains, and not surprisingly, these were mostly antimicrobials and antiseptics. The activity of 18 selected repurposing candidates, that is, drugs that show antimicrobial activity that are not already considered antimicrobials, observed in the primary screen was confirmed in dose-response experiments. Finally, a subset of nine of these drug candidates was tested against preformed biofilms of S. aureus We found that three of these drugs, niclosamide, carmofur, and auranofin, possessed antimicrobial activity against preformed biofilms, making them attractive candidates for repurposing as novel antibiofilm therapies.

Can immediate postoperative random growth hormone levels predict long-term cure in patients with acromegaly?

BACKGROUND: Growth hormone (GH) levels following oral glucose tolerance test (OGTT) at 12 weeks or later after surgery have been accepted as the most reliable parameter for defining remission and/or cure in patients with acromegaly. However, the role of random GH in predicting remission in the immediate postoperative period using modern criteria is not known. This study was undertaken to evaluate the role of random GH levels in first 5 postoperative days as an early predictive tool for long-term remission of patients with acromegaly following transsphenoidal pituitary surgery (TSS). PATIENTS AND METHODS: Seventy-five consecutive acromegaly patients with at least three postoperative OGTT values at 3, 6, and 12 months of follow-up were included in the study. GH levels were measured just before surgery, in the immediate postoperative period, at 6 h and on day 1 to day 5 after surgery. Remission was defined as normal age-specific insulin-like growth factor-1 and either basal fasting GH <1 ng/ml or a nadir GH following OGTT <0 .4 ng/ml at 3 months of surgery. RESULTS: Of the 75 patients with acromegaly who underwent TSS, long-term remission was achieved in 42 (56%) patients. GH values ≤1.55 ng/ml at 6 h of surgery showed the highest predictive power for long-term remission, with a sensitivity of 81.2% and a specificity of 83.3%. The duration of disease and tumor volume had no effect on the 6 h GH value-related prediction of cure. CONCLUSION: Early postoperative GH values may be used to predict long-term cure. A value of ≤1.5 ng/ml at 6 h following surgery may predict long-term cure in two-thirds of the patients with acromegaly who undergo TSS.

Silencing of high-mobility group box 2 (HMGB2) modulates cisplatin and 5-fluorouracil sensitivity in head and neck squamous cell carcinoma.

Dysregulation of protein expression is associated with most diseases including cancer. MS-based proteomic analysis is widely employed as a tool to study protein dysregulation in cancers. Proteins that are differentially expressed in head and neck squamous cell carcinoma (HNSCC) cell lines compared to the normal oral cell line could serve as biomarkers for patient stratification. To understand the proteomic complexity in HNSCC, we carried out iTRAQ-based MS analysis on a panel of HNSCC cell lines in addition to a normal oral keratinocyte cell line. LC-MS/MS analysis of total proteome of the HNSCC cell lines led to the identification of 3263 proteins, of which 185 proteins were overexpressed and 190 proteins were downregulated more than twofold in at least two of the three HNSCC cell lines studied. Among the overexpressed proteins, 23 proteins were related to DNA replication and repair. These included high-mobility group box 2 (HMGB2) protein, which was overexpressed in all three HNSCC lines studied. Overexpression of HMGB2 has been reported in various cancers, yet its role in HNSCC remains unclear. Immunohistochemical labeling of HMGB2 in a panel of HNSCC tumors using tissue microarrays revealed overexpression in 77% (54 of 70) of tumors. The HMGB proteins are known to bind to DNA structure resulting from cisplatin-DNA adducts and affect the chemosensitivity of cells. We observed that siRNA-mediated silencing of HMGB2 increased the sensitivity of the HNSCC cell lines to cisplatin and 5-FU. We hypothesize that targeting HMGB2 could enhance the efficacy of existing chemotherapeutic regimens for treatment of HNSCC. All MS data have been deposited in the ProteomeXchange with identifier PXD000737 (http://proteomecentral.proteomexchange.org/dataset/PXD000737).

Structural insight and flexible features of NS5 proteins from all four serotypes of Dengue virus in solution.

