Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.

BACKGROUND: In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA. PATIENTS AND METHODS: Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization). RESULTS: For STRIDE, durvalumab, and sorafenib, median [95% confidence interval (CI)] follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified. CONCLUSIONS: These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.

Utility of serum Galactomannan in diagnosing COVID-19 patients with suspected IPA: an observational study in resource limited settings.

OBJECTIVE: To study the utility of Galactomannan (GM) antigen as a screening marker for diagnosing invasive pulmonary aspergillosis (IPA) in coronavirus disease 2019 (COVID-19) patients. PATIENTS AND METHODS: The serum samples from patients with severe COVID-19 diseases admitted to the Critical Care Unit were collected on the 5th day of admission for GM screening. The samples were analysed by enzyme linked immune sorbent assay (ELISA) and GM index of more than 1 was considered as positive. All GM positive patients were serially followed until discharge or death. RESULTS: The GM was raised in serum of 12 out of 38 patients, indicating an incidence of possible COVID-19 associated IPA (CAPA) in 31.57% of patients. The median age of these CAPA patients was 56.5 years, males were significantly more affected than females. The inflammatory marker serum ferritin was raised in all 12 patients (median value of 713.74 ng/ml), while IL-6 was raised in 9 patients (median value of 54.13 ng/ml). None of these patients received antifungals. Their median length of hospital stay was 20 days (IQR: 12, 34 days). All these patients succumbed to the illness. CONCLUSIONS: The serum GM appears to be sensitive diagnostic tool to identify early IPA in COVID-19 patients and pre-emptive antifungal therapy could play a role in salvaging these patients.

Towards automated extraction of 2D standard fetal head planes from 3D ultrasound acquisitions: A clinical evaluation and quality assessment comparison.

INTRODUCTION: Clinical evaluation of deep learning (DL) tools is essential to compliment technical accuracy metrics. This study assessed the image quality of standard fetal head planes automatically-extracted from three-dimensional (3D) ultrasound fetal head volumes using a customised DL-algorithm. METHODS: Two observers retrospectively reviewed standard fetal head planes against pre-defined image quality criteria. Forty-eight images (29 transventricular, 19 transcerebellar) were selected from 91 transabdominal fetal scans (mean gestational age = 26 completed weeks, range = 20+5-32+3 weeks). Each had two-dimensional (2D) manually-acquired (2D-MA), 3D operator-selected (3D-OS) and 3D-DL automatically-acquired (3D-DL) images. The proportion of adequate images from each plane and modality, and the number of inadequate images per plane was compared for each method. Inter and intra-observer agreement of overall image quality was calculated. RESULTS: Sixty-seven percent of 3D-OS and 3D-DL transventricular planes were adequate quality. Forty-five percent of 3D-OS and 55% of 3D-DL transcerebellar planes were adequate. Seventy-one percent of 3D-OS and 86% of 3D-DL transventricular planes failed with poor visualisation of intra-cranial structures. Eighty-six percent of 3D-OS and 80% of 3D-DL transcerebellar planes failed due to inadequate visualisation of cerebellar hemispheres. Image quality was significantly different between 2D and 3D, however, no significant difference between 3D-modalities was demonstrated (p < 0.005). Inter-observer agreement of transventricular plane adequacy was moderate for both 3D-modalities, and weak for transcerebellar planes. CONCLUSION: The 3D-DL algorithm can automatically extract standard fetal head planes from 3D-head volumes of comparable quality to operator-selected planes. Image quality in 3D is inferior to corresponding 2D planes, likely due to limitations with 3D-technology and acquisition technique. IMPLICATIONS FOR PRACTICE: Automated image extraction of standard planes from US-volumes could facilitate use of 3DUS in clinical practice, however image quality is dependent on the volume acquisition technique.

The relationship between alertness and spatial attention under simulated shiftwork.

Higher and lower levels of alertness typically lead to a leftward and rightward bias in attention, respectively. This relationship between alertness and spatial attention potentially has major implications for health and safety. The current study examined alertness and spatial attention under simulated shiftworking conditions. Nineteen healthy right-handed participants (M = 24.6 ± 5.3 years, 11 males) completed a seven-day laboratory based simulated shiftwork study. Measures of alertness (Stanford Sleepiness Scale and Psychomotor Vigilance Task) and spatial attention (Landmark Task and Detection Task) were assessed across the protocol. Detection Task performance revealed slower reaction times and higher omissions of peripheral (compared to central) stimuli, with lowered alertness; suggesting narrowed visuospatial attention and a slight left-sided neglect. There were no associations between alertness and spatial bias on the Landmark Task. Our findings provide tentative evidence for a slight neglect of the left side and a narrowing of attention with lowered alertness. The possibility that one's ability to sufficiently react to information in the periphery and the left-side may be compromised under conditions of lowered alertness highlights the need for future research to better understand the relationship between spatial attention and alertness under shiftworking conditions.

Adiponectin in onset and progression of T2DM with cardiac dysfunction in rats.

Cardiovascular disease and type 2 diabetes mellitus (T2DM) patients have low level of adiponectin, however, till now the role of adiponectin in progression of 'T2DM with cardiac dysfunction' in animal model has not been characterized. Therefore, the aim of the present study was to develop and characterize T2DM animal model with cardiac dysfunction and to study the role of cardiac adiponectin expression in cardiac dysfunction. For this, Wistar rats (M/F) were fed a high-fat diet for different time periods: 3, 4 and 5 weeks and given a single, low-dose streptozotocin (25mg/kg), intraperitoneal injection 1 week prior to the experiments. Rats in T2DM group (3 weeks) developed hyperglycaemia, hyperlipidaemia, oxidative stress with normoinsulinaemia and mild cardiac dysfunction suggesting onset of T2DM with cardiac dysfunction. Extended high-fat feeding, that is, 4 and 5 weeks induced insulin resistance accompanied with cardiac hypertrophy, cardiac dysfunction and reduced baroreflex sensitivity indicating development of T2DM with cardiac dysfunction. Cardiac adiponectin expression did not change in rats of T2DM group (3 weeks), however, it significantly decreased in rats of two T2DM groups (4 and 5 weeks) along with increased intracellular adhesion molecule-1 levels. Thus, the present study for the first time indicates that in the present T2DM animal model, as T2DM progresses cardiac adiponectin expression also decreases which might be the precipitating factor for cardiac hypertrophy and decrease in baroreflex sensitivity, which induces cardiac dysfunction.

Salivary levels of alpha-amylase are associated with neurobehavioral alertness during extended wakefulness, but not simulated night-shift work.

Sleep loss is one of the most common causes of accidents and errors in operational environments. Currently, no single method satisfies all of the requisite criteria of an effective system for assessing the risk of injury prior to safety being compromised. Research has concentrated towards the development of a biomarker for individualized assessment of sleepiness-related deficits in neurobehavioral alertness, with salivary alpha-amylase (sAA) recently reported as a potential biomarker during acute total sleep deprivation. The present study extends on previous research by investigating the association between sAA and neurobehavioral alertness during simulated night-shift work, during individuals are required to work at night when biological processes are strongly promoting sleep and sleep during the day when endogenous processes are promoting wakefulness. In a laboratory-controlled environment, 10 healthy non-shift working males aged 24.7 ±â€¯5.3 years (mean ±â€¯SD) underwent four consecutive nights of simulated night-shift work. Between 17:30-04:30 h participants provided saliva samples and completed a 3 min psychomotor vigilance test (PVT-B), 40 min simulated driving task, and 3 min digit symbol substitution test (DSST). Higher sAA levels were associated with faster response speed on the PVT-B, reduced lane variability on the simulated driving task, and improved information processing speed on the DSST during the first night-shift. There were no associations between sAA levels and performance outcomes during subsequent night-shifts. Findings indicate that the usability of sAA to assess the risk of neurobehavioral deficits during shift-work operations is limited. However, the robust circadian rhythm exhibited by sAA during the protocol of circadian misalignment suggests that sAA could serve as a potential circadian marker.

Challenges in culture-negative cases of Madurella mycetomatis: A case report re-accentuating PCR as an essential diagnostic tool.

Identification of dematiaceous fungi responsible for black-grain mycetoma has remained cumbersome and time consuming for years leading to delayed diagnosis and thereby increased agony to patients. Moreover, difficult morphology of some of these fungi demanding enough expertise for species identification in addition to culture-negativity has often led to misdiagnosis and hence inapt treatment to the patients. We report the identification of Madurella mycetomatis from culture-negative black granules discharged from foot nodular lesions of a 27 years old male using PCR followed by sequencing of the internal transcribed spacer region. The patient's lesions were successfully treated using a combination of itraconazole (200mg) and terbinafine (250mg), confirming our diagnosis. Our case study proves the clinical value of PCR as the best, rapid and accurate diagnostic method for the identification of Madurella mycetomatis and related fungi, particularly in culture-negative cases.

Aberrant Pancreatic Tissue in a Mediastinal Enteric Duplication Cyst: A Rarity with Review of Literature.

Mediastinal enteric duplication cysts are a rare congenital malformation encountered mainly in neonates and infants. It is a distinct entity within the family of foregut duplication cysts. It can present with respiratory distress due to mass effect and hence surgical excision is the preferred treatment. Histologically, it is characterised by a double layered smooth muscle wall with intestinal lining epithelium. We report a case of mediastinal enteric duplication cyst with aberrant pancreatic tissue in a neonate due to its rarity and early presentation. A neonate presented with respiratory distress and a cystic mass in the right posterior mediastinum. The lesion was excised and on histopathological analysis the diagnosis of mediastinal enteric duplication cyst was made. Also, aberrant pancreatic tissue which has been reported rarely was noted in this case. We discuss this case and review similar cases reported in literature.

Structure of Leishmania donovani coronin coiled coil domain reveals an antiparallel 4 helix bundle with inherent asymmetry.

Coiled coils are ubiquitous structural motifs that serve as a platform for protein-protein interactions and play a central role in myriad physiological processes. Though the formation of a coiled coil requires only the presence of suitably spaced hydrophobic residues, sequence specificities have also been associated with specific oligomeric states. RhXXhE is one such sequence motif, associated with parallel trimers, found in coronins and other proteins. Coronin, present in all eukaryotes, is an actin-associated protein involved in regulating actin turnover. Most eukaryotic coronins possess the RhXXhE trimerization motif. However, a unique feature of parasitic kinetoplastid coronin is that the positions of R and E are swapped within their coiled coil domain, but were still expected to form trimers. To understand the role of swapped motif in oligomeric specificity, we determined the X-ray crystal structure of Leishmania donovani coronin coiled coil domain (LdCoroCC) at 2.2Å, which surprisingly, reveals an anti-parallel tetramer assembly. Small angle X-ray scattering studies and chemical crosslinking confirm the tetramer in solution and is consistent with the oligomerization observed in the full length protein. Structural analyses reveal that LdCoroCC possesses an inherent asymmetry, in that one of the helices of the bundle is axially shifted with respect to the other three. The analysis also identifies steric reasons that cause this asymmetry. The bundle adapts an extended a-d-e core packing, the e residue being polar (with an exception) which results in a thermostable bundle with polar and apolar interfaces, unlike the existing a-d-e core antiparallel homotetramers with apolar core. Functional implications of the anti-parallel association in kinetoplastids are discussed.

A hospital-based study on knowledge and attitude related to vitiligo among adults visiting a tertiary health facility of central India.

BACKGROUND: Vitiligo is one of the common stigmatizing dermatosis in the Indian society and the vitiligo patients have to face significant psychological hurt and social neglect. The severity of the stigma is related to the society's attitude and knowledge about it. AIMS AND OBJECTIVES: To document the prevalent knowledge and attitude in general public towards vitiligo patients, and to identify the determinants of good/poor knowledge and attitude. MATERIALS AND METHODS: A systematic random sampling technique was adopted to enroll 700 adult participants visiting an urban tertiary healthcare facility of central India. We developed a questionnaire to collect information on knowledge and attitude of the participants. A composite score was developed for good knowledge and attitude and performance of the participants was compared with the selected determinants. Data analysis was conducted by Stata software version 11. RESULTS: The overall knowledge score was good for 66.3% (95% confidence interval [CI]: 62.8%, 69.8%) of the participants. However, the score for attitude was comparatively poor i.e., only 16.9% (95% CI: 13.9%, 19.5%). None of the studied parameters could be significantly correlated with the knowledge score. Being married and being engaged in a health care related occupation were significant predictors of good attitude levels with P = 0.042 and 0.034 respectively, whereas female gender was the significant predictor for poor attitude with an odds ratio of 0.54 (95% CI: 0.33, 0.9) and P = 0.018. CONCLUSIONS: There were widespread myths prevalent about vitiligo in the studied population. The knowledge scores were better than attitude scores.

Polymorphisms in MIR137HG and microRNA-137-regulated genes influence gray matter structure in schizophrenia.

Evidence suggests that microRNA-137 (miR-137) is involved in the genetic basis of schizophrenia. Risk variants within the miR-137 host gene (MIR137HG) influence structural and functional brain-imaging measures, and miR-137 itself is predicted to regulate hundreds of genes. We evaluated the influence of a MIR137HG risk variant (rs1625579) in combination with variants in miR-137-regulated genes TCF4, PTGS2, MAPK1 and MAPK3 on gray matter concentration (GMC). These genes were selected based on our previous work assessing schizophrenia risk within possible miR-137-regulated gene sets using the same cohort of subjects. A genetic risk score (GRS) was determined based on genotypes of these four schizophrenia risk-associated genes in 221 Caucasian subjects (89 schizophrenia patients and 132 controls). The effects of the rs1625579 genotype with the GRS of miR-137-regulated genes in a three-way interaction with diagnosis on GMC patterns were assessed using a multivariate analysis. We found that schizophrenia subjects homozygous for the MIR137HG risk allele show significant decreases in occipital, parietal and temporal lobe GMC with increasing miR-137-regulated GRS, whereas those carrying the protective minor allele show significant increases in GMC with GRS. No correlations of GMC and GRS were found in control subjects. Variants within or upstream of genes regulated by miR-137 in combination with the MIR137HG risk variant may influence GMC in schizophrenia-related regions in patients. Given that the genes evaluated here are involved in protein kinase A signaling, dysregulation of this pathway through alterations in miR-137 biogenesis may underlie the gray matter loss seen in the disease.

Unconventional actins and actin-binding proteins in human protozoan parasites.

Actin and its regulatory proteins play a key role in several essential cellular processes such as cell movement, intracellular trafficking and cytokinesis in most eukaryotes. While these proteins are highly conserved in higher eukaryotes, a number of unicellular eukaryotic organisms contain divergent forms of these proteins which have highly unusual biochemical and structural properties. Here, we review the biochemical and structural properties of these unconventional actins and their core binding proteins which are present in commonly occurring human protozoan parasites.

Measurement of spatial and temporal behavior of H(α) emission from Aditya tokamak using a diagnostic based on a photomultiplier tube array.

A photo multiplier tube (PMT) array based spectroscopic diagnostic with fast time response of 10 µs and spatial resolution ∼3 cm has been developed and installed on Aditya tokamak to study the spatial and temporal behavior of Hα emissions from typical discharges. Collimated light has been collected from the plasma along 16 lines of sight passing through entire plasma poloidal cross section of Aditya and detected by two 8 channels PMT arrays after selecting Hα emission using interference filter. The studies are carried out during plasma formation phase of Aditya by changing vertical field and its delay with respect to loop voltage. It is observed that plasma initiated in the high field side in typical discharges of Aditya. The plasma formation position is matched with null field location estimated through simulation.

Subcutaneous mycoses caused by Rhytidhysteron species in an immunocompetent patient.

Subcutaneous mycoses are chronic fungal infections of the skin and subcutaneous tissues caused by variety of fungal agents and usually occur following trauma with vegetative matter. We report a case of subcutaneous mycoses caused by rare fungus belonging to the genus Rhytidhysteron, in an immunocompetent male who presented with a subcutaneous nodule on left foot. This unusual species was identified and confirmed by molecular methods.

DNA translocation through short nanofluidic channels under asymmetric pulsed electric field.

Investigation of single molecule DNA dynamics in confined environments has led to important applications in DNA analysis, separation, and sequencing. Here, we studied the electrophoretic transport of DNA molecules through nanochannels shorter than the DNA contour length and calculated the associated translocation time curves. We found that the longer T4 DNA molecules required a longer time to traverse a fixed length nanochannel than shorter λ DNA molecules and that the translocation time decreased with increasing electric field which agreed with theoretical predictions. We applied this knowledge to design an asymmetric electric pulse and demonstrate the different responses of λ and T4 DNA to the pulses. We used Brownian dynamics simulations to corroborate our experimental results on DNA translocation behaviour. This work contributes to the fundamental understanding of polymer transport through nanochannels and may help in designing better separation techniques in the future.

Depletion of cells and abundant proteins from biological samples by enhanced dielectrophoresis.

Platforms that are sensitive and specific enough to assay low-abundance protein biomarkers, in a high throughput multiplex format, within a complex biological fluid specimen, are necessary to enable protein biomarker based diagnostics for diseases such as cancer. The signal from an assay for a low-abundance protein biomarker in a biological fluid sample like blood is typically buried in a background that arises from the presence of blood cells and from high-abundance proteins that make up 90% of the assayed protein mass. We present an automated on-chip platform for the depletion of cells and highly abundant serum proteins in blood. Our platform consists of two components, the first of which is a microfluidic mixer that mixes beads containing antibodies against the highly abundant proteins in the whole blood. This complex mixture (consisting of beads, cells, and serum proteins) is then injected into the second component of our microfluidic platform, which comprises a filter trench to capture all the cells and the beads. The size-based trapping of the cells and beads into the filter trench is significantly enhanced by leveraging additional negative dielectrophoretic forces to push the micron sized particles (cells and beads which have captured the highly abundant proteins) down into the trench, allowing the serum proteins of lower abundance to flow through. In general, dielectrophoresis using bare electrodes is incapable of producing forces beyond the low piconewton range that tend to be insufficient for separation applications. However, by using electrodes passivated with atomic layer deposition, we demonstrate the application of enhanced negative DEP electrodes together with size-based flltration induced by the filter trench, to deplete 100% of the micron sized particles in the mixture.