Development of a Novel Protocol for Germline Testing in Pancreatic Cancer.

BACKGROUND: Guidelines now recommend universal germline genetic testing (GGT) for all pancreatic ductal adenocarcinoma (PDAC) patients. Testing provides information on actionable pathogenic variants and guides management of patients and family. Since traditional genetic counseling (GC) models are time-intensive and GC resources are sparse, new approaches are needed to comply with guidelines without overwhelming available resources. METHODS: A novel protocol was developed for physician-led GGT. Completed test kits were delivered to the GC team, who maintained a prospective database and mailed all orders. If results revealed pathogenic variants for PDAC, patients were offered comprehensive GC, whereas negative and variant of uncertain significance (VUS) test results were reported to patients via brief calls. RESULTS: During protocol implementation between January 2020 and December 2022, 310 (81.5%) patients underwent GGT, with a physician compliance rate of 82.6% and patient compliance rate of 98.7%. Of 310 patients tested, 44 (14.2%) patients had detection of pathogenic variants, while 83 (26.8%) patients had VUS. Pathogenic variants included BRCA1/BRCA2/PALB2 (n = 18, 5.8%), ATM (n = 9, 2.9%), CFTR (n = 4, 1.3%), EPCAM/MLH1/MSH2/MSH6/PMS2 (n = 3, 1.0%), and CDKN2A (n = 2, 0.7%). The GC team successfully contacted all patients with pathogenic variants to discuss results and offer comprehensive GC. CONCLUSION: Our novel protocol facilitated GGT with excellent compliance despite limited GC resources. This framework for GGT allocates GC resources to those patients who would benefit most from GC. As we continue to expand the program, we seek to implement methods to ensure compliance with cascade testing of high-risk family members.

The Top Ten Annals of Surgical Oncology Original Articles on Twitter/X: 2020-2023.

Social media has become omnipresent in society, especially given that it enables the rapid and widespread communication of news, events, and information. Social media platforms have become increasingly used by numerous surgical societies to promote meetings and surgical journals to increase the visibility of published content. In September 2020, Annals of Surgical Oncology (ASO) established its Social Media Committee (SMC), which has worked to steadily increase the visibility of published content on social media platforms, namely X (formerly known as Twitter). The purpose of this review is to highlight the 10 ASO original articles with the most engagement on X, based on total number of mentions, since the founding of the SMC. These articles encompass a wide variety of topics from various oncologic disciplines including hepatopancreatobiliary, breast, and gynecologic surgery.

PyFaceWipe: a new defacing tool for almost any MRI contrast.

RATIONALE AND OBJECTIVES: Defacing research MRI brain scans is often a mandatory step. With current defacing software, there are issues with Windows compatibility and researcher doubt regarding the adequacy of preservation of brain voxels in non-T1w scans. To address this, we developed PyFaceWipe, a multiplatform software for multiple MRI contrasts, which was evaluated based on its anonymisation ability and effect on downstream processing. MATERIALS AND METHODS: Multiple MRI brain scan contrasts from the OASIS-3 dataset were defaced with PyFaceWipe and PyDeface and manually assessed for brain voxel preservation, remnant facial features and effect on automated face detection. Original and PyFaceWipe-defaced data from locally acquired T1w structural scans underwent volumetry with FastSurfer and brain atlas generation with ANTS. RESULTS: 214 MRI scans of several contrasts from OASIS-3 were successfully processed with both PyFaceWipe and PyDeface. PyFaceWipe maintained complete brain voxel preservation in all tested contrasts except ASL (45%) and DWI (90%), and PyDeface in all tested contrasts except ASL (95%), BOLD (25%), DWI (40%) and T2* (25%). Manual review of PyFaceWipe showed no failures of facial feature removal. Pinna removal was less successful (6% of T1 scans showed residual complete pinna). PyDeface achieved 5.1% failure rate. Automated detection found no faces in PyFaceWipe-defaced scans, 19 faces in PyDeface scans compared with 78 from the 224 original scans. Brain atlas generation showed no significant difference between atlases created from original and defaced data in both young adulthood and late elderly cohorts. Structural volumetry dice scores were ≥ 0.98 for all structures except for grey matter which had 0.93. PyFaceWipe output was identical across the tested operating systems. CONCLUSION: PyFaceWipe is a promising multiplatform defacing tool, demonstrating excellent brain voxel preservation and competitive defacing in multiple MRI contrasts, performing favourably against PyDeface. ASL, BOLD, DWI and T2* scans did not produce recognisable 3D renders and hence should not require defacing. Structural volumetry dice scores (≥ 0.98) were higher than previously published FreeSurfer results, except for grey matter which were comparable. The effect is measurable and care should be exercised during studies. ANTS atlas creation showed no significant effect from PyFaceWipe defacing.