Infection by the four serotypes of Dengue virus (DENV-1 to DENV-4) causes an important arthropod-borne viral disease in humans. The multifunctional DENV nonstructural protein 5 (NS5) is essential for capping and replication of the viral RNA and harbours a methyltransferase (MTase) domain and an RNA-dependent RNA polymerase (RdRp) domain. In this study, insights into the overall structure and flexibility of the entire NS5 of all four Dengue virus serotypes in solution are presented for the first time. The solution models derived revealed an arrangement of the full-length NS5 (NS5FL) proteins with the MTase domain positioned at the top of the RdRP domain. The DENV-1 to DENV-4 NS5 forms are elongated and flexible in solution, with DENV-4 NS5 being more compact relative to NS5 from DENV-1, DENV-2 and DENV-3. Solution studies of the individual MTase and RdRp domains show the compactness of the RdRp domain as well as the contribution of the MTase domain and the ten-residue linker region to the flexibility of the entire NS5. Swapping the ten-residue linker between DENV-4 NS5FL and DENV-3 NS5FL demonstrated its importance in MTase-RdRp communication and in concerted interaction with viral and host proteins, as probed by amide hydrogen/deuterium mass spectrometry. Conformational alterations owing to RNA binding are presented.

Influence of pre-operative use of serotonergic antidepressants (SADs) on the risk of bleeding in patients undergoing different surgical interventions: a meta-analysis.

PURPOSE: Serotonergic antidepressants (SADs) are one of the most widely prescribed group of drugs. Of late, the use of SADs is being associated with an increased risk of perioperative bleeding. However, the results are inconsistent. The present analysis was planned to evaluate the association between preoperative SADs use and the risk of bleeding/mortality in patients undergoing surgery. METHODS: Studies that had reported the effects of preoperative SADs use on the perioperative bleeding outcomes and/or mortality in adult patients undergoing surgical interventions were identified and evaluated for inclusion in the analysis. Outcomes evaluated were reoperation for bleeding event, requirement of blood/RBC transfusion and mortality. A meta-analysis was conducted, and a pooled estimate of odds ratio (OR) was calculated using the inverse variance method. RESULTS: Eight cohort studies, comprising a total of 79 976 SADs users and 485 336 non-antidepressant users were included in the final analysis. SADs use was not associated with increased risk of requirement of reoperation for bleeding event [OR = 1.48 (0.84-2.62)]. However, there was an increased requirement of transfusion [OR = 1.19(1.09-1.30)], which was not observed in the subgroup of patients undergoing coronary artery bypass graft (CABG) [OR = 1.06(0.90-1.24)]. SADs use was associated with a substantial increase in mortality [OR = 1.53 (1.15-2.04)] in patients undergoing CABG but not in the overall population [OR = 1.1 (0.99-1.22)]. CONCLUSIONS: Preoperative SADs use is associated with increased bleeding risk with respect to requirement of transfusion; nevertheless, the results should not be generalized to all surgical groups. The divergence between bleeding risk and mortality in CABG surgery patients needs further evaluation.

Prospective comparison of simple suturing and elevation debridement in compound depressed fractures with no significant mass effect.

BACKGROUND: Compound depressed fractures have conventionally been managed surgically with elevation and debridement to avoid infection, especially when there is dural penetration, nonetheless with little evidence. This study was to prospectively compare outcomes after simple suturing and elevation debridement in patients with compound depressed fractures. METHODS: Patients of compound depressed fracture with GCS of five or more, no serious systemic injury, and no significant mass effect were prospectively studied for various factors in relation to infection, hospital stay, survival, and late post-traumatic seizures. Univariate and multivariate analyses were performed using SPSS21. RESULTS: Of the total 232 patients with complete clinico-radiological and follow-up data, 183 underwent simple cleansing and suturing, and 49 underwent surgical elevation debridement. The surgical group at baseline had significantly lower GCS, greater dural violation, and brain matter herniation compared to the conservative arm. Univariate analysis showed simple suturing group to have significantly shorter hospital stay (2.4 vs. 10.3 days) (p < 0.001), lesser infection among survivors (4 vs. 21 %) (p = 0.001), and greater 'survival with no infection' (85 vs. 69 %) (p = 0.01). Multivariate analysis adjusting for age, sex, GCS, dural penetration, and surgical intervention confirmed significantly shorter hospital stay (p < 0.001) and lesser infection among survivors (p = 0.02) in the simple suturing group. Overall, there was no benefit offered by surgical debridement. Simple suturing had a better outcome in most subgroups, except in those with brain matter herniation and GCS 5-8, which showed non-significant benefit with surgical intervention. CONCLUSIONS: Simple suturing seems to be an equally good option in patients with compound depressed fracture with no significant mass effect or brain matter herniation.