Safety and efficacy of parsaclisib in combination with rituximab, bendamustine + rituximab, or ibrutinib in patients with previously treated B-cell lymphoma: analysis of a phase 1 dose-finding study (CITADEL­112).

Parsaclisib, a potent and highly selective phosphoinositide 3-kinase δ inhibitor, has shown clinical activity in relapsed/refractory (R/R) B-cell lymphoma. The phase 1 CITADEL-112 (NCT03424122) study assessed safety and efficacy of parsaclisib in combination with investigator choice standard of care (SOC; rituximab [Treatment A], rituximab plus bendamustine [Treatment B], or ibrutinib [Treatment C]) in 50 patients with R/R B-cell lymphoma. The most common treatment-emergent adverse events included neutropenia (62.5%, 50.0%, and 50.0% of patients in Treatments A, B, and C, respectively); diarrhea (37.5%) and anemia (31.3%) in Treatment A; abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Treatment B; and increased alanine and aspartate aminotransferase (each 37.5%) in Treatment C. Objective responses were observed in 13 patients (81.3%) in Treatment A, 10 (55.6%) in Treatment B, and 8 (50.0%) in Treatment C. Parsaclisib combined with SOC therapies had an expected safety profile and promising efficacy in patients with R/R B-cell lymphomas.

Acute intestinal obstruction secondary to ingested foreign body in an adult with autism spectrum disorder: A rare case report and review of literature.

Key Clinical Message: Foreign body ingestion is common in pediatric age group however can be found in any age group with intellectual disability and neurodevelopmental delay. There is usually a delay in presentation and interventions following foreign body ingestion in patients with neurodevelopmental delay, leading to increased morbidity, mortality, and complications owing to inability of such patients giving relevant history. Most ingested foreign bodies naturally pass through the digestive tract without untoward effects. Only a few patients may require surgical interventions. Principle of management should be to reduce anxiety among patients and their visitors. Speedy recovery is enhanced so that they can return to their familiar environment soon. Abstract: Foreign body ingestion is common in pediatric populations and may be found in any age group with intellectual disability and neurodevelopmental delay. As the patient cannot give a clear and relevant history, there is usually a delay in presentation and interventions following foreign body ingestion in patients with neurodevelopmental delay, leading to increased morbidity, mortality, and complications. Most foreign bodies pass through the digestive system without any complications, and very few require surgical intervention. The goal should be to reduce anxiety among patients and their visitors and to enhance speedy recovery so that they can return to their familiar environment soon. Here we report a case of Acute intestinal obstruction secondary to ingestion of the head portion of a doll which was managed with emergency laparotomy with enterotomy and removal of foreign body in a 16 years female with Autism Spectrum Disorder.

Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas.

The combination of the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single-agent therapy. This phase 1 study (NCT02914938) included a dose-finding stage in patients with relapsed/refractory (R/R) B-cell malignancies (n = 20) and disease-specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1-7 plus zanubrutinib 80 mg twice daily continuously in 28-day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3-4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression-free survival (PFS) were not reached in either group. The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.

Traumatic Abdominal wall hernia with ileal perforation following blunt trauma abdomen: A rare case report and review of literature.

Blunt trauma abdomen with abdominal wall herniation with bowel perforation is an acute emergency condition. Road traffic accidents causing blunt trauma are common in a youngster like in our case. Once the patient is resuscitated, ultrasonography and Computed tomography must be done. Early surgical exploration with mesh or primary repair of the defect is the mainstay of management. We have a case of a 25-year-old male with blunt trauma abdomen and anterior wall hernia following a road traffic accident who was managed with emergency exploratory laparotomy as computed tomography suggested anterior abdominal wall herniation of bowel content.

Malignant rectal GIST managed with chemotherapy (Imatinib Mesylate): A case report and a comprehensive review.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors involving the gastrointestinal tract, arising from the interstitial cells of Cajal. GIST comprises about 1% of all GI tumors. Rectal GISTs are rare and comprise of approximately 5% of all GISTs and only 0.1% of rectal tumors are found to be GISTs. Rectal GISTs may be diagnosed incidentally or present with symptoms, including defecation problems, bleeding, and/or pain. We report a case of a 46-year-old male with rectal GIST metastasized to the liver and bilateral lung parenchyma managed by Imatinib Mesylate (IM) regimen. Rectal GIST although being rare, must be considered as a differential diagnosis in a patient presenting with defecatory problems with bleeding.

Utilising anterolateral bladder flap to create a continent cutaneous diversion in a patient with pelvic fracture urethral injury.

A male child in the first decade of life presented to us with a history of a pelvic fracture and urethral injury resulting from a road traffic accident 4 months prior. He had previously undergone an exploratory laparotomy and suprapubic cystostomy at another medical centre. He was circumcised and exhibited a substantial urethral defect on the retrograde urethrogram, as well as on the micturating cystourethrogram. Following a careful assessment of the patient's and caregivers' expectations, a continent cutaneous catheterisable channel was planned. This procedure involved the use of an anterolateral bladder flap, and continence was achieved through the creation of a Nissen-type seromuscular invagination. Three months postoperatively, the child remains continent, can easily catheterise the stoma and has resumed his education.

Probing the Formation of Dark Interlayer Excitons via Ultrafast Photocurrent.

Optically dark excitons determine a wide range of properties of photoexcited semiconductors yet are hard to access via conventional time-resolved spectroscopies. Here, we develop a time-resolved ultrafast photocurrent technique (trPC) to probe the formation dynamics of optically dark excitons. The nonlinear nature of the trPC makes it particularly sensitive to the formation of excitons occurring at the femtosecond time scale after the excitation. As a proof of principle, we extract the interlayer exciton formation time of 0.4 ps at 160 µJ/cm2 fluence in a MoS2/MoSe2 heterostructure and show that this time decreases with fluence. In addition, our approach provides access to the dynamics of carriers and their interlayer transport. Overall, our work establishes trPC as a technique to study dark excitons in various systems that are hard to probe by other approaches.

Household and plot-level survey data on adoption, outcomes, and perceptions of early sown wheat and zero tillage in Northwest India.

This study collected evidence on the use of early sown wheat varieties and complementary zero tillage technologies in Northwest India. Detailed information on farmers' knowledge, adoption decisions, personal experience, and perceptions of early sown wheat and zero tillage technologies were collected at the household level using different survey tools. Additional information on agricultural practices during the Rabi Season 2021/22 were collected at the plot level and geocoded. Overall, the dataset comprises responses from 1206 wheat farmers in 70 villages across 7 districts in Punjab and Haryana that were collected between September and October 2022. The villages were selected using stratified random sampling based on a sampling frame of 1722 communities that had been identified as predominantly wheat growing areas based on remote-sensing data from satellite images. The dataset provides rich information that may be used for assessing the diffusion and impact of recently developed wheat varieties designed for early sowing, identifying barriers to the wider adoption of these technologies, and informing policy making aimed at improving adoption and usage decisions of agricultural innovations.

Cough syrup bottle at rectum in elderly male: a rare case report.

Foreign body in the anal canal may be inserted for sexual gratification or sexual assault or accidental or drug trafficking. We report a case of a male who accidentally inserted a cough syrup bottle in his rectum. Presentation is usually late due to fear and embarrassment. The manual attempt of removal may be tried under adequate anesthesia. Post-procedure sigmoidoscopy or colonoscopy may be helpful to diagnose laceration or mucosal injury.

Smartphone-based point-of-care anemia screening in rural Bihar in India.

BACKGROUND: The high prevalence of anemia in resource-constrained settings calls for easy-to-use, inexpensive screening tools. The Sanguina Smartphone App, an innovative tool for non-invasive hemoglobin estimation via color-sensitive, algorithm-based analysis of fingernail bed images, was validated in the United States. This study evaluates the performance of the App in a population with different socio-economic, ethnic, demographic and cultural composition in rural Bihar, India. METHODS: For 272 mainly adult patients of a private health centre, hemoglobin measurement with the App is compared with the gold standard laboratory blood analysis. For a second sample of 179 children attending pre-schools, hemoglobin measurement with the App is compared to the results of the HemoCue Hb 301, a point-of-care device using a small blood sample, serving as the reference standard for field-based settings. RESULTS: The App reaches ±4.43 g/dl accuracy and 0.38 g/dl bias of comparator values in the clinic-based sample, and ±3.54 g/dl and 1.30 g/dl, respectively in the pre-school sample. After retraining the algorithm with the collected data, the validity of the upgraded version is retested showing an improved performance (accuracy of ±2.25 g/dl, bias of 0.25 g/dl), corresponding to the results of the original validation study from the United States. CONCLUSIONS: The initial version of the App does not achieve the accuracy needed for diagnosis or screening. After retraining the algorithm, it achieves an accuracy sufficient for screening. The improved version with the potential for further adaptions is a promising easy-to-use, inexpensive screening tool for anemia in resource-constrained point-of-care settings.