The effect of friction stir processing on mechanical, wear and corrosion characteristics of Cu-AlN-BN surface composite.

This research investigates the impact of hybrid particles dispersed onto the surface of a copper matrix using Friction Stir Processing (FSP) on its microstructural, mechanical, and corrosion behavior. The hybrid particles under study consist of equal fractions of Aluminium Nitride (AlN) and Boron Nitride (BN). Microstructural characterization confirms breakdown of grain size due to dynamic recrystallization and presence of particles, along with their effective bonding to copper matrix. Attained results indicated a significant enhancement in hardness, with an increase of up to 3.9 % upon the introduction of particles onto the surface. Moreover, the tensile properties exhibit noticeable improvements in terms of ultimate tensile strength (6.39 %) and yield strength (6.12 %), albeit at the expense of reduced ductility in the copper matrix. Furthermore, the wear rate (decreases up to 22 %) and corrosion rate of the developed composites demonstrate a decreasing trend with the introduction of particles. This improvement can be attributed to the reduction in grain size during the FSP process and the formation of a nitride passive layer facilitated by the reinforced hybrid particles, thereby effectively inhibiting the corrosion rate.

Are changes in sleep problems associated with changes in life satisfaction during the retirement transition?

Retirement reduces sleep problems, but changes in life satisfaction during the retirement transition are multifactorial and partly unknown. The aim of this prospective cohort study was to examine whether changes in sleep problems are associated with changes in total and domain-specific life satisfaction during the retirement transition (on average 0.5 years before and 0.5 years after retirement). The study population consisted of Finnish public sector employees (n = 3518) from the Finnish Retirement and Aging (FIREA) study who responded to annual surveys before and after transition to statutory retirement. Sleep problems were measured with Jenkins Sleep Problem Scale questionnaire and participants were grouped into four sleep problem groups depending on the state of their sleep problems during the retirement transition: 'Never,' 'Decreasing,' 'Increasing,' and 'Constant' sleep problems. Life satisfaction was measured with the Life Satisfaction Scale questionnaire including four domains (interestingness, happiness, easiness, togetherness). We found that the improvement in total life satisfaction was greatest for participants in the 'Decreasing' (0.17, 95% CI 0.11-0.23, SMD 0.27) and 'Constant' (0.12, 95% CI 0.07-0.18, SMD 0.19) sleep problem groups. Of the specific life satisfaction domains, similar findings were observed only for the easiness domain. It seems that decreasing or constant sleep problems are associated with improved life satisfaction during the retirement transition, especially in the feeling of easiness of life. This may be due to the fact that as the demands of working life are removed, sleep problems are alleviated or it becomes easier to live with them, which improves life satisfaction.

Energy based techno-economic and environmental feasibility study on PV/T and PV/T heat pump system with phase change material-a numerical comparative study.

A sustainable, affordable, and eco-friendly solution has been proposed to address water heating, electricity generation, space cooling, and photovoltaic (PV) cooling requirements in scorching climates. The photovoltaic thermal system (PV/T) and the direct expansion PV/T heat pump (PV/T DXHP) were numerically studied using MATLAB. A butterfly serpentine flow collector (BSFC) and phase change material (PCM) were assimilated in the PV system and MATLAB model was developed to evaluate the economic and enviroeconomic performance of the PV/T water system (PV/T-W), PV/T PCM water system (PV/T PCM-W), the PV/T DXHP system, and the PV/T PCM heat pump system (PV/T-PCM-DXHP). In this study, annual energy production, socioeconomic factors, enviro-economic indicators, and environmental characteristics are assessed and compared. Also, an economic, environmental, and enviro-economic analysis was conducted to assess the commercial viability of the suggested system. The PV/T PCM-DXHP demonstrated the highest electrical performance of 53.69%, which is comparatively higher than the other three configurations. The discounted levelized cost of energy (DLCOE) and payback period (DPP) of the PV/T PCM-DXHP were ₹2.87 per kW-h and 3-4 years, respectively, resulting in a total savings of ₹67,7403 over its lifetime. Furthermore, installing this system mitigated 280.72 tonnes of CO2 emissions and saved the mitigation cost by ₹329,700 throughout its operational lifecycle.

Hybrid Heterocycles: Ag(I)-Catalyzed C-C/C-N/C-O Coupled Cascade Dual Cyclization to Valuable Indolo-4H-indolones and Indolo-4H-chromenes.

Herein, we report a highly efficient Ag(I)-catalyzed indolyzation with Friedel-Crafts alkylation through a cascade cyclization strategy for accessing valuable hybrid heterocycles for the first time. This general strategy consists of forming four C-C/C-N/C-O bonds toward dual annulation reactions of 2-alkynylanilines with methyl benzoate-2-carboxaldehydes and aromatic amines, as well as with salicylaldehydes and malononitrile. Variably substituted new indolo-4H-phthalimidines and indolo-4H-chromenes were synthesized with excellent yields (85-93%) under mild reaction conditions.

Phase I Safety and Feasibility Pilot of Hepatic Artery Infusion Chemotherapy in a Rural Catchment Area Using The Codman Vascular Catheter with The Medtronic SynchroMed II Pump for Intrahepatic Cancers.

BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.

Intranasal sphenopalatine ganglion block by lignocaine spray for postdural puncture headache following spinal anesthesia: a randomized clinical trial.

INTRODUCTION: In a randomized clinical study, we investigated the effectiveness of nasal lignocaine spray and swabs in treating postdural puncture headache (PDPH) after spinal anesthesia. MATERIAL AND METHODS: Group S patients received two puffs of lignocaine 10% spray in both nostrils followed by cotton soaked in normal saline, and group B patients received two puffs of saline spray in both nostrils followed by a cotton swab soaked in lignocaine 2%. Patients were assessed before the procedure and 30 minutes, 60 minutes, 2 h, 24 h, 48 h, and 72 h after the procedure for pain relief with the help of a visual analogue scale (VAS). Hemodynamic parameters and adverse effects were also recorded. Normally distributed continuous variables were expressed as mean (95% confidence interval) whereas non-normally distributed variables were expressed as median (IQR). Repeated measures analysis of variance was used to compare the VAS score at different time points between test and control groups. The difference in means between the two groups was compared using the independent sample t -test. The paired t-test was used to compare the changes in clinical and laboratory variables. RESULTS: At each time point, the mean VAS score for pain was substantially different between the two groups. Moreover, until the second hour, the VAS score was significantly lower in group S than in group B. No significant intervention-related adverse effect was observed in either group. CONCLUSIONS: Without any noticeable side effects, lignocaine 10% spray is more successful in treating PDPH after spinal anesthesia, particularly in the first two hours.

Correlation of Acoustic Radiation Force Impulse Imaging with Chronicity Markers in Native Renal Biopsy.

Introduction. Acoustic Radiation Force Impulse (ARFI) is an ultrasound parameter which has shown promise in assessing liver stiffness, but there are limited data on the correlation of ARFI with chronicity markers in renal biopsies. Objectives. Determine ARFI values in ultrasound and correlate with chronicity markers in renal biopsy. Determine whether ARFI can be used as a non-invasive chronicity predictor compared to renal length, Resistive Index (RI), and cortical thickness. Patients and Methods. Two hundred and fifty patients were enrolled in the study. The ultrasound variables ARFI, renal length, RI, and cortical thickness values were assessed by the radiologist prior to renal biopsy. The biopsy slides were graded as per the Mayo Clinic consensus report scoring system by an experienced pathologist. Results. Among 250 study participants, 167 were males and 83 were females. IgA nephropathy was the most common pathology (n=47;19%), followed by diabetic nephropathy (n=42;17%), membranous nephropathy (n=35;14%), FSGS (n=27;11%), and MCD (n=19; 8%). The mean eGFR was 55.9 ± 42.12 ml/min/1.73 m2. The average renal length was 10.086 ± 1.01 cm. The average cortical thickness was 0.707 ± 0.134 cm. Resistive index was 0.68 ± 0.09. Acoustic radiation force impulse had weak negative correlation (r=-0.286; p=0.0001) with total pathological score and weak positive correlation with eGFR (r=0.279; p=0.0001). RI was a better indicator for histologically evaluated chronicity with positive correlation coefficient (r=0.416; p=0.0005) compared to renal length, cortical thickness, and ARFI. Conclusion. ARFI didn't corelate with the pathological score in renal biopsies. RI had better predictive value for chronicity in native renal biopsies.

Feasibility assessment of a stepped solar still integrated with hexagram fin: an experimental and numerical approach toward sustainability.

Effective utilization and conservation of freshwater is a global concern due to the rapid population growth and industrial usage. To address this challenge, various approaches have been developed and implemented to convert brackish water into freshwater and meet the global water demand. This study introduces hexagram-shaped aluminum fins attached to a powder-coated basin to improve the freshwater production rate of stepped solar still. The experiment involved testing the modified stepped solar still (MSSS) equipped with hexagram fins and the conventional stepped solar still (CSSS) without hexagram fins during summer days at the Sathyamangalam location (11.49° N, 77.27° E). A mathematical model was used to analyze the performance of the solar stills, and the simulation results were validated by comparing CSSS and MSSS in terms of their freshwater production. The results indicate that the productivity of CSSS increased by 40% using hexagram fins, and the MSSS with hexagram fins produced a maximum of 4.45 l/m2 of fresh water daily. The annual performance of MSSS and CSSS in the experimental location reveals a 12.6% reduction in the payback period of the solar still due to the presence of fins. The study recommends using fins in solar stills in hot climates for efficient and cost-effective water desalination applications to achieve sustainable development objectives while reducing carbon emissions.

Statins abrogate gemcitabine-induced PD-L1 expression in pancreatic cancer-associated fibroblasts and cancer cells with improved therapeutic outcome.

A combination of chemotherapy with immunotherapy has been proposed to have better clinical outcomes in Pancreatic Ductal Adenocarcinoma (PDAC). On the other hand, chemotherapeutics is known to have certain unwanted effects on the tumor microenvironment that may mask the expected beneficial effects of immunotherapy. Here, we have investigated the effect of gemcitabine (GEM), on two immune checkpoint proteins (PD-L1 and PD-L2) expression in cancer associated fibroblasts (CAFs) and pancreatic cancer cells (PCCs). Findings of in vitro studies conducted by using in-culture activated mouse pancreatic stellate cells (mPSCs) and human PDAC patients derived CAFs demonstrated that GEM significantly induces PD-L1 and PD-L2 expression in these cells. Moreover, GEM induced phosphorylation of STAT1 and production of multiple known PD-L1-inducing secretory proteins including IFN-γ in CAFs. Upregulation of PD-L1 in PSCs/CAFs upon GEM treatment caused T cell inactivation and apoptosis in vitro. Importantly, Statins suppressed GEM-induced PD-L1 expression both in CAFs and PCCs while abrogating the inactivation of T-cells caused by GEM-treated PSCs/CAFs. Finally, in an immunocompetent syngeneic orthotopic mouse pancreatic tumor model, simvastatin and GEM combination therapy significantly reduced intra-tumor PD-L1 expression and noticeably reduced the overall tumor burden and metastasis incidence. Together, the findings of this study have provided experimental evidence that illustrates potential unwanted side effects of GEM that could hamper the effectiveness of this drug as mono and/or combination therapy. At the same time the findings also suggest use of statins along with GEM will help in overcoming these shortcomings and warrant further clinical investigation.

Characterizing patterns of seasonal drought stress for use in common bean breeding in East Africa under present and future climates.

Common bean (Phaseolus vulgaris L.) is the second most important source of dietary protein and the third most important source of calories in Africa, especially for the poor. In East Africa, drought is an important constraint to bean production. Therefore, breeding programs in East Africa have been trying to develop drought resistant varieties of common bean. To do this, breeders need information about seasonal drought stress patterns including their onset, intensity, and duration in the target area of the breeding program, so that they can mimic this pattern during field trials. Using the Decision Support for Agrotechnology Transfer (DSSAT) v4.7 model together with historical and future (Coupled Model Inter-comparison Project 6, CMIP6) climate data, this study categorized Ethiopia, Tanzania, and Uganda into different target population of environments (TPEs) based on historical and future seasonal drought stress patterns. We find that stress-free conditions generally dominate across the three countries under historical conditions (50-80% frequency). These conