Another Notch in the Belt of Rheumatoid Arthritis.

Notch ligands and receptors, including JAG1/2, DLL1/4, and Notch1/3, are enriched on macrophages (MΦs), fibroblast-like synoviocytes (FLS), and/or endothelial cells in rheumatoid arthritis (RA) compared with normal synovial tissues (ST). Power Doppler ultrasound-guided ST studies reveal that the Notch family is highly involved in early active RA, especially during neovascularization. In contrast, the Notch family is not implicated during the erosive stage, evidenced by their lack of correlation with radiographic damage in RA ST. Toll-like receptors and tumor necrosis factor (TNF) are the common inducers of Notch expression in RA MΦs, FLS, and endothelial cells. Among Notch ligands, JAG1 and/or DLL4 are most inducible by inflammatory responses in RA MΦs or endothelial cells and transactivate their receptors on RA FLS. TNF plays a central role on Notch ligands, as anti-TNF good responders display JAG1/2 and DLL1/4 transcriptional downregulation in RA ST myeloid cells. In in vitro studies, TNF increases Notch3 expression in MΦs, which is further amplified by RA FLS addition. Specific disease-modifying antirheumatic drugs reduced JAG1 and Notch3 expression in MΦ and RA FLS cocultures. Organoids containing FLS and endothelial cells have increased expression of JAG1 and Notch3. Nonetheless, Methotrexate, interleukin-6 receptor (IL-6R) antibodies, and B cell blockers are mostly ineffective at decreasing Notch family expression. NF-κB, MAPK, and AKT pathways are involved in Notch signaling, whereas JAK/STATs are not. Although Notch blockade has been effective in RA preclinical studies, its small molecule inhibitors have failed in phase I and II studies, suggesting that alternative strategies may be required to intercept their function.

Centrifugal technique of plasma exchange and low-dose steroid to treat very severe alcoholic hepatitis patients: A retrospective analysis.

BACKGROUND: Low-volume plasma exchange (PLEX) and low-dose steroid improve survival in severe alcoholic hepatitis. We aimed to compare one-year survival of very severe alcoholic hepatitis (VSAH) patients treated with centrifugal PLEX (cPLEX), membrane PLEX (mPLEX) or standard medical treatment (SMT). METHODS: We retrospectively analyzed survival in consecutive VSAH patients treated at our department from November 2017 to September 2021. PLEX patients received low-volume PLEX along with low-dose steroid (tab. prednisolone 10 mg or 20 mg daily). To adjust for baseline differences between the three treatment (cPLEX, mPLEX or SMT) groups, propensity score (PS) matching was done. Acute-on-chronic liver failure (ACLF) was defined as per European Association for the Study of the Liver (EASL). The primary study outcome was one-year transplant-free survival of PS-matched VSAH patients treated with cPLEX compared to SMT. RESULTS: Of 101 PLEX-eligible VSAH patients, 30 patients were treated with cPLEX, 21 with mPLEX and 50 with SMT. On comparing 30 PS-matched patients each in the cPLEX group vs. the SMT group, transplant-free survival in the cPLEX group was 86.7% at one month, 70% at three months and 52.4% at one year and in the SMT group was 33.3% at one month, 23.3% at three months and 16.7% at one year with hazard ratio (HR [95% CI]) in favor of the cPLEX group (0.29 [0.15-0.56], p < 0.001). Total 21 patients each (PS-matched) in cPLEX and mPLEX groups were compared and one-year survival was better with cPLEX (0.33 [0.16-0.69], p = 0.001). The sub-group analysis of VSAH (PS-matched cohort) patients with ACLF also showed better survival with cPLEX compared to SMT (0.38 [0.17-0.83], p = 0.003) and compared to mPLEX (0.43 [0.17-0.95], p = 0.03). CONCLUSION: Better one-year transplant-free survival was noted among PS-matched VSAH patients treated with cPLEX (and low-dose steroid) compared to SMT (without steroid).

Midperipheral mini-capsulorhexis as an additional step for safe phacoemulsification in white intumescent cataracts.

The present article describes a novel surgical technique of a primary mini-capsulorhexis in midperiphery to minimize surgical complications in white intumescent cataracts. Patients with white mature cataracts with a convex anterior capsule or swollen lens fibers were selected. An initial puncture was made 3-4 mm away from the center, in the midperipheral anterior capsule, with a conventional cystitome. A mini-capsulorhexis (2-2.5 mm) was created. Loose cortical matter and fluidic contents were aspirated to reduce the intralenticular pressure. Two cuts were made at the margin of the mini-capsulorhexis, and an adequately sized secondary rhexis was completed, after which phacoemulsification was done. A circular curvilinear capsulorhexis was successfully achieved in all cases, including those with a small pupil. Rhexis could be completed in a patient where an initial extension occurred due to head movement. This refined technique aims to enhance the safety and precision of capsulorhexis in intumescent cataracts, thereby reducing the risk of complications such as the Argentinian flag sign. Further exploration and validation of this approach through clinical trials are warranted to establish its efficacy and safety profile.

Irrigation strengthens climate resilience: Long-term evidence from Mali using satellites and surveys.

Agriculture in the Sahel and much of sub-Saharan Africa remains to a large extent rainfed. At the same time, climate change is already causing less predictable rainfall patterns in the region, even as rising temperatures increase the amount of water needed for agricultural production. We assess to what extent irrigation can strengthen the climate resilience of farming communities. Our study sample consists of nearly 1,000 distinct locations in Mali in which small-scale, river-based irrigation was introduced over the past two decades, as weather conditions worsened and political upheaval erupted. Using the staggered roll-out of the irrigation and repeated observations over 20 years allows us to compare the pre- and postirrigation outcomes of locations while adjusting for confounding factors. We geospatially link data on irrigation interventions with agricultural conditions measured using satellite imagery and surveys, as well as child nutrition and health outcomes and conflict event data. Using a two-way fixed effects model to quasi-experimentally estimate counterfactual outcomes, we find that the introduction of irrigation led to substantial increases in agricultural production on supported fields, with these gains persisting even a decade later. Children in nearby communities are less likely to be stunted or wasted due to the irrigation, and conflict risks decrease in the closest communities. Some of these gains are offset by worsening conditions farther away from the newly installed irrigation. These findings suggest that, even with political conflicts in semi-arid areas already increasing, sustainable irrigation may offer a valuable tool to improve communities' long-term well-being and social cohesion.

High Mortality With Non-O1/Non-O139 Vibrio cholera Bacteraemia in Patients With Cirrhosis.

Background: Data on non-O1/non-O139 Vibrio cholera (NOVC) infection in liver disease is limited. We studied the clinical features and outcome of patients with cirrhosis with non-NOVC bacteraemia and/or spontaneous bacterial peritonitis (SBP) when compared to non-extended spectrum beta lactamase (non-ESBL) Escherichia coli (E. coli). Methods: Hospital information system of patients with cirrhosis admitted with bacteraemia and/or SBP from 2010 to 2020 was searched to include patients with NOVC infection. Non-ESBL E. coli bacteraemia/bacterascites were chosen as a comparator group, matched for the date of admission within 5 days of index case. Propensity score matching (PSM) was done for patient's age and Child score to compare outcome at discharge between NOVC-infected and E. coli-infected cirrhotic patients. Results: There were 2545 patients admitted with bacteraemia and/or SBP during the study period; 29 had NOVC isolated (M:F = 23:6; age: 39, 18-54 years; median, range; model for end-stage liver disease [MELD] score: 25, 12-38; Child score: 11, 10-12.5) from either blood (26), ascites (3), or both (8). Of these, 26 isolates were pan-sensitive to antibiotic sensitivity tests. Fifty-three patients with non-ESBL E. coli were isolated (M: F = 43:10; age: 48; 18-69 years; MELD score: 25, 20-32; Child score:12,11-13) from blood (31), ascites (17), or both (5) within the selected time frame. Of these, 48 isolates were sensitive to the empirical antibiotics initiated.After PSM, in comparison with 29 non-ESBL E. coli patients (age: 41, 18-55 years; MELD score: 24, 19-31; Child score: 12, 11-13), NOVC patients had higher incidence of circulatory failure at admission (14 [49 %] vs 4 [13 %]; P: 0.01) and significantly higher in-hospital mortality (15 [52 %] vs 6 [20 %];P: 0.028]. Conclusions: Bacteraemia due to non-O1/non-O139 strains of V. cholera, is an uncommon cause of bacteraemia or bacterascites in patients with cirrhosis and is associated with high incidence of circulatory failure and significant mortality.

Single-Centre Experience With Low-Volume Plasma Exchange and Low-Dose Steroid to Treat Patients With Idiosyncratic Drug-Induced Acute Liver Failure.

Background: Idiosyncratic drug-induced liver injury (iDILI) causing acute liver failure (ALF) carries high short-term mortality and patients who meet King's College criteria for liver transplantation have 1-month survival of 34% without liver transplantation (PMID: 20949552). We present our experience with low-volume plasma exchange (PLEX-LV, 50% of estimated plasma volume exchanged per session) and low-dose steroid to treat iDILI ALF. Methods: We retrospectively analysed data of patients with iDILI (diagnosed as per RUCAM score), treated with PLEX-LV and low-dose steroid (prednisolone: 10 mg OD, with rapid taper) in our department from 2016 to 2022. Baseline and dynamic parameters (post-PLEX) were assessed as predictors of 1-month liver transplantation-free survival. Results: Twenty-two iDILI patients [probable: possible iDILI: 20:2, males: 9, age: 30 (14-84) years, median (range); MELD score: 30.5 (19-43)] underwent PLEX-LV for ALF during the study period. Causative agents were complementary and alternative medications (36%), antiepileptics (18%) antimicrobials (14%), antitubercular drugs (14%), antifungal drugs (9%) and others (9%). All patients had jaundice and encephalopathy; 9 patients also had ascites. None of the patients underwent liver transplantation. Study patients underwent 3 (1-7) PLEX sessions and 1.4 (0.6-1.6) litres of plasma was exchanged per session. One-month transplant-free survival was 59% (13/22) in the study population and 63% (12/19) among patients who fulfilled Kings College criteria for liver transplantation. Reduction of ≥25% in plasma von Willebrand factor (VWF) levels after PLEX-LV predicted improved survival (HR: 0.09, 95% CI: 0.01-0.65; AUROC: 0.81; 95% CI: 0.6-1.0). Conclusion: Low-volume PLEX and low-dose steroid appears a promising treatment option in patients with iDILI-induced ALF not opting for liver transplantation. Dynamic changes in VWF level after PLEX predict 1-month survival in these patients.

Dissection of QTLs conferring drought tolerance in B. carinata derived B. juncea introgression lines.

BACKGROUND: Drought is one of the important abiotic stresses that can significantly reduce crop yields. In India, about 24% of Brassica juncea (Indian mustard) cultivation is taken up under rainfed conditions, leading to low yields due to moisture deficit stress. Hence, there is an urgent need to improve the productivity of mustard under drought conditions. In the present study, a set of 87 B. carinata-derived B. juncea introgression lines (ILs) was developed with the goal of creating drought-tolerant genotypes. METHOD: The experiment followed the augmented randomized complete block design with four blocks and three checks. ILs were evaluated for seed yield and its contributing traits under both rainfed and irrigated conditions in three different environments created by manipulating locations and years. To identify novel genes and alleles imparting drought tolerance, Quantitative Trait Loci (QTL) analysis was carried out. Genotyping-by-Sequencing (GBS) approach was used to construct the linkage map. RESULTS: The linkage map consisted of 5,165 SNP markers distributed across 18 chromosomes and spanning a distance of 1,671.87 cM. On average, there was a 3.09 cM gap between adjoining markers. A total of 29 additive QTLs were identified for drought tolerance; among these, 17 (58.6% of total QTLs detected) were contributed by B. carinata (BC 4), suggesting a greater contribution of B. carinata towards improving drought tolerance in the ILs. Out of 17 QTLs, 11 (64.7%) were located on the B genome, indicating more introgression segments on the B genome of B. juncea. Eight QTL hotspots, containing two or more QTLs, governing seed yield contributing traits, water use efficiency, and drought tolerance under moisture deficit stress conditions were identified. Seventeen candidate genes related to biotic and abiotic stresses, viz., SOS2, SOS2 like, NPR1, FAE1-KCS, HOT5, DNAJA1, NIA1, BRI1, RF21, ycf2, WRKY33, PAL, SAMS2, orf147, MAPK3, WRR1 and SUS, were reported in the genomic regions of identified QTLs. CONCLUSIONS: The significance of B. carinata in improving drought tolerance and WUE by introducing genomic segments in Indian mustard is well demonstrated. The findings also provide valuable insights into the genetic basis of drought tolerance in mustard and pave the way for the development of drought-tolerant varieties.

Etiopathology, Clinical and Imaging Characteristics of Border Zone Strokes.

Introduction: A border zone infarct (BI) is defined as an infarction that is localized to watersheds or border zones in the brain. BI is further classified into cortical border zone infarct (CBZ) and internal border zone infarct (IBZ). This study was conducted to explore the clinical and radiological characteristics of BI. Materials and Method: The study was conducted on eligible 400 acute ischemic stroke patients out of which 52 BI patients (diagnosed by the radiologist on DWI MRI images), patients >18 yrs of age were selected and divided into two groups of IBZ and CBZ infarct patients. The degree of intracranial and extracranial stenosis and characteristics on clinical presentation were assessed. The data were collected and analyzed using SPSS version 20.0 software at significance level p-value <0.05. Results: 25% and 75% of CBZ and IBZ patients, respectively, had history of presyncope or syncope before stroke. On vascular evaluation, 3.9% and 51.9% were in MCA and ICA stenosis group, respectively. Evidence of cardio embolism was found in 17.3% of patients. 53.3% of CBZ and 53.8% of IBZ patients were in ICA stenosis group, and 6.7% of CBZ and 7.7% of IBZ patients were in MCA stenosis group, with a statistically insignificant relation (p-value >0.05). Conclusion: Association of BI with events causing hypotension or hypovolemia is well-established in our study, association of BI with large vessel atherosclerosis is common, and its contribution to CBZ and IBZ seems to be equal.

Glauco-Claw: A novice implant for chronic angle-closure glaucoma.

This article describes 1-year outcomes of a new intra-ocular implant, "Glauco-Claw," in refractory chronic angle-closure glaucoma (ACG). Glauco-Claw is a novice polymethylmethacrylate implant with a central ring and five claws placed circumferentially. It was placed in the anterior chamber and the peripheral iris was tucked into the claws, thus causing goniosynechialysis and preventing the reformation of goniosynechiae. It was implanted in five eyes of five patients, and they were followed up for 1 year. Target intra-ocular pressure was achieved and maintained in all the patients till the last follow-up. Two patients did not require any anti-glaucoma medication. No significant complications were observed in any patient. Glauco-Claw could be another armamentarium in the management of refractory chronic ACG.

Profiling endogenous, environmental, and infectious disease mutational signatures in blastic plasmacytoid dendritic cell neoplasms.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic disease derived from plasmacytoid dendritic lineage cells. The disease typically shows skin as well as frequent bone marrow and peripheral blood involvement. However, the pathogenesis of this disease is still not well understood. While somatic point mutations and genetic rearrangements have been described in BPDCN, the types and origins of these mutations and relationships to other cancer types is not well understood. MATERIALS AND METHODS: To probe the origins of BPDCN, we analyzed the exome sequence data of 9 tumor-normal pair cases of BPDCN. We utilized SignatureAnalyzer, SigProfiler and a custom microbial analysis pipeline to understand the relevance of endogenous and environmental mutagenic processes. RESULTS: Our results identified a significant tobacco exposure and aging genetic signature as well as signatures related to nucleotide excision repair deficiency, ultra violet (UV) exposure, and endogenous deamination in BPDCN. We also assessed the samples for microbial infectious disease organisms but did not find a link to a microbial etiology. CONCLUSION: The identification of a tobacco exposure and aging genetic signature in patients with BPDCN suggests that environmental and endogenous genetic changes may be central to the oncogenesis of BPDCN.

Copy Number Loss at Chromosome 14q11.2 Correlates With the Proportion of T Cells in Biopsies and Helps Identify T-Cell Neoplasms.

CONTEXT.­: Evidence of T-cell clonality is often critical in supporting the diagnosis of a T-cell lymphoma. OBJECTIVES.­: To retrospectively explore the significance of copy number losses at the 14q11.2 T-cell receptor α locus in relation to the presence of a T-cell neoplasm and proportion of T cells by targeted next-generation sequencing. DESIGN.­: Targeted next-generation sequencing data from 139 tissue biopsies, including T-cell lymphomas, B-cell lymphomas, classic Hodgkin lymphomas, nonhematopoietic malignancies, and normal samples, were reviewed for copy number losses involving the T-cell receptor α gene segments at chr14q11.2. RESULTS.­: We found that biallelic or homozygous deletion of 14q11.2 was found in most (28 of 33, 84.8%) T-cell lymphomas. The magnitude of 14q11.2 loss showed a statistically significant correlation with the proportion of T cells in lymphoma tissue samples. Copy number losses could also be detected in other lymphomas with high numbers of T cells (8 of 32, 25% of B-cell lymphomas, 4 of 4 classical Hodgkin lymphomas), though biallelic/homozygous deletion of 14q11.2 was not significantly observed outside of T-cell lymphomas. Most nonhematopoietic neoplasms and normal tissues (59 of 64, 92.2%) showed no significant copy number losses involving the T-cell receptor α locus at chr14q11.2. CONCLUSIONS.­: Analysis of copy number losses at the T-cell receptor α locus chr14q11.2 with targeted next-generation sequencing can potentially be used to estimate the proportion of T cells and detect T-cell neoplasms.

An Analysis of the Pathologic Features of Blastic Plasmacytoid Dendritic Cell Neoplasm Based on a Comprehensive Literature Database of Cases.

CONTEXT.­: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcome. BPDCN diagnostically overlaps with entities such as acute myeloid leukemia, histiocytic/dendritic cell neoplasms, and natural killer/T-cell lymphomas. Unfortunately, large, patient-centered studies that comprehensively analyze clinical, pathologic, and other diagnostic features are lacking. As such, there is an incomplete understanding of this disease. OBJECTIVE.­: To better characterize BPDCN, a multicenter working group consisting of hematopathologists and dermatopathologists gathered in person and remotely to review the current understanding of BPDCN, discuss specific issues regarding the diagnosis and differential diagnosis, and perform a retrospective analysis of the literature. DATA SOURCES.­: The working group curated a database of published BPDCN patient cases (BPDCN Network literature database), and following careful discussion and review, 361 articles were identified, comprising a total of 1513 individually annotated patients. CONCLUSIONS.­: By conducting an in-depth analysis, not only did we confirm known findings such as frequent skin involvement (84% of patients; 861 of 1028) and a male predominance among older patients (>60 years old; male to female ratio of 3.5:1; 617:177), but we also identified a number of underrecognized features, such as significant central nervous system involvement (38% of cases; 24 of 64), and a more equal male to female prevalence among patients younger than 40 years (male to female ratio of 1.25:1; 167:134). Furthermore, we were able to accurately summarize the immunophenotypic, cytogenetic, and molecular features of this disease. BPDCN is a complex disease with distinct morphologic, immunophenotypic, and molecular findings. Continual updates of the literature database generated here and further analysis can allow for prospective refinement of our understanding of this orphan disease.

Targeted Mutational Profiling Reveals Clonal Relationships in Metachronous Occurrence of Classic Hodgkin and Mediastinal Large B-Cell Lymphomas.

Classic Hodgkin lymphoma (CHL) patients may infrequently present with a prior or recurrent disease with discordant histology resembling non-Hodgkin lymphomas. These include primary mediastinal large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL), or mediastinal gray-zone lymphoma (MGZL). Such patients are often refractory to standard therapy and their diagnosis is hampered by significant morphologic and immunophenotypic overlap and insufficient molecular data. Among 509 CHL patients seen at an academic medical center, 6 patients had a prior or subsequent diagnosis different from CHL. Paired tissue samples were evaluated by targeted mutational analysis using a 164-gene panel. Our findings show multiple shared variants indicative of a clonal relationship between the CHL and the PMBL, DLBCL, or MGZL diagnoses. Most frequent mutated genes included TNFAIP3 (4 of 6, 66.7%), STAT6 (3 or 6, 50%), ARID1A (3 of 6, 50%), and XPO1 (3 of 5, 60%). Three patients showed the same oncogenic variant within the XPO1 gene (E571K), and mutations in TNFAIP3 and B2M were observed in 2 of the 5 patients with shared variants. In addition, differences in the mutation profile between the lymphoma pairs were also observed, which could represent clonal evolution. Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact.

Suspended Particulate Matter Analysis of Pre and During Covid Lockdown Using Google Earth Engine Cloud Computing: A Case Study of Ukai Reservoir.

Presence of suspended particulate matter (SPM) in a waterbody or a river can be caused by multiple parameters such as other pollutants by the discharge of poorly maintained sewage, siltation, sedimentation, flood and even bacteria. In this study, remote sensing techniques were used to understand the effects of pandemic-induced lockdown on the SPM concentration in the lower Tapi reservoir or Ukai reservoir. The estimation was done using Landsat-8 OLI (Operational Land Imager) having radiometric resolution (12-bit) and a spatial resolution of 30 m. The Google Earth Engine (GEE) cloud computing platform was used in this study to generate the products. The GEE is a semi-automated workflow system using a robust approach designed for scientific analysis and visualization of geospatial datasets. An algorithm was deployed, and a time-series (2013-2020) analysis was done for the study area. It was found that the average mean value of SPM in Tapi River during 2020 is lowest than the last seven years at the same time.

Reference Values for the Cross Sectional Area of Normal Tibial Nerve on High-resolution Ultrasonography.

Aim: The aim of the study was to establish reference values for the cross-sectional area of the tibial nerve on high-resolution ultrasonography and to investigate the relationship between the cross-sectional area of the tibial nerve and subject's age, gender, height (in cm), weight (in kg) and body mass index. Methods: Two hundred subjects of either gender and over 18 years of age with no history of peripheral neuropathy or trauma to the lower limb were evaluated with high-resolution ultrasonography. Mean cross-sectional areas of tibial nerves were measured at two different levels in both lower limbs, first at 1 cm below the bifurcation of the sciatic nerve into tibial and common peroneal nerves (level I) and the second at 1 cm superior and posterior to the medial malleolus (level II). Results: The mean cross-sectional area measured at level I (0.196 + 0.014 cm2) was larger than the one measured at level II (0.111 ± 0.011 cm2). A positive correlation was found between the mean cross-sectional area and height, weight, and body mass index (p <0.05). Women had smaller cross-sectional areas of the tibial nerves than men at both sites. In addition, no significant relationship was found with the age of the subjects (p >0.05). Conclusion: The established reference values of the cross-sectional area of the tibial nerve will aid in early diagnosis of peripheral neuropathy.