Hemoglobin is a protein in the blood that is required to move oxygen around the body. Anemia is a condition that occurs when levels of hemoglobin are too low. Anemia can lead to serious problems with the heart and lungs. This study assesses the accuracy of using a Smartphone App to measure hemoglobin levels by taking photos of a person's nails in rural Bihar, India. Results from the App are compared with those obtained by measuring hemoglobin in blood samples. Initially, measurements of hemoglobin obtained using the App were inaccurate, however when the App was modified using data from some of the people in India, the App was more accurate. This study shows that the App can and should be adapted for use in different populations and can enable anemia to be diagnosed outside of hospitals and other healthcare settings.

Peripheral T-Cell Lymphoma in a Patient Previously Diagnosed With Sarcoidosis.

Sarcoidosis is a multisystem disorder characterized by granulomatous inflammation on histopathological evaluation. Diagnosis of sarcoidosis requires thorough elimination of malignancy and alternative causes of noncaseating granulomatous inflammation. Sarcoidosis and several subtypes of lymphoma have similar clinical presentations and can potentially have similar histopathological findings. Patients with a histopathology-confirmed diagnosis of sarcoidosis are at higher risk of developing malignancies. In this report, we present a case of a 64-year-old male diagnosed with sarcoidosis 2 years before presenting to the emergency department with a 4-month history of generalized weakness, cough, and very high fever. After a thorough workup involving cervical lymph node biopsy and bone marrow biopsy, he was diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Due to the patient's current lymphoma diagnosis and features noted on pathology, a retrospective review of the prior biopsy specimen was performed, finding similar hematopathological features on both initial lymph node biopsy diagnosing sarcoidosis and current biopsies diagnosing lymphoma. Given these findings, our patient likely had early manifestation of PTCL misdiagnosed as sarcoidosis. In summary, lymphoma should be considered in all patients with suspected sarcoidosis, especially those who do not respond to treatment or who present with persistent hematological abnormalities.

Strain control of hybridization between dark and localized excitons in a 2D semiconductor.

Mechanical strain is a powerful tuning knob for excitons, Coulomb-bound electron-hole complexes dominating optical properties of two-dimensional semiconductors. While the strain response of bright free excitons is broadly understood, the behaviour of dark free excitons (long-lived excitations that generally do not couple to light due to spin and momentum conservation) or localized excitons related to defects remains mostly unexplored. Here, we study the strain behaviour of these fragile many-body states on pristine suspended WSe2 kept at cryogenic temperatures. We find that under the application of strain, dark and localized excitons in monolayer WSe2-a prototypical 2D semiconductor-are brought into energetic resonance, forming a new hybrid state that inherits the properties of the constituent species. The characteristics of the hybridized state, including an order-of-magnitude enhanced light/matter coupling, avoided-crossing energy shifts, and strain tunability of many-body interactions, are all supported by first-principles calculations. The hybridized excitons reported here may play a critical role in the operation of single quantum emitters based on WSe2. Furthermore, the techniques we developed may be used to fingerprint unidentified excitonic states.

Arylcoumarin perturbs SARS-CoV-2 pathogenesis by targeting the S-protein/ACE2 interaction.

The vaccination drive against COVID-19 worldwide was quite successful. However, the second wave of infections was even more disastrous. There was a rapid increase in reinfections and human deaths due to the appearance of new SARS-CoV-2 variants. The viral genome mutations in the variants were acquired while passing through different human hosts that could escape antibodies in convalescent or vaccinated individuals. The treatment was based on oxygen supplements and supportive protocols due to the lack of a specific drug. In this study, we identified three lead inhibitors of arylated coumarin derivatives 4,6,8-tri(naphthalen-2-yl)-2H-chromen-2-one (NF1), 8-(4-hydroxyphenyl)-4,6-di(naphthalen-2-yl)-2H-chromen-2-one (NF12) and 8-(4-hydroxyphenyl)-3,6-di(naphthalen-2-yl)-2H-chromen-2-one (NF-13) that showed higher binding affinity towards the junction of SARS-CoV-2 spike glycoprotein (S-protein) and human angiotensin-converting enzyme 2 (ACE2) receptor. Using molecular docking analysis, we identified the putative binding sites of these potent inhibitors. Notably, molecular dynamics (MD) simulation and MM-PBSA studies confirmed that these inhibitors have the potential ability to bind Spike-protein/ACE2 protein complex with minimal energy. Further, the two major concerns are an adaptive mutation of spike proteins- N501Y and D614G which displayed strong affinity towards NF-13 in docking analysis. Additionally, in vitro and in vivo studies are required to confirm the above findings and develop the inhibitors as potential drugs against SARS-CoV-2.

Outcomes of laparoscopic repair in complicated groin hernia: A single institutional based cohort study in Nepal.

Introduction: Laparoscopic hernia repairs have comparable recurrence rate with less persisting pain and numbness and quicker return to usual activities as compared to open mesh repair. The excellent outcomes of minimally invasive surgery encourage us to extend the laparoscopic technique to complicated groin hernia. Method: A total of 22 patients with complicated groin hernia who presented to our institute from September 2017 to September 2018 were included in this prospective cohort study. Inclusion criteria were patients with age greater than 18 years and clinically diagnosed as complicated groin hernia. Patients with peritonitis, those with previous abdominal surgery and unfit for general anesthesia were excluded from our study. Results: The most common age group was 51-60 (31.8%) years.17 cases were repaired with totally laparoscopic approach (12 TEP, 5 TAPP). Laparoscopic repair with additional procedure was needed in 3 cases and 2 cases were converted to open for completion of the procedure. The mean operating time was 154.8 ± 51.6 (range: 90 to 230) minutes. The average length of hospital stay was 3.8 ± 3 (range: 1 to 12) days. Bleeding from the inferior epigastric and testicular vessels were the major intra-operative complication (11.8%). Seroma and surgical site infection were seen in 2 (11.8%) patients. Conclusion: Laparoscopic approach in cases of complicated groin hernia can achieve desirable patient outcomes without major complications, provided good patient selection and expertise. The evidence for laparoscopic repair as the choice of procedure in complicated groin hernia can be established from further comparative studies.

Correlation between placental histopathology and perinatal outcome in COVID-19.

Objectives: An alarming rate of adverse perinatal outcomes as well as maternal deaths has been reported worldwide during this pandemic. It would be prudent to start thinking on the lines of acute or chronic intrauterine fetal hypoxia due to placental microvascular pathology or villitis caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Autopsy studies of deceased patients with severe COVID-19 have revealed the presence of diffuse pulmonary alveolar damage, thrombosis, and microvascular injuries. It is expected that similar pathological features such as microvascular injuries could be found in the placenta of infected pregnant women. Materials and Methods: Placentas of singleton pregnancies from 42 SARS-CoV-2 positive mothers delivered at term were submitted for histopathological examination. Those with multifetal gestation, hypertensive disorder, fetal growth restriction, structural or chromosomal anomalies in the fetus, thrombophilia, prolonged prelabor rupture of membranes, and placenta accreta spectrum were excluded from the study. Histopathological examination was done by two pathologists independently and only those results concurred by both were reported. Histopathological features and corresponding neonatal outcome were analyzed. Results: Reports of 42 placentas from patients with SARS-CoV-2, delivered at term (37-40 weeks) were analyzed in our study. Features of maternal vascular malperfusions (MVM) were present in 45% (n = 19) cases. Features of fetal vascular malperfusions (FVM) were present in 23.8% (n = 10) cases. There were 47.6% (n = 20) cases showing at least one feature of acute inflammatory pathology (AIP) and 42.8% (n = 18) showing features of chronic inflammatory pathology (CIP). Neonatal respiratory distress syndrome was found in 19% (n = 8) of the neonates. Correspondingly, nearly all placentas (n = 7) of these neonates showed features of MVM, FVM, AIP and CIP. There was no maternal or neonatal mortality in our study group. Conclusion: The main findings of our study include maternal as well as fetal vascular malperfusions and placental inflammatory pathology. These findings provide an outline for better understanding of etiological factors and pathogenesis of adverse perinatal outcomes in SARS-CoV-2 infection.

Clinico-pathological characteristics of obstructing colorectal cancer and its management outcomes at a tertiary referral center of Eastern Nepal.

BACKGROUND: The aim of this study is to explore the treatment strategies being followed for patients with obstructing colorectal cancer (OCRC) at our institute and to know the management outcomes. METHODS: This study included 28 patients who were diagnosed with obstructing colorectal cancer (OCRC) either preoperatively or intraoperatively over a period of 5 years. RESULTS: Most were in the younger age group with mean age of 49.78 ± 15.96 years with 1/4th of the patients being younger than 40. There was no difference in incidence of OCRC among genders. It was found to be common in rural areas of the eastern Nepal, 16(57%) patients from such areas. 21.4% patients had complete bowel obstruction at presentation. The investigating modalities used were abdominal X-ray, ultrasonoghraphy of abdomen/pelvis, abdominal CT-scan, colonoscopy, serum CEA, punch biopsy and Faecal occult blood test. The anatomical shift to the right was observed with 54% lesions in the proximal colon. Majority were in advanced stage (stage 3:53.6%, stage 4:32.1%) with histologically adenocarcinoma (100%) and a higher incidence of synchronous lesion (28.6%). Patients averaged 13.82 days in the hospital with post-operative mortality rate of 3.6%. The 1-year and 2-years disease free survivals were 89.3% and 82.1% while overall survivals were 92.8% and 82.1% respectively. CONCLUSION: In developing countries like ours, relatively younger patients present to health center with obstructive colorectal cancer with anatomical shift to the right sided lesions. The treatments provided at our center and their outcomes are not inferior to that of the developed world.

Machine learning approaches and their applications in drug discovery and design.

This review is focused on several machine learning approaches used in chemoinformatics. Machine learning approaches provide tools and algorithms to improve drug discovery. Many physicochemical properties of drugs like toxicity, absorption, drug-drug interaction, carcinogenesis, and distribution have been effectively modeled by QSAR techniques. Machine learning is a subset of artificial intelligence, and this technique has shown tremendous potential in the field of drug discovery. Techniques discussed in this review are capable of modeling non-linear datasets, as well as big data of increasing depth and complexity. Various machine learning-based approaches are being used for drug target prediction, modeling the structure of drug target, binding site prediction, ligand-based similarity searching, de novo designing of ligands with desired properties, developing scoring functions for molecular docking, building QSAR model for biological activity prediction, and prediction of pharmacokinetic and pharmacodynamic properties of ligands. In recent years, these predictive tools and models have achieved good accuracy. By the use of more related input data, relevant parameters, and appropriate algorithms, the accuracy of these predictions can be further improved.

In silico identification and validation of triarylchromones as potential inhibitor against main protease of severe acute respiratory syndrome coronavirus 2.

The ongoing pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused COVID-19 has emerged as a severe threat to the life of human kind. The identification and designing of appropriate and reliable drug molecule for the treatment of COVID-19 patients is the pressing need of the present time. Among different drug targets, the main protease of SARS-CoV-2 is being considered as most effective target. In addition to the drug repurposing, different compounds of natural as well as synthetic origins are being investigated for their efficacy against different drug targets of SARS-CoV-2 virus. In that context, the chromone based natural flavonols have also exhibited significant antiviral properties against different targets of SARS-CoV-2. The in silico studies presented here discloses the efficacy of triarylchromones (TAC) as potential inhibitor against main protease of SARS-CoV-2. The molecular docking and ADMET study performed using 14 arylchromones which could easily be accessed through simple synthetic protocols, revealed best binding affinities in case of TAC-3 (-11.2 kcal/mol), TAC-4 (-10.5 kcal/mol), TAC-6 (-11.2 kcal/mol), TAC-7 (-10.0 kcal/mol). Additional validation studies including molecular dynamics simulation and binding energy calculation using MMGBSA for protein ligand complex for 100 ns revealed the best binding interaction of TAC-3, TAC-4, TAC-6, TAC-7 against main protease of SARS-CoV-2. Moreover, the in vitro and preclinical validation of identified compounds will help us to understand the molecular mechanisms of regulation of TACs against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Non-malignant gall bladder perforation: Our experience from an institution-based retrospective analysis of 25 cases.

Gallbladder perforation still continues to perplex surgeons; 25 such patients diagnosed either pre- or intra-operatively and managed at our institute over the last 10 years period were analysed. Only eight were diagnosed pre-operatively, while a large majority (17) had a wrong initial working diagnosis. Symptoms and signs were variable. No blood investigation was specific. A computed tomography scan was generally better than ultrasound in detecting the perforation. All our cases were managed operatively with no mortality and a mean duration of hospital stay of 6.8 days. Most perforations were extra-hepatic (84%) and those of Niemeier's type I (52.2%). Because of its varied clinical presentation, gallbladder perforation is often an intra-operative diagnosis, but early intervention carries a good outcome.

Spin/Valley Coupled Dynamics of Electrons and Holes at the MoS2-MoSe2 Interface.

The coupled spin and valley degrees of freedom in transition metal dichalcogenides (TMDs) are considered a promising platform for information processing. Here, we use a TMD heterostructure MoS2-MoSe2 to study optical pumping of spin/valley polarized carriers across the interface and to elucidate the mechanisms governing their subsequent relaxation. By applying time-resolved Kerr and reflectivity spectroscopies, we find that the photoexcited carriers conserve their spin for both tunneling directions across the interface. Following this, we measure dramatically different spin/valley depolarization rates for electrons and holes, ∼30 and <1 ns-1, respectively, and show that this difference relates to the disparity in the spin-orbit splitting in conduction and valence bands of TMDs. Our work provides insights into the spin/valley dynamics of photoexcited carriers unaffected by complex excitonic processes and establishes TMD heterostructures as generators of spin currents in spin/valleytronic devices.