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Aims Transoesophageal echocardiography-guided percutaneous transcatheter mitral valve repair (TOE-guided PMVR) using edge-to-edge leaflet plication is typically performed under general anaesthesia (GA). Increasing evidence supports the efficacy and safety of PMVR performed under conscious sedation (CS) or deep sedation (DS). We performed a meta-analysis comparing safety and efficacy of CS/DS vs. GA in PMVR. Methods and results A comprehensive search was performed using PubMed, CINAHL, Ovid MEDLINE, Embase, and the Cochrane Library. Study characteristics, participant demographics, and procedural outcomes with both types of anaesthesia were analysed. Out of 73 articles, five met inclusion criteria. Overall, there was no significant difference in the primary outcome of procedural success rate [odds ratio (OR) 0.75; 95% confidence interval (CI) 0.30–1.88, I2= 0.0%, P = 0.538] or post-procedure in-hospital mortality (OR 1.02; 95% CI 0.38–2.71, I2= 0.0%, P = 0.970) in the patients undergoing PMVR under CS/DS vs. GA. The secondary endpoint of intensive care unit (ICU) length of stay (LOS) was significantly shorter in patients under CS/DS vs. GA (standardized mean difference, SMD = −0.97; 95% CI −1.75 to −0.20; P = 0.014), but the hospital LOS (SMD = 0.36; 95% CI −0.77 to 0.04, P = 0.078) did not show a statistically significant difference between the groups, although it was shorter in the CS/DS group. No difference was observed between CS/DS and GA in fluoroscopy time, procedure time, or complications, including pneumonia, stroke/transient ischaemic attack, and major bleeding. Conclusion CS or DS has lower ICU LOS, but comparable procedural success rate and in-hospital mortality, making it a potential alternative to GA for TOE-guided PMVR.

6 pages, 2 figures.-- Open access, A dynamic model is structurally identifiable if it is possible to infer its unknown parameters by observing its output. Structural identifiability depends on the system dynamics, output, and input, as well as on the specific values of initial conditions and parameters. Here we present a symbolic method that characterizes the input that a model requires to be structurally identifiable. It determines which derivatives must be non-zero in order to have a sufficiently exciting input. Our approach considers structural identifiability as a generalization of nonlinear observability and incorporates extended Lie derivatives. The methodology assesses structural identifiability for time-varying inputs and, additionally, it can be used to determine the input profile that is required to make the parameters structurally locally identifiable. Furthermore, it is sometimes possible to replace an experiment with time-varying input with multiple experiments with constant inputs. We implement the resulting method as a MATLAB toolbox named STRIKE-GOLDD2. This tool can assist in the design of new experiments for the purpose of parameter estimation, This work was supported in part by the European Union Framework Programme for Research and Innovation (Horizon 2020, CanPathPro) under Grant 686282, and in part by the Spanish Ministerio de Economía y Competitividad and the European Regional Development Fund (SYNBIOCONTROL) under Grant DPI2017-82896-C2-2-R

Trauma has a lasting effect on both physical as well as mental well-being of an individual. Traumatic dental injury can be distressing for anyone right from a pre-schooler to a teenager to an adult. Hence it’s imperative to restore the affected teeth to reinstate not only the lost confidence but also the lost aesthetics and functionality. This report showcases an intricate case of a 12-year-old male, where uncomplicated crown fracture was associated with extrusive luxation injury in a tooth with open apex which became devitalized and was managed by splinting followed by apexification. Management of even such cases with guarded prognosis can be done conservatively to ensure functional as well as aesthetic rehabilitation. Restoring the tooth to function will help the patient regain his lost confidence. Hence, there cannot be a cookbook approach to manage dental traumatic injuries as many times fractures and luxation injuries occur concurrently. Keywords : Extrusive luxation, Splinting, Apexification, Traumatic dental injury, Calcium hydroxide.

Purpose of review HIV persists in distinct cellular and anatomical compartments in the body including blood, Central nervous system, and lymphoid tissues (spleen, lymph nodes [LNs], gut-associated lymphoid tissue) by diverse mechanisms despite antiretroviral therapy. Within LNs, human and animal studies have highlighted that a specific CD4 T cell subset - called T follicular helper cells locating in B cell follicles is enriched in cells containing replication-competent HIV as compared to extra-follicular CD4 T cells. Therefore, the objective of the present review is to focus on the potential mechanisms allowing HIV to persist within LN microenvironment. Recent findings The combination of factors that might be involved in the regulation of HIV persistence within LNs remain to be fully identified but may include - the level of activation, antiretroviral drug concentrations, presence of cytolytic mechanisms and/or regulatory cells, in addition to cell survival and proliferation propensity which would ultimately determine the fate of HIV-infected cells within LN tissue areas. Summary HIV persistence in blood and distinct body compartments despite long-standing and potent therapy is one of the major barriers to a cure. Given that the HIV reservoir is established early and is highly complex based on composition, viral diversity, distribution, replication competence, migration dynamics across the human body and possible compartmentalization in specific tissues, combinatorial therapeutic approaches are needed that may synergize to target multiple viral reservoirs to achieve a cure for HIV infection.

The aim of the study was to investigate the use of serial measurements of TSH-receptor autoantibodies (TRAb) with the newest available assay technology to predict the course of Graves’ Orbitopathy (GO) during the first 24 months from disease onset. Serial serum samples from patients with GO (103 mild/135 severe) were collected between 2007 and 2017 and retrospectively analyzed. The course of GO were classified into mild/severe 12 months after manifestation (severe: NOSPECS≥5; mild

Background Transesophageal echocardiography (TEE) is the standard imaging modality used to assess the left atrial appendage (LAA) after transcatheter device occlusion. Cardiac computed tomography angiography (CCTA) offers an alternative non-invasive modality in these patients. We aimed to conduct a comparison of the two modalities. Methods We performed a comprehensive systematic review of the current literature pertaining to CCTA to establish its usefulness during follow-up for patients undergoing LAA device closure. Studies that reported the prevalence of inadequate LAA closure on both CCTA and TEE were further evaluated in a meta-analysis. 19 studies were used in the systematic review, and six studies were used in the meta-analysis. Results The use of CCTA was associated with a higher likelihood of detecting LAA patency than the use of TEE (OR, 2.79, 95% CI 1.34–5.80, p ​= ​0.006, I2 ​= ​70.4%). There was no significant difference in the prevalence of peridevice gap ≥5 ​mm (OR, 3.04, 95% CI 0.70–13.17, p ​= ​0.13, I2 ​= ​0%) between the two modalities. Studies that reported LAA assessment in early and delayed phase techniques detected a 25%–50% higher prevalence of LAA patency on the delayed imaging. Conclusion CCTA can be used as an alternative to TEE for LAA assessment post occlusion. Standardized CCTA acquisition and interpretation protocols should be developed for clinical practice.

The cultivated Brassica species include numerous vegetable and oil crops of global importance. Three genomes (designated A, B and C) share mesohexapolyploid ancestry and occur both singly and in each pairwise combination to define the Brassica species. With organizational errors (such as misplaced genome segments) corrected, we showed that the fundamental structure of each of the genomes is the same, irrespective of the species in which it occurs. This enabled us to clarify genome evolutionary pathways, including updating the Ancestral Crucifer Karyotype (ACK) block organization and providing support for the Brassica mesohexaploidy having occurred via a two-step process. We then constructed genus-wide pan-genomes, drawing from genes present in any species in which the respective genome occurs, which enabled us to provide a global gene nomenclature system for the cultivated Brassica species and develop a methodology to cost-effectively elucidate the genomic impacts of alien introgressions. Our advances not only underpin knowledge-based approaches to the more efficient breeding of Brassica crops but also provide an exemplar for the study of other polyploids. Correcting organizational errors of the Brassica A, B and C genomes reveals the conserved structure of each genome across species and genome evolutionary pathways. Genus-wide pan-genomes were constructed, helping to elucidate the genomic impacts of alien introgressions.

BACKGROUND Air trapping (AT) is one of the hallmarks of allograft dysfunction after lung transplantation (LT). Inert gas‒based ventilation‒perfusion (VQ) lung scintigraphy has excellent sensitivity in the detection of AT. METHODS We reviewed the charts of patients who underwent single or double LT between January 2012 and December 2014 (N = 193). Patients without a VQ scintigraphy at the first annual visit (n = 16) and those who did not survive till 1 year (n = 26) were excluded (final n = 151, mean age = 55.8 [SD =14] years, male = 85, female = 66). VQ scintigraphy was independently reviewed and reconciled for the presence and severity of AT by 2 investigators blinded to the clinical data (D.F.P. and D.M.). A 3-year post-transplant survival was the primary end-point. RESULTS AT was common (n = 73, 48.3%). Patients with obstructive lung diseases as the underlying diagnosis (adjusted odds ratio [OR], 4.36, 95% CI: 1.64‒11.6; p = 0.003) and those with lower body mass index (BMI) (BMI < 25 kg/m2 and 25‒30 kg/m2; p < 0.001) had an increased risk of developing AT in the allograft. The presence of AT (adjusted OR, 2.33, 95% CI: 1.01‒5.36; p = 0.04) and peak forced expiratory volume in 1 sec (FEV1)

Objective Rotavirus A (RVA) remains the main causative agent of gastroenteritis in young children and the young of many mammalian and avian species. In this study we describe a RVA strain detected from a 6-month-old child from Central African Republic (CAR). Results We report the 11 open reading frame sequences of a G29-P[6]-I2-R2-C2-M2-A2-N2-T2-E2-H2 rotavirus strain, RVA/Human-wt/CAR/CAR91/2014/G29P[6]. Nine genes (VP1–VP3, VP6, NSP1–NSP5) shared 90–100% sequence similarities with genogroup 2 rotaviruses. Phylogenetically, backbone genes, except for VP3 and NSP4 genes, were linked with cognate gene sequences of human DS-1-like genogroup 2, hence their genetic origin. The VP3 and NSP4 genes, clustered genetically with both human and animal strains, an indication genetic reassortment human and animal RVA strains has taken place. The VP7 gene shared nucleotide (93–94%) and amino acid (95.5–96.7%) identities with Kenyan and Belgian human G29 strains, as well as to buffalo G29 strain from South Africa, while the VP4 gene most closely resembled P[6]-lineage I strains from Africa and Bangladesh (97%).

Introduction Extradural hematoma diagnosed more than 14 days after head injury is classified as a chronic extradural hematoma (CEDH). In the present study, we presented a series of 8 patients with CEDH in a span of 6 months. Materials and Methods In this article, we reported 8 cases of CEDH who presented to Nil Ratan Sircar Medical College, Kolkata, West Bengal, India, within a span of 6 months. Discussion Extratemporal epidural hematomas (EDHs) are often due to venous bleeding from the diploic veins or dural sinuses or to delayed rupture of a middle meningeal pseudoaneurysm. In these cases, cerebrospinal fluid may redistribute from the lateral ventricles and thus allowing room for the enlarging hematoma producing vague neurological symptoms and signs. The incidence rate of CEDH reported in the literature ranges from 3.9 to 30% of all EDHs. Computed tomography (CT) scan in CEDH often shows a low-density center surrounded by a high-density margin. Calcification of the displaced dura mater may also occur. Some are identified incidentally, whereas others are diagnosed when investigating for persistent and/or progressive neurological symptoms. Symptomatic CEDH should be surgically evacuated and has an excellent outcome the earlier it is done. In patients with no or mild symptoms, normal neurological status, and a small-sized CEDH spontaneous resolution may be expected. Conclusion In the post-CT era, it is always said that CEDH is a rare entity. However, in developing countries we still encounter a large number of such cases and the question arises whether CEDH is still a rare entity.

Diabetes mellitus contributes to macro- and microvascular complications, leading to adverse cardiovascular events. This study examined the effects of vitamin D deficiency on the vascular function and tissue oxidative status in the microcirculation of diabetic rats and to determine whether these effects can be reversed with calcitriol (active vitamin D metabolite) supplementation. Streptozotocin-induced diabetic rats were fed for 10 weeks with control diet (DC) or vitamin D-deficient diet without (DD) or with oral calcitriol supplementation (0.15 μg/kg) in the last four weeks (DDS) (10 rats each group). A nondiabetic rat group that received control diet was also included (NR). After 10 weeks, rats were sacrificed; mesenteric arterial rings with and without endothelium were studied using wire myograph. Western blotting of the mesenteric arterial tissue was performed to determine the protein expression of endothelial nitric oxide synthase (eNOS) enzyme. Antioxidant enzyme superoxide dismutase (SOD) activity and oxidative stress marker malondialdehyde (MDA) levels in the mesenteric arterial tissue were also measured. The DC group had significantly lower acetylcholine-induced relaxation and augmented endothelium-dependent contraction, with reduced eNOS expression, compared to NR rats. In mesenteric arteries of DD, acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent relaxations were lower than those in DC. Calcitriol supplementation in DDS restored endothelium-dependent relaxation. Mesenteric artery endothelium-dependent contraction of DD was greater than DC; it was not affected by calcitriol supplementation. The eNOS protein expression and SOD activity were significantly lower while MDA levels were greater in DD compared to DC; these effects were not observed in DDS that received calcitriol supplementation. In conclusion, vitamin D deficiency causes eNOS downregulation and oxidative stress, thereby impairing the vascular function and posing an additional risk for microvascular complications in diabetes. Calcitriol supplementation to diabetics with vitamin D deficiency could potentially be useful in the management of or as an adjunct to diabetes-related cardiovascular complications.

Unsweetened natural cocoa (UNCP) was evaluated for reproductive toxicity in rats. A preliminary genotoxic potential was evaluated by the DNA comet assay test using C57Bl/6 mice. Both therapeutic dose (TD; 900 mg/kg) and high dose (HD; 9000 mg/kg) of UNCP were used. White Wistar rats were used in two experimental groups. The females received UNCP 15 days before crossing with untreated males. The males received UNCP for 48 days before mating with untreated females. Subacute toxicity was observed during a 14-day oral administration of UNCP. Results show that a high tail DNA% was observed with methyl mesylate administration in all tissues analysed. The lowest tail DNA% value was observed in the liver (1.64 ± 0.26) and kidney (1.63 ± 0.30) during UNCP (TD) administration. UNCP did not induce observable physical congenital malformations on the pubs of treated female and male rats, lacks genotoxic potential, and did not adversely affect pregnancy index, pub weights, and survival index, but UNCP exhibited proimplantation potential ( p > 0.05 ).

Psoriasis and atopic dermatitis (eczema) are both common immune-mediated inflammatory skin diseases associated with changes in skin's stratum corneum lipid structure and barrier functionality. The present study aimed to investigate healthy, eczematous, and psoriatic excised human tissue for the effect of non-infectious skin diseases on skin characteristics (surface color, pH, transepidermal water loss, electrical resistance, and histology), as well as on permeation and retention profile of hydrocortisone. Further, differences in percutaneous absorption on application of iontophoresis on healthy and diseased skin were also investigated. Measurements of transepidermal water loss and electrical resistance showed a significant difference in psoriasis skin samples indicating a damaged barrier function. In vitro permeation studies on full-thickness human skin using vertical diffusion cells further confirmed these results as the drug amount retained in the psoriatic tissue was significantly higher when compared with the other groups. Despite no significant difference, the presence of the drug in the receptor chamber in both diseased groups can be concerning as it suggests the increased possibility of systemic absorption and adverse reactions associated with it in the use of topical corticosteroids. Application of anodal iontophoresis resulted in greater distribution of hydrocortisone into deeper layers of skin and the receptor chamber, in comparison to passive permeation. However, no significant differences were observed due to the healthy or diseased condition of skin.

Objective The aim of this study was to analyze the outcomes of a standardized protocol using routine CSFD, neuromonitoring, LL reperfusion, and selective TASP to prevent SCI during F-BEVAR. Background SCI is to be the most devastating complication for the patient, family, and surgeon, with impact on patient's quality of life and long-term prognosis. An optimal standardized protocol may be used to improve outcomes. Methods Patients enrolled in a prospective, nonrandomized single-center study between 2013 and 2018. A SCI prevention protocol was used for TAAAs or complex abdominal aneurysms with ≥5-cm supraceliac coverage including CSFD, neuromonitoring, LL reperfusion, and selective TASP. End-points included mortality and rates of SCI. Results SCI prevention protocol was used in 170 of 232 patients (73%) treated by F-BEVAR. Ninety-one patients (55%) had changes in neuromonitoring, which improved with maneuvers in all except for 9 patients (10%) who had TASP. There was one 30-day or in-hospital mortality (0.4%). Ten patients (4%) developed SCIs including in 1% (1/79) of patients with normal neuromonitoring and 10% (9/91) of those who had decline in neuromonitoring (P = 0.02). Permanent paraplegia occurred in 2 patients (1%). Factors associated with SCI included total operating time (odds ratio 1.5, 95% confidence interval 1.1-2.2, P = 0.02) and persistent changes in neuromonitoring requiring TASP (odds ratio 15.7, 95% confidence interval 2.9-86.2, P = 0.001). Conclusion This prospective nonrandomized study using a standardized strategy to prevent SCI was associated with low incidence of the SCI during F-BEVAR. Permanent paraplegia occurred in 1%.

Chronic Lung Allograft Dysfunction (CLAD) remains the major limitation in long term survival after lung transplantation. Our objective is to evaluate for the presence of autoantibodies to self-antigens, which is a pathway along with complex interplay with immune as well as non-immune mechanisms that leads to a fibroproliferative process resulting in CLAD.Serum profiles of IgG autoantibodies were evaluated using customized proteomic microarray with 124 antigens. Output from microarray analyzed as antibody scores is correlated with bronchiolitis obliterans (BOS) subtype of CLAD using Mann-Whitney U test or Fisher exact test. Autoantibodies were evaluated for their predictive value for progressive BOS using a Cox proportional hazard model. BOS free survival and overall survival was analyzed using Kaplan-Meier survival analysis.Forty- two patients included in the study are grouped into "stable BOS" and "progressive BOS" for comparisons. Pulmonary fibrosis is the major indication for lung transplantation in our cohort. Progressive BOS group had significantly worse survival (p 0.005). Sixteen IgG autoantibodies are significantly elevated at baseline in progressive BOS group. Six among them correlated with worse BOS free survival (p 0.05). In addition, these six IgG autoantibodies remain elevated at three months and one year after lung transplantation.Pre-existing IgG autoantibodies correlate with progressive BOS and survival in a single center, small cohort of lung transplant recipients. Further validation with larger sample size, external cohort and confirmation with additional tissue, bronchoalveolar lavage samples are necessary to confirm the preliminary findings in our study.

Background Nymphaea lotus L. (N. lotus) is an aquatic plant with anecdotal reports suggesting its use in the traditional management of cancer. However, there is a paucity of data on the antioxidant, anti-inflammatory and cytotoxic properties of N. lotus in relation to its phytochemical and elemental contents. This study aimed at determining the antioxidant, anti-inflammatory and cytotoxic properties of the hydro-ethanolic extract of N. lotus leaves (NLE), and its phenolic, flavonoid and elemental constituents. Methods The antioxidant property of NLE was determined using total phenolic and flavonoid, DPPH radical scavenging, lipid peroxidation and reducing power assays. The anti-inflammatory activity of NLE (100–250-500 mg/kg), diclofenac and hydrocortisone (positive controls) were determined by paw oedema and skin prick tests in Sprague Dawley rats. Also, the erythrocyte sedimentation rate (ESR) was determined by Westergren method. The macro/micro-elements content was determined by the XRF method. The cytotoxic property of NLE was determined by the MTT assay, on two cancer cell lines (MCF-7 and Jurkat) and compared to a normal cell line (Chang liver). Inhibitory concentrations were determined as IC50 values (±SEM). Results The extract had appreciable levels of phenolic and flavonoids compounds and was two-fold more potent in scavenging DPPH radicals than Butylated hydroxytoluene (BHT). However, NLE was three- and six-fold less potent than ascorbic acid and BHT, respectively, in reducing Fe3+ to Fe2+. The extract was six-fold more potent than gallic acid in inhibiting lipid peroxidation. The extract caused a dose-dependent decrease in rat paw oedema sizes, comparable to diclofenac, and a significant decrease in wheel diameters and ESR. The elemental analysis revealed relevant concentrations of Mg2+, P2+, S2+, K2+, Mn+, Fe+, Cu+, Zn+ and Cd+. The extract exhibited cytotoxic activity on both MCF-7 (IC50 = 155.00 μg/ml) and Jurkat (IC50 = 87.29 μg/ml), with higher selectivity for Jurkat cell line. Interestingly, the extract showed low cytotoxicity to the normal Chang liver cell line (IC50 = 204.20 μg/ml). Conclusion N. lotus leaves extract exhibited high antioxidant, anti-inflammatory and cancer-cell-specific cytotoxic properties. These aforementioned activities could be attributed to its phenolic, flavonoid and elemental constituents. Graphical abstract

BACKGROUND Premenstrual symptoms are generally seen 7 - 10 days before the menstruation period and are collectively called as premenstrual syndrome. Dysmenorrhea is the most common premenstrual symptom that affects the lifestyle and activity of young women. This study was aimed at estimating the prevalence of premenstrual symptoms and its severity in female medical student population of Government Medical college, Patiala, Punjab. METHODS 500 female medical students aged between 18 - 28 years were included in the study. Female students were asked to fill preformed questionnaire to elicit gynaecological information as well as the 4-point grading scale menstrual distress questionnaires. Symptoms were divided into two groups: physical symptoms and behavioural / psychological symptoms. RESULTS Only 30.24 % of the students reported one or more symptoms; of these, 22.76 % were having mild, 5.6 % moderate and 1.87 % severe degree of symptoms. From physical and behavioural / psychological symptoms, it was noticed that behavioural / psychological symptoms predominate. Among physical symptoms, breast tenderness is experienced most followed by bloating, and weight gain during premenstrual phase. Among psychological / behavioural symptoms, irritability predominates followed by restlessness & mood swings. CONCLUSIONS Diagnosis is best achieved through daily rating symptoms over at least one menstrual cycle; clinicians can ask patients to choose their worst symptoms and chart the severity daily, or can select a validated scale such as the Daily Record of Severity of Problems. Disappearance of symptoms after menstruation is the key to diagnosis. KEYWORDS Premenstrual Syndrome, Depressive Disorder, Prevalence, Dysmenorrhea

Introduction There is limited data on the impact of extracorporeal membrane oxygenation (ECMO) on pulmonary physiology and imaging in adult patients. The current study sought to evaluate the serial changes in oxygenation and pulmonary opacities after ECMO initiation. Methods Records of patients started on veno-venous, or veno-arterial ECMO were reviewed (n=33; mean (SD): age 50(16) years; Male: Female 20:13). Clinical and laboratory variables before and after ECMO, including daily PaO2 to FiO2 ratio (PFR), were recorded. Daily chest radiographs (CXR) were prospectively appraised in a blinded fashion and scored for the extent and severity of opacities using an objective scoring system. Results ECMO was associated with impaired oxygenation as reflected by the drop in median PFR from 101 (interquartile range, IQR: 63-151) at the initiation of ECMO to a post-ECMO trough of 74 (IQR: 56-98) on post-ECMO day 5. However, the difference was not statistically significant. The appraisal of daily CXR revealed progressively worsening opacities, as reflected by a significant increase in the opacity score (Wilk’s Lambda statistic 7.59, p=0.001). During the post-ECMO period, a >10% increase in the opacity score was recorded in 93.9% of patients. There was a negative association between PFR and opacity scores, with an average one-unit decrease in the PFR corresponding to a +0.010 increase in the opacity score (95% confidence interval: 0.002 to 0.019, p-value=0.0162). The median opacity score on each day after ECMO initiation remained significantly higher than the pre-ECMO score. The most significant increase in the opacity score (9, IQR: -8 to 16) was noted on radiographs between pre-ECMO and forty-eight hours post-ECMO. The severity of deteriorating oxygenation or pulmonary opacities was not associated with hospital survival. Conclusions The use of ECMO is associated with an increase in bilateral opacities and a deterioration in oxygenation that starts early and peaks around 48 hours after ECMO initiation.

Background Extracorporeal membrane oxygenation (ECMO) is associated with complications that are separate from the underlying diagnoses that require its use. One of the foremost complications of ECMO is a high incidence of bleeding, including alveolar hemorrhage (AH), which is believed to be due to both prophylactic anticoagulation and critical illness-induced systemic coagulopathy. However, akin to systemic inflammatory response syndrome after cardiopulmonary bypass, ECMO causes widespread systemic inflammation and acute lung injury, which likely further predisposes patients to AH. The burden of clinically significant AH among patients on ECMO for advanced lung disease remains unknown. Patients and methods Charts of patients with advanced lung disease who required ECMO at a single institution were reviewed. The clinical course and variables of patients who developed AH and those who did not were compared. Results This report describes five patients who developed AH after initiation of venovenous ECMO for refractory hypoxemia. Clinical and laboratory variables did not predict the development or the prognosis of AH. Two of these patients with refractory hypoxemia and AH were treated with pulse-dose corticosteroids, with a dramatic response in one case. Conclusion The acute decompensation of the patients and response to corticosteroids suggest AH was mediated by a systemic inflammatory process, as opposed to coagulopathy alone. Judicious use of steroids may be considered among select patients who develop AH without symptoms of systemic coagulopathy after initiation of ECMO. How to cite this article Williams S, Batra K, Mohanka M, Bollineni S, Kaza V, Torres F, et al. Insult to Injury: Development of Alveolar Hemorrhage after Initiation of Extracorporeal Membrane Oxygenation. Indian J Crit Care Med 2020;24(12):1201–1205.

Contains fulltext : 229465.pdf (Publisher’s version ) (Closed access) BACKGROUND: Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen during preservation might improve post-transplant outcomes, particularly for kidneys subjected to greater degrees of preservation injury. This study aimed to investigate whether supplemental oxygen during hypothermic machine perfusion (HMP) could improve the outcome of kidneys donated after circulatory death. METHODS: This randomised, double-blind, paired, phase 3 trial was done in 19 European transplant centres. Kidney pairs from donors aged 50 years or older, donated after circulatory death, were eligible if both kidneys were transplanted into two different recipients. One kidney from each donor was randomly assigned using permuted blocks to oxygenated hypothermic machine perfusion (HMPO(2)), the other to HMP without oxygenation. Perfusion was maintained from organ retrieval to implantation. The primary outcome was 12-month estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation in pairs of donated kidneys in which both transplanted kidneys were functioning at the end of follow-up. Safety outcomes were reported for all transplanted kidneys. Intention-to-treat analyses were done. This trial is registered with the ISRCTN Registry, ISRCTN32967929, and is now closed. FINDINGS: Between March 15, 2015, and April 11, 2017, 197 kidney pairs were randomised with 106 pairs transplanted into eligible recipients. 23 kidney pairs were excluded from the primary analysis because of kidney failure or patient death. Mean eGFR at 12 months was 50·5 mL/min per 1·73 m(2) (SD 19·3) in the HMPO(2) group versus 46·7 mL/min per 1·73m(2) (17·1) in HMP (mean difference 3·7 mL/min per 1·73m(2), 95% CI -1·0 to 8·4; p=0·12). Fewer severe complications (Clavien-Dindo grade IIIb or more) were reported in the HMPO(2) group (46 of 417, 11%, 95% CI 8% to 14%) than in the HMP group (76 of 474, 16%, 13% to 20%; p=0·032). Graft failure was lower with HMPO(2) (three [3%] of 106) compared with HMP (11 [10%] of 106; hazard ratio 0·27, 95% CI 0·07 to 0·95; p=0·028). INTERPRETATION: HMPO(2) of kidneys donated after circulatory death is safe and reduces post-transplant complications (grade IIIb or more). The 12-month difference in eGFR between the HMPO(2) and HMP groups was not significant when both kidneys from the same donor were still functioning 1-year post-transplant, but potential beneficial effects of HMPO(2) were suggested by analysis of secondary outcomes. FUNDING: European Commission 7th Framework Programme.

Purpose The purpose of this study is improvement of human gait by customized design of ankle foot orthosis (AFO). An has been the most frequently used orthosis in children with cerebral palsy. AFOs are designed to boost existing features or to avoid depression or traumatize muscle contractures. The advantages of AFO’s utilized for advancement in human walk attributes for the improvement in foot deformities patients or youngsters with spastic loss of motion. In this research on the customized design of AFO's to improve gait, there are limitations during walking of foot drop patients. In children with foot drops, specific AFOs were explicitly altered to improve parity and strength which are beneficial to walking positions. Design/methodology/approach This study proposes the customized design of AFOs using computerized and additive manufacturing for producing advances to alter the design and increase comfort for foot drop patients. Structuring the proposed design fabricated by using additive manufacturing and restricted material, the investigation was finalized at the Design Analysis Software (ANSYS). The system that performs best under investigation can additionally be printed using additive manufacturing. Findings The results show that the customized design of AFOs meets the patient’s requirements and could also be an alternative solution to the existing AFO design. The biomechanical consequences and mechanical properties of additive manufactured AFOs have been comparable to historically synthetic AFOs. While developing the novel AFO designs, the use of 3D printing has many benefits, including stiffness and weight optimization, to improve biomechanical function and comfort. To defeat the issues of foot drop patients, a customized AFO is used to improve the human gait cycle with new material and having better mechanical properties. Originality/value This research work focuses on the biomechanical impacts and mechanical properties of customized 3D-printed AFOs and compares them to traditionally made AFOs. Customized AFO design using 3D printing has numerous potential advantages, including new material with lightweight advancement, to improve biomechanical function and comfort. Normally, new applications mean an incremental collection of learning approximately the behavior of such gadgets and blending the new design, composite speculation and delivered substance production. The test results aim to overcome the new AFO structure issues and display the limited components and stress examination. The outcome of the research is the improved gait cycle of foot drop patients.

Acinetobacter species, particularly those within Acinetobacter calcoaceticus–A. baumannii complex (ACB complex), have emerged as clinically relevant pathogens in hospital environments worldwide. Early and quick detection and identification of Acinetobacter infections is challenging, and traditional culture and biochemical methods may not achieve adequate levels of speciation. Moreover, currently available techniques to identify and differentiate closely related Acinetobacter species are insufficient. The objective of this review is to recapitulate the current evolution in phenotypic and automated techniques used to identify the ACB complex. Compared with other automated or semiautomated systems of bacterial identification, matrix-assisted laser desorption–ionization time-of-flight mass spectrometry (MALDI-TOF MS) demonstrates a high level of Acinetobacter species identification and discrimination, including newly discovered species A. seifertii and A. dijkshoorniae.

IntroductionThe purpose of this study was to establish a reliable panel of antibodies for immunohistochemical corroboration of a diagnosis of clear cell sarcoma of kidney (CCSK), taking into consideration the various genotypic subsets of CCSK.MethodsWe conducted full genotypic analysis for evidence of YWHAE-NUTM2, BCOR internal tandem duplication (ITD), and BCOR-CCNB3 in 68 archival cases of CCSK and then immunostained all cases for CCND1, TLE1, and BCOR along with 63 control samples representing tumor types that may enter into the differential diagnosis of CCSK, including 7 congenital mesoblastic nephromas, 2 desmoplastic small round cell tumors, 13 malignant rhabdoid tumors, 9 Ewing sarcomas/primitive neuroectodermal tumor, 5 synovial sarcomas, and 27 Wilms' tumors.ResultsMolecular assays showed that 54 CCSKs harbored a BCOR-ITD, 1 case expressed a YWHAE-NUTM2 fusion transcript while none expressed the BCOR-CCNB3 fusion. The remaining 13 CCSKs were designated “triple-negative” based on the molecular findings. CCND1 showed positive immunoreactivity across all subgroups. TLE1 was positive in 94% of cases, including 1 YWHAE-NUTM2 fusion-positive case. Three BCOR-ITD-positive tumors were TLE1-negative. BCOR immunostaining was most variable among subgroups, with triple-negative tumors showing the weakest staining. In all, 10/68 (15%) tumors did not stain for BCOR, of which 4 were triple-negative (4/13 = 31%) and 6 were BCOR-ITD-positive (6/54 = 11%). The single YWHAE-NUTM2-positive tumor showed strong staining for all 3 markers. No single case was negative for all 3 stains; however, 3 cases showed no reactivity for either BCOR or TLE1 of which 1 was triple-negative and 2 BCOR-ITD-positive.ConclusionHaving completed the first comprehensive evaluation of immunostaining of 68 fully genotyped CCSK tumors, we show herein that there is a rationale for the use of a small panel of antibodies to assist in the diagnosis of CCSK regardless of genotype, and we demonstrate that in combination CCND1, TLE1, and BCOR are compelling markers in aiding CCSK diagnosis.

Graves’ disease (GD) is an autoimmune condition with the appearance of anti-TSH receptor (TSHR) autoantibodies in the serum. The consequence is the development of hyperthyroidism in most of the patients. In addition, in the most severe cases, patients can develop orbitopathy (GO), achropachy and dermopathy. The central role of the TSHR for the disease pathology has been well accepted. Therefore immunization against the TSHR is pivotal for the creation of in vivo models for the disease. However, TSHR is well preserved among the species and therefore the immune system is highly tolerant. Many differing attempts have been performed to break tolerance and to create a proper animal model in the last decades. The most successful have been achieved by introducing the human TSHR extracellular domain into the body, either by injection of plasmid or adenoviruses. Currently available models develop the whole spectrum of Graves’ disease—autoimmune thyroid disease and orbitopathy and are suitable to study disease pathogenesis and to perform treatment studies. In recent publications new immunomodulatory therapies have been assessed and also diseaseprevention by inducing tolerance using small cyclic peptides from the antigenic region of the extracellular subunit of the TSHR.

Nucleic acid amplification technology (NAAT) has assumed a critical position in disease diagnosis in recent times and contributed significantly to healthcare. Application of these methods has resulted in a more sensitive, accurate and rapid diagnosis of infectious diseases than older traditional methods like culture-based identification. NAAT such as the polymerase chain reaction (PCR) is widely applied but seldom available to resource-limited settings. Isothermal amplification (IA) methods provide a rapid, sensitive, specific, simpler and less expensive procedure for detecting nucleic acid from samples. However, not all of these IA techniques find regular applications in infectious diseases diagnosis. Disease diagnosis and treatment could be improved, and the rapidly increasing problem of antimicrobial resistance reduced, with improvement, adaptation, and application of isothermal amplification methods in clinical settings, especially in developing countries. This review centres on some isothermal techniques that have found documented applications in infectious diseases diagnosis, highlighting their principles, development, strengths, setbacks and imminent potentials for use at points of care.

Frailty is associated with significant morbidity and mortality for patients undergoing transcatheter aortic valve implantation (TAVI). In addition to clinical outcomes, cost is an important factor to inform clinical decision-making around TAVI. However, the association of frailty with cost is unknown. This study tested whether frailty was associated with cost for adult patients who underwent TAVI at a moderate-volume single center between December 2012 and April 2018 (n = 431). Frailty was determined from pre-TAVI clinical visits as a composite of 2 markers: 5-meter walk time (abnormal:6 seconds or unable to perform) and serum albumin (abnormal:3.5 g/dl). Patients were excluded if missing frailty assessment or covariate data (24). Cost data were derived from financial statements, and assigned at the department-level by charge code. Multivariable regression models were adjusted for age, gender, and procedural co-morbidities. Of 407 patients in the analytical sample (mean age 81 years, 49% female), 74 (18%) were determined to be frail. Adjusted mean total costs were $6,397 higher for frail patients ($78,823 vs $72,425, p = 0.042) compared with nonfrail. Higher total costs were driven by department-level charges associated with longer in-hospital length of stay (7.6 vs 3.3 days, p0.001): room, physical therapy, pharmacy, laboratory, supply, and imaging services. Providers must address frailty proactively to salvage the benefit associated with TAVI.

Background: Thyrotropin (TSH) and thyroid-stimulating antibodies (TSAbs) activate TSH receptor (TSHR) signaling by binding to its extracellular domain. TSHR signaling has been studied extensively in animal thyrocytes and in engineered cell lines, and differences in signaling have been observed in different cell systems. We, therefore, decided to characterize and compare TSHR signaling mediated by TSH and monoclonal TSAbs in human thyrocytes in primary culture. Methods: We used quantitative reverse transcription-polymerase chain reaction to measure mRNA levels of thyroid-specific genes thyroglobulin (TG), thyroperoxidase (TPO), iodothyronine deiodinase type 2 (DIO2), sodium-iodide symporter (NIS), and TSHR after stimulation by TSH or two monoclonal TSAbs, KSAb1 and M22. We also compared secreted TG protein after TSHR activation by TSH and TSAbs using an enzyme-linked immunosorbent assay. TSHR cell surface expression was determined using fluorescence activated cell sorting (FACS). Results: We found that TSH at low doses increases and at high doses (>1 mU/mL) decreases levels of gene expression for TSHR, TG, TPO, NIS, and DIO2. The biphasic effect of TSH on signaling was not caused by downregulation of cell surface TSHRs. This bell-shaped biphasic dose–response curve has been termed an inverted U-shaped dose–response curve (IUDRC). An IUDRC was also found for TSH-induced regulation of TG secretion. In contrast, KSAb1- and M22-induced regulation of TSHR, TG, TPO, NIS, and DIO2 gene expression, and secreted TG followed a monotonic dose–response curve that plateaus at high doses of activating antibody. Conclusions: Our data demonstrate that the physiological activation of TSHRs by TSH in primary cultures of human thyrocytes is characterized by a regulatory mechanism that may inhibit thyrocyte overstimulation. In contrast, TSAbs do not exhibit biphasic regulation. Although KSAb1 and M22 may not be representative of all TSAbs found in patients with Graves' disease, we suggest that persistent robust stimulation of TSHRs by TSAbs, unrelieved by a decrease at high TSAb levels, fosters chronic stimulation of thyrocytes in Graves' hyperthyroidism.

Vitamin D deficiency is prevalent all over the world, especially in tropical countries. In epileptics, antiepileptic drugs (AED) and associated comorbidities further impact vitamin D status. The aim of this study is to estimate the prevalence of 25(OH) vitamin D deficiency in epileptic children and evaluate probable risk factors. A cross-sectional study of 200 children between 1 and 18 years of age on AED was undertaken in the pediatric neurology clinic of a tertiary care center of Northern India. In all children, serum 25(OH) vitamin D levels, calcium, phosphorus, and alkaline phosphatase were estimated. The deficiency levels of vitamin D were categorized as: deficiency 30 ng/mL. The potential risk factors for hypovitaminosis D, including type of epilepsy, AED regimen (specific medications, polytherapy vs. monotherapy), cerebral palsy, ambulatory status, intellectual disability, body mass index, gender, and vegetarianism were examined. Among the 200 enrolled children (60% boys), 106/200 (53%) were vitamin D deficient. There was no significant relation of vitamin D levels with gender, type of epilepsy, neurological deficit, and type of AED. An inverse relationship of higher phenytoin doses during monotherapy associated with lower vitamin D levels in monotherapy was found, thereby suggesting adverse effect of high doses of phenytoin on vitamin D levels. VDD is common among epileptic children on AED therapy. Vitamin D deficiency is common prevalent among epileptic children on AED therapy, and its detection and treatment correction should be an integral part of epilepsy management.

Rationale: Tuberculosis (TB) remains the leading cause of death among infectious diseases worldwide. Poor compliance of TB patients to the lengthy treatment increases the risk of relapse and leads to the emergence of multidrug-resistant and extensively drug-resistant TB (MDR-TB and XDR-TB). More effective therapies for TB are urgently needed. We hypothesized that granulysin-mediated clearance of M. tuberculosis parasited inside and outside of alveolar macrophages in presumptive infected hosts might enhance the chemotherapeutic efficacy on TB. Methods: Recombinant adenovirus type 5 (rAd5) based therapeutic vaccines rAdhGLi and rAdhGLs (rAds) were respectively developed to express intracellular and extracellular granulysin. The ex vivo bactericidal effects of rAdhGLi and rAdhGLs were evaluated on U937 and RAW264.7 cells. The efficacy of immunotherapy with both rAdhGLi and rAdhGLs on TB SCID mice, or immunotherapy combined with chemotherapy on drug-susceptible TB or MDR-TB mouse models were further evaluated. Results: rAdhGLs, as well as rAdhGLi, showed a direct bactericidal effect on extracellular or intracellular M. tuberculosis H37Rv and MDR-TB clinical strains, respectively. Immunotherapy with a dose of 109 PFU of rAdhGLi and 109 PFU of rAdhGLs demonstrated a more significant bactericidal effect on M. tuberculosis H37Rv infected SCID mice and prolonged their survival periods than rAdhGLi or rAdhGLs alone. More importantly, chemotherapy combined with rAds immunotherapy shortened the chemotherapeutic duration to 4 months on M. tuberculosis H37Rv infected mice and prevented the relapse. Combination of rAds with chemotherapy on MDR-TB mice also more significantly decreased organ bacterial load than their single use. Conclusions: Delivery of granulysin by recombinant adenovirus to the infected lung could enhance the clearance of TB in vivo and might be a promising adjunct therapeutic vaccine for TB and MDR-TB.

19 pages, 6 figures, 2 tables.-- This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, Ordinary differential equation models are nowadays widely used for the mechanistic description of biological processes and their temporal evolution. These models typically have many unknown and nonmeasurable parameters, which have to be determined by fitting the model to experimental data. In order to perform this task, known as parameter estimation or model calibration, the modeller faces challenges such as poor parameter identifiability, lack of sufficiently informative experimental data and the existence of local minima in the objective function landscape. These issues tend to worsen with larger model sizes, increasing the computational complexity and the number of unknown parameters. An incorrectly calibrated model is problematic because it may result in inaccurate predictions and misleading conclusions. For nonexpert users, there are a large number of potential pitfalls. Here, we provide a protocol that guides the user through all the steps involved in the calibration of dynamic models. We illustrate the methodology with two models and provide all the code required to reproduce the results and perform the same analysis on new models. Our protocol provides practitioners and researchers in biological modelling with a one-stop guide that is at the same time compact and sufficiently comprehensive to cover all aspects of the problem, European Union’s Horizon 2020 Research and Innovation Programme (grant no. 686282) (‘CANPATHPRO’); Spanish MINECO/FEDER Project SYNBIOCONTROL (DPI2017-82896-C2-2-R to J.R.B.); Ramón y Cajal Fellowship (RYC-2019-027537-I to A.F.V.) from the Ministerio de Ciencia e innovación, Spain; Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia (ED431F 2021/003 to A.F.V.); Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy (EXC 2151 - 390873048 to J.H.), (EXC-2047/1 - 390685813 to D.P.); German Federal Ministry of Economic Affairs and Energy (grant no. 16KN074236 to D.P.). Ministerio de Ciencia e Innovación, Spain (grant PID2020-117271RB-C22, ‘BIODYNAMICS’, to J.R.B.; Funding for open access charge: Universidade de Vigo/CISUG)

BACKGROUND Bone anchored hearing implants (BAHI) are widely used and highly successful, accompanied with a high level of patient satisfaction across most techniques. A large UK teaching hospital switched from the previously used wide diameter titanium fixture and drilling system to the novel minimally invasive technique and laser ablated titanium implant. Before this change the rates of fixture failure and skin problems necessitating abutment change were 1% each. METHODS Retrospective case note review of consecutive BAHI patients drawn from an electronic database between January 2015 and October 2016. RESULTS Data from a total of 118 procedures were reviewed, with different combinations of surgical techniques and implant types. Sixty procedures were performed via the novel minimally invasive technique with 21 failures (35%). Fourty-eight modified minimally invasive technique procedures were performed with seven failures. In 64 of the procedures, laser ablated titanium fixtures were placed with 21 failures (32.8%). In 54 procedures wide diameter titanium fixtures were placed with eight failures (5%). CONCLUSION Initial experience with the novel minimally invasive technique and laser ablated titanium fixture showed significantly higher failure rates than expected. This prompted a change to an open technique and subsequent abandonment of the laser ablated titanium fixture and custom drilling solution in our institution.

The T‐cell response is central in the adaptive immune‐mediated elimination of pathogen‐infected and/or cancer cells. This activated T‐cell response can inflict an overwhelming degree of damage to the targeted cells, which in most instances leads to the control and elimination of foreign invaders. However, in conditions of chronic infection, persistent exposure of T cells to high levels of antigen results in a severe T‐cell dysfunctional state called exhaustion. T‐cell exhaustion leads to a suboptimal immune‐mediated control of multiple viral infections including the human immunodeficiency virus (HIV). In this review, we will discuss the role of T‐cell exhaustion in HIV disease progression, the long‐term defect of T‐cell function even in aviremic patients on antiretroviral therapy (ART), the role of exhaustion‐specific markers in maintaining a reservoir of latently infected cells, and exploiting these markers in HIV cure strategies.

Cystic lesions of jaws are fairly common of which radicular cysts that form as a result of inflammatory changes associated with a non-vital pulp are most frequent. The removal of source of infection by either root canal treatment or extraction of the involved tooth leads to resolution of inflammatory cysts. However, infrequently, certain lesions may persist even after appropriate treatment which are termed as ‘residual cysts’. Although residual cysts are histopathologically indistinguishable from radicular cysts, certain changes may occur owing to removal of the aggravating stimulus which may lead to a varied histopathological picture. The present case report comprises of a residual cyst with a relatively unusual histopathological presentation. Keywords: Inflammatory cyst, Prosoplasia, Metaplasia.

Aim: The aim of this systematic analysis was to assess the prevalence of dentinal microcracks at various levels (3, 6, and 9 mm from the apex) after using instruments made with conventional, R-Phase, and M-Wire NiTi alloys and the SAF system. Materials and Methods: Electronic searches were conducted in the databases Embase, Cochrane Library, Scopus, PubMed, and Web of Science. To arrange search methods, “MeSH” terms and/or keywords typically associated with the subject were paired with the Boolean operators “AND” and “OR.” Additional searches were conducted on the websites of four separate endodontic journals. After reading the titles and excluding duplicates, 1000 of the 1343 documents originally found were eliminated. Upon reviewing the abstracts, 310 of the remaining 343 experiments were also eliminated. Based on qualifying requirements, only 13 of the remaining 33 articles were included in the qualitative review. Results: All systems triggered dentinal microcracks; however, when chemo-mechanical preparation was performed using Self-Adjusting File (SAF) and systems manufactured with R-phase technology—K3XF and Twisted File Adaptive (TFA)—less of these defects were found when compared to those manufactured with traditional NiTi—ProTaper Universal and Mtwo—and with M-Wire—ProTaper Next, Reciproc, and WaveOne. Conclusions: A lower prevalence of dentinal microcracks was observed after using SAF and endodontic systems manufactured with R-phase.

Background. Mortality among children with severe acute malnutrition remains an immense health concern in the hospitals in developing countries, but its attributes are not completely assessed in various hospital settings. The aim of this study was to determine the proportion of mortality, the comorbidities, and factors associated with in-hospital mortality among children under five years of age admitted with severe acute malnutrition at Jinja Regional Referral Hospital, Eastern Uganda. Methods. This was a hospital-based analytical and descriptive prospective cohort study conducted in the nutritional unit of Jinja Regional Referral Hospital. A total of 338 children and their caretakers who met the criteria were consecutively enrolled into the study. Descriptive statistics were used to each of the independent factors, and comorbidities were subjected to chi-squared test followed by logistic regression analysis to assess its association incidence of mortality among children. All independent variables with p values ≤ 0.05 were entered into a multivariate model for factors and comorbidities independently. Factors and comorbidities with p values ≤ 0.05 were considered as associates of mortality among children. Results. Of the 338 children under 5 years of age enrolled, 49 (14.5%) died, although the majority of children were diagnosed with dehydration, 128 (37.9%); pneumonia, 127(37.6%); and malaria, 87(25.7%). Anemia ( aRR = 2.9 , 95% CI: 1.23-6.62, p = 0.01 ), bacteremia ( aRR = 10.0 , 95% CI: 3.62-29.01, p = 0.01 ), HIV ( aRR = 4.8 , 95% CI: 1.42-16.30, p < 0.01 ), TB ( aRR = 4.3 , 95% CI: 1.28-14.49, p < 0.02 ), and shock ( aRR = 60.9 , 95% CI: 9.05-410.28, p < 0.01 ) were the comorbidities significantly associated with a likelihood of mortality. Conclusions. The mortality among children under 5 years of age admitted with severe acute malnutrition is still high (14.5% versus 5%). The comorbidities are significantly associated with mortality. The clinicians are recommended to follow-up closely patients with severe acute malnutrition and to focus on the critical comorbidities identified.

9 pages, 2 figures, 2 tables.-- This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, Motivation: Kinetic models contain unknown parameters that are estimated by optimizing the fit to experimental data. This task can be computationally challenging due to the presence of local optima and ill-conditioning. While a variety of optimization methods have been suggested to surmount these issues, it is difficult to choose the best one for a given problem a priori. A systematic comparison of parameter estimation methods for problems with tens to hundreds of optimization variables is currently missing, and smaller studies provided contradictory findings. Results: We use a collection of benchmarks to evaluate the performance of two families of optimization methods: (i) multi-starts of deterministic local searches and (ii) stochastic global optimization metaheuristics; the latter may be combined with deterministic local searches, leading to hybrid methods. A fair comparison is ensured through a collaborative evaluation and a consideration of multiple performance metrics. We discuss possible evaluation criteria to assess the trade-off between computational efficiency and robustness. Our results show that, thanks to recent advances in the calculation of parametric sensitivities, a multi-start of gradient-based local methods is often a successful strategy, but a better performance can be obtained with a hybrid metaheuristic. The best performer combines a global scatter search metaheuristic with an interior point local method, provided with gradients estimated with adjoint-based sensitivities. We provide an implementation of this method to render it available to the scientific community. Availability and implementation: The code to reproduce the results is provided as Supplementary Material and is available at Zenodo https://doi.org/10.5281/zenodo.1304034., This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 686282 (‘CANPATHPRO’), from the Spanish MINECO/FEDER projects SYNBIOFACTORY (DPI2014-55276-C5-2-R) and SYNBIOCONTROL (DPI2017-82896-C2-2-R), and from the German Research Foundation (DFG) through the Graduate School of Quantitative Biosciences Munich (QBM; F.F.)

We investigated phenotypic variations for pod shattering, pod length and number of seeds per pod in large germplasm collections of Brassica juncea (2n = 36; AABB) and its progenitor species, B. rapa (2n = 20; AA) and B. nigra (2n = 16; BB). Pod shatter resistance was measured as energy required for rupturing a mature dry pod, with a specially fabricated pendulum machine. Rupture energy (RE) ranged from 3.3 to 11.0 mJ in B. juncea. MCP 633, NR 3350 and Albeli required maximum energy to shatter a pod. It ranged from 2.5 to 7.8 mJ for B. rapa with an average of 5.5 mJ. B. nigra possessed easy to rupture pods. Correlation analysis showed strong associations among these traits in B. juncea and B. rapa. Genome wide association studies were conducted with select sets of B. juncea and B. rapa germplasm lines. Significant and annotated associations predict the role of FRUITFULL, MANNASE7, and NAC secondary wall thickening promoting factor (NST2) in the genetic regulation of shatter resistance in B. juncea. NST2 and SHP1 appeared important for pod length and seeds per pod in B. rapa. Candidate gene based association mapping also confirmed the role of SHP1 and NST2 in regulating pod shattering and related pod traits in B. rapa and B. juncea. Footprints of selection were detected in SHP1, SHP2 (B. rapa, B. nigra and B. juncea), RPL (B. rapa) and NAC (B. juncea). Our results provide insights into the genetic architecture of three pod traits. The identified genes are relevant to improving and securing crop productivity of mustard crop.

ObjectivesCOVIDTrach is a UK multicentre prospective cohort study project that aims to evaluate the outcomes of tracheostomy in patients with COVID-19 receiving mechanical ventilation and record the incidence of SARS-CoV-2 infection among healthcare workers involved in the procedure.DesignData on patient demographic, clinical history and outcomes were entered prospectively and updated over time via an online database (REDCap). Clinical variables were compared with outcomes, with logistic regression used to develop a model for mortality. Participants recorded whether any operators tested positive for SARS-CoV-2 within 2 weeks of the procedure.SettingUK National Health Service departments involved in treating patients with COVID-19 receiving mechanical ventilation.ParticipantsThe cohort comprised 1605 tracheostomy cases from 126 UK hospitals collected between 6 April and 26 August 2020.Main outcome measuresMortality following tracheostomy, successful wean from mechanical ventilation and length of time from tracheostomy to wean, discharge from hospital, complications from tracheostomy, reported SARS-CoV-2 infection among operators.ResultsThe median time from intubation to tracheostomy was 15 days (IQR 11, 21). 285 (18%) patients died following the procedure. 1229 (93%) of the survivors had been successfully weaned from mechanical ventilation at censoring and 1049 (81%) had been discharged from hospital. Age, inspired oxygen concentration, positive end-expiratory pressure setting, fever, number of days of ventilation before tracheostomy, C reactive protein and the use of anticoagulation and inotropic support independently predicted mortality. Six reports were received of operators testing positive for SARS-CoV-2 within 2 weeks of the procedure.ConclusionsTracheostomy appears to be safe in mechanically ventilated patients with COVID-19 and to operators performing the procedure and we identified clinical parameters that are predictive of mortality.Trial registration numberThe study is registered with ClinicalTrials.Gov (NCT04572438).

Background: The target ranges (TR) for anticoagulation with vitamin K antagonists (VKA) in the Netherlands were changed in 2016 from INR 2.0 & ndash;3.5 (& lsquo;low intensity & rsquo;) and INR 2.5 & ndash;4.0 (& lsquo;high intensity & rsquo;) to INR 2.0 & ndash;3.0 and INR 2.5 & ndash;3.5, respectively.Aim: To assess the effect of the TR change on therapeutic quality control (TQC) in a Dutch regional thrombosis center taking care of approximately 3600 & ndash;5500 patients annually.Methods: TQC of chronically treated patients was assessed as the average time in therapeutic range (TTR). Evaluations were performed for non-self-management (NSM), as well as self-management patients. INR percentiles were assessed from all INR determinations in all patients, i.e. including those of induction episodes and patients treated for a short-term.Results: The number of NSM patients treated chronically decreased gradually, while their average age increased, with a marginal but significant gradual increase in bleeding complications. In the period 2011 & ndash;2015, i.e. before the TR change, there was a gradual increase of the TTR in NSM patients from 77.5% to 88.9% (low intensity) and from 75.3% to 84.1% (high intensity). In the same period, the median INR of all patients in the low and high intensity ranges decreased from 2.9 to 2.7, and from 3.3 to 3.2, respectively. The TTR in self-management patients remained virtually constant. After TR changes from 2016 on, the TTR of all NSM patients in the low and high intensity groups decreased to 77% and 70%, respectively, and median INRs decreased to 2.6 and 3.0, respectively.Conclusions: Introduction of internationally harmonized target ranges in 2016 resulted in further lowering of median INR values in both target ranges. As expected, TTR was reduced slightly. These findings, together with a slight increase in average age and concomitant bleeding complications, suggest that the patients on long-term VKA treatment will require intensified monitoring and treatment.

We report two cases of rescue strategies for nonopening of Pipeline flow-diverter device for the treatment of intracranial aneurysm. The first patient, a 65-year-old female, presented with complaints of headache for 3 months and was found to have giant supraclinoid internal carotid artery (ICA) (ophthalmic segment) aneurysm. We planned endovascular partial coiling and flow-diverter placement for the treatment of ICA aneurysm. During the progressive deployment of PED, there was nonopening of Pipeline embolization device (PED) at its proximal end. We tried multiple attempts to navigate Marksman microcatheter over the PED delivery microwire and Echelon microcatheter over the Traxcess microwire across the pinched site, but we were not able to achieve success. After that, we tried opposite transcranial approach across prominent anterior communicating artery with the Synchro and Transcend microguidewire which finally resulted in the opening of the device; however, there was acute extravasation of dye on check angiogram. Thus, our technical success turned into disaster. The second patient, a 55-year-old female, presented with complaint of seizures for 3 months due to mass effect of cavernous sinus aneurysm. Pipeline Flex flow-diverter placement was done across the aneurysm neck. During the progressive deployment of device, there was nonopening of the mid and proximal segment of Pipeline Flex which was successfully managed by intra-Navien deployment of device followed by simultaneous push of Marksman microcatheter and pull of Navien catheter. In our case series, two rescue strategies were applied to successfully open the proximal constricted portion of Pipeline Flex; however, technical success in one case resulted in unmanageable disasters. Thus, transcranial rescue strategy for opening the constricted Pipeline Flex device should be cautiously used in our endovascular practice.

Background Takotsubo cardiomyopathy (TC) is diagnosed in 1% to 2% of patients presenting with suspected acute coronary syndromes. Readmission patterns after TC have been less studied. Thus, we sought to perform a study to evaluate the etiologies, trends, and predictors of 90-day readmission in TC. Methods The Nationwide Readmissions Database (NRD), 2014, was used to select the study cohort. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic code 429.83 was used to identify TC. Admissions within 90 days of index admission were considered early readmissions. Readmission etiologies were identified by an ICD-9-CM code. Hierarchical multivariate models were used to evaluate predictors of early readmission. Results A total of 28,079 patients were identified during the study period, of whom 24.3% (n = 6841) were readmitted within 90 days of discharge. In-hospital mortality during index admissions was 5.69%. The most common etiologies for readmission were cardiac (18.56%), respiratory (17.20%), and infections (13.12%). Among cardiac complications, acute heart failure was the most common etiology (7.48%). The highest number of readmissions happened on the first day after discharge (n = 125). On multivariate analysis, the age of 50–64 years, diabetes, heart failure, chronic pulmonary disease, peripheral vascular disease, anemia, and malignancy were shown to be significant predictors of readmission. Patients of female gender are less likely to be readmitted and have lower in-hospital mortality. Conclusions Patients with TC are highly likely to be readmitted within the first month after discharge, most likely with secondary to cardiac or respiratory complications. These findings warrant close post-discharge transition to reduce morbidity and improve healthcare outcomes. Summary This analysis from the Nationwide Readmission Database outlines a detailed analysis on etiologies, trends, and predictors of 90-day readmission for patients presenting with takotsubo cardiomyopathy.

Endodontic treatment works as a successful treatment modality in several cases. However, it may fail due to some reasons unforeseeable by the dentist. Many failures can be prevented by carefully assessing the difficulty level of the case before initiating treatment or by referral to a specialist. This study presents an approach using machine learning to generate an algorithm which can help predict the difficulty level of the case and decide about a referral, with the help of the standard American Association of Endodontists (AAE) Endodontic Case Difficulty Assessment Form. Using the AAE Endodontic Case Difficulty Form after obtaining the patients’ consent, 500 potential root canal patients were diagnosed. The filled forms were assessed by two pre-calibrated endodontists, and, in cases of conflicting opinion, a third endodontist’s opinion was taken. Artificial neural network was used for generating the algorithm. Using 500 filled AAE forms, a sensitivity of 94.96% was achieved by the machine learning algorithm. This study provides an option for automation to the conventional method of predicting the difficulty level of a case, thus increasing the speed of decision-making and referrals if necessary. An AAE Endodontic Case Difficulty Assessment Form when utilized along with machine learning can assist general dentists in rapid assessment of the case difficulty. This is a helpful tool in developing countries, where endodontic treatment and referral guidelines are often neglected. It also helps to make difficulty level assessments easier for novice practitioners, when they are in doubt about the same.

In Canada, South Asian (SA) children are more likely to be overweight and physically inactive than non-SAs. This study uses a mixed-methods embedded design to investigate factors associated with physical activity (PA) among SAs, and develops a culturally-relevant exercise intervention for SA children ages 8-11. Twenty-eight (28) participants including children, parents, principals, teachers, and Bhangra instructors across four elementary schools in Surrey, BC participated in semi-structured interviews and a self-report survey. Using the immersion/crystallization approach, four major themes were identified: (1) awareness of the importance and benefits of PA, (2) discrepancy between expectations and actual opportunities for PA in the school-setting, (3) sub-optimal conditions for PA at school and home, and (4) intervention characteristics conducive for promoting exercise in SA children. Competing demands and lack of opportunities posed as prominent obstacles. To address these barriers, a culturally-appealing exercise intervention may offer a viable approach to motivate SA children to exercise.

Thyroid peroxidase (TPO) is the key enzyme involved in thyroid hormone synthesis. Autoantibodies to TPO (TPOAbs) are a hallmark of autoimmune thyroid disease (AITD). Here, we highlight recent progress over several years in understanding TPO biochemistry and function in various pathologies. TPO undergoes complex post-translational modifications as a dimer in endoplasmic reticulum during secretory pathway to apical membrane of thyrocytes. In silico modelling of TPO dimer has provided new information into the two enzyme active site regions and autoantigenic determinants. TPO and hydrogen peroxide generating DUOX and caveolin-1 form a complex known as thyroxisome to bring together in close proximity the components of hormone synthesis in apical membrane. Autoimmunity to TPO is characterised by autoantibodies and T cell reactivity in Hashimoto's disease and Graves' disease. TPOAbs are directed predominantly to two immunodominant determinants (IDR) termed IDR-A and IDR-B regions, with the latter antibodies more predominant in autoimmune disease. Strong genetic risk has been shown to be associated with TPOAbs for AITD development. A different antibody with unusual features of bispecificity for both TPO and thyroglobulin may play protective role in Hashimoto's disease. In the context of TPO biology in human cancer, thyroid tumor tissue and breast cancer differ in TPO expression and isoform composition. In thyroid cancer, TPO expression is decreased partly by the BRAF(V600E) mutation, with direct impact on significant hormone production. TPOAbs may play a protective role in breast cancer development. An understanding of TPO and its unique two enzymatic active sites and autoantigenic determinants continues to add new knowledge on the biochemistry and immunology of this enzyme.

Safety surveillance is required for each season’s influenza vaccines to rapidly detect and evaluate potential new safety concerns before the peak period of immunization. Here we report the results of an enhanced passive safety surveillance for a trivalent split-virion inactivated influenza vaccine (IIV3; Vaxigrip®), an intradermal version of this vaccine (IIV3-ID; Intanza® 15 µg), and a recently licensed quadrivalent version (IIV4; VaxigripTetraTM) during the 2017/18 influenza season in the UK and Republic of Ireland. The primary objective was to determine the rates of adverse reactions (ARs) occurring within 7 days following routine vaccination. Between September and November 2017, 979 safety report cards were distributed to vaccinees receiving IIV3-ID, 1005 to those receiving IIV3, and 957 to those receiving IIV4. At least one AR was reported by 28 participants (2.9%) vaccinated with IIV3-ID, 14 participants (1.4%) vaccinated with IIV3, and 20 participants (2.1%) vaccinated with IIV4. The most frequent ARs were injection-site reactions and headache. One participant vaccinated with IIV3-ID reported two suspected serious ARs (dyskinesia and a shock symptom), although these could not be confirmed as vaccine-related. Rates of ARs for IIV3 and IIV3-ID for 2017/18 did not differ from the 2016/17 rates. For IIV4, in its first season since licensure, AR frequencies were similar to those in the Summary of Product Characteristics. In conclusion, no change was found compared to the known or expected AR rates for IIV3, IIV3-ID, or IIV4 during the 2017/18 season.

A complete circle of Willis (CoW) is considered an important collateral network to maintain blood flow during cross-clamping in carotid endarterectomy (CEA). The aim of this study was to evaluate the impact of an incomplete CoW with isolated middle cerebral artery (iMCA) on immediate neurologic events (INEs) after CEA.We prospectively collected the clinical data and outcomes of 902 patients who underwent CEA under general anesthesia between 2013 and 2015. All patients had preoperative computed tomography angiography of the extracranial and intracranial cerebral circulation. Indications were asymptomatic (52%) and symptomatic (48%) carotid artery disease. Patients who had CEA with shunt (n = 35) and those with inadequate intracranial imaging to assess CoW were excluded (n = 322) only. Computed tomography angiography images were reviewed retrospectively and independently by two vascular radiologists who were blinded for treatment outcomes. Imaging assessment included the vertebral and carotid circulation and each segment of the CoW, which was classified as normal, hypoplastic (diameter 0.8 mm) or absent. The ipsilateral MCA was considered isolated if there was an absence of the anterior and posterior communicating branches from the contralateral carotid or posterior circulations. INE was defined as any transient ischemic attack (TIA) and stroke diagnosed immediately after the procedure.Of the 545 included patients (331 males; mean age, 69 ± 8 years), 12 (2.2%) had a stroke in the postoperative period. There were 20 INEs (8 strokes and 12 TIAs). A complete CoW was rare; it was only detected in 19 patients (3.5%) and an iMCA was found in 34 patients (6.3%). When at least one collateral circulation was complete (in 330 patients), we observed only four INEs (1.2%). Of the 34 patients with an iMCA, 8 (24%) had INE (6 TIAs and 2 strokes). Overall, iMCA was an independent predictor of INEs (odds ratio, 11.12; 95% confidence interval, 3.57-35.87; P .001). With logistic regression, the model included hypertension, smoking, diabetes, hyperlipidemia, carotid clamping time (minutes), contralateral significant internal carotid artery stenosis of greater than 90%, ipsilateral significant internal carotid artery stenosis of greater than 90%, preoperative symptoms in 6 months, and iMCA; above iMCA only symptomatic patients had significant risk (odds ratio, 3.34; 95% confidence interval, 1.19-9.73; P = .02), whereas all other parameters were not significant.An iMCA carries more than a 10-fold higher the risk of INEs after CEA with cross-clamping without shunt protection. In these patients, routine shunting is recommended to prevent INEs.

Delivery of imaging reagents and drugs to tumors is essential for cancer diagnosis and therapy. In addition to therapeutic and diagnostic functionalities, peptides have potential benefits such as biocompatibility, ease to synthesize, smaller size, by-passing off-target side effects, and achieving the beneficial effects with lower-administered dosages. A particular type of peptide known as cell penetrating peptides (CPP) have been predominantly studied during last twenty years as they are not only capable to translocate themselves across membranes but also allow carrier drugs to translocate across plasma membrane, by different mechanisms depending on the CPP. This is of great potential importance in drug delivery systems, as the ability to pass across membranes is crucial to many drug delivery systems. In spite of significant progress in design and application of CPP, more investigations are required to further improve their delivery to tumors, with reduced side-effect and enhanced therapeutic efficacy. In this review, we emphasis on current advancements in preclinical and clinical trials based on using CPP for more efficient delivery of anti-cancer drugs and imaging reagents to cancer tissues and individual cells associated with them. We discuss the evolution of the CPPs-based strategies for targeted delivery, their current status and strengths, along with summarizing the role of CPPs in targeted drug delivery. We also discuss some recently reported diagnostic applications of engineered protease-responsive substrates and activable imaging complexes. We highlight the recent clinical trial data by providing a road map for better design of the CPPs for future preclinical and clinical applications.

Background: The ligamentum mucosum is composed of dense regular connective tissue and traverses from the distal femur to the infrapatellar fat pad. While the gross and histologic morphology has been studied, there is currently no evidence concerning the biomechanical properties of the ligamentum mucosum and the potential of anterior knee pain. The purpose of this study was to determine the anatomical, mechanical and histological properties of the ligamentum mucosum. Methods: Dissections were performed on cadaveric knee specimens (N = 18) and histological analysis (n = 6) was performed to define the anatomical characteristics of the ligamentum mucosum using standard hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemical methods. Biomechanical testing (n = 5) was conducted to determine the tensile properties of the ligamentum mucosum. The peak load at failure, stiffness, and strain were analyzed. Results: Sixty-four percent of the knees had a ligamentum mucosum and the histological analysis confirmed it to be composed of dense regular connective tissue. Small peripheral nerves were identified in the junction between the ligamentum mucosum and the fat pad. The average (SD) peak force of failure, stiffness, and strain were 31.9 N (19.0), 5.1 N/mm (3.59), and 0.83 (0.14), respectively. Conclusions: The tensile strength and stiffness of the ligamentum mucosum is considerably less than the primary stabilizers of the knee joint. Based on these findings, it is improbable that the ligamentum mucosum has a meaningful effect on the kinematics of the extensor mechanism; perturbations of the tissue and the connected infrapatellar fat pad could potentially play a role in the pathogenesis of anterior knee pain. (C) 2018 Elsevier B.V. All rights reserved.

Anatomic variants in the right atrium are under-recognized and under-reported phenomena in cardiac imaging. In the fetus, right atrium serves as a conduit for oxygenated blood to be delivered to the left heart bypassing the right ventricle and the nonfunctional lungs. The anatomy in the fetal right atrium is designed for such purposeful circulation. The right and left venous valves are prominent structures in the fetal heart that direct inferior vena caval flow towards the foramen ovale. These anatomic structures typically regress and the foramen ovale closes after birth. However, the venous valves can persist leading to a range of anatomic, physiological, and pathological consequences in the adult. We describe various presentations of persistent venous valves, focusing on the right venous valve in this illustrated multimodality imaging article.

BACKGROUND To describe characteristics and outcomes among lung transplantation (LT) patients with respiratory syncytial virus (RSV) infection and elucidate the predictors of 1-year survival after RSV infection. METHODS This was a retrospective chart review study among LT patients with RSV infection between 2013 and 2018 (90 episodes among 87 patients; mean age 56.3 ± 13.1 years, M:F 52:35). A contemporaneous control group consisting of LT patients without RSV infection (n = 183) was included. One-year survival after the RSV infection was the primary endpoint. RESULTS Median time from LT to RSV infection was 30 (1-155) months. Before RSV infection, the median decline in forced vital capacity (FVC) was 9.7 cc (-17.8 to 83 cc) or 0.29% (-1.4% to 4.6%) per month, while the forced expiratory volume (FEV1 ) decline was 7.5 cc (-8.8 to 58 cc) or 0.3% (-0.57% to 4.3%) per month with no statistically significant change after RSV infection. One-year survival among patients with RSV infection was 86.2% (75/87). Pre-infection diagnosis of chronic lung allograft dysfunction (CLAD; adjusted HR: 4.29, 1.08-17.0; P = .038) and FVC or FEV1 decline >10% during 6 months post infection (adjusted HR: 35.1, 3.26-377.1; P = .003) were independently associated with worse survival. On propensity score matched analysis, RSV infection was not associated with worse post-transplant survival (HR with 95% CI: 0.79, 0.47-1.34; P = .38). CONCLUSIONS A majority of LT patients in the current cohort did not experience an alteration in the trajectory of FVC or FEV1 decline after developing RSV infection, and their post-transplant survival was not adversely impacted. Established CLAD at the time of RSV infection and post infection >10% decline in FVC or FEV1 are independently associated with worse survival after RSV infection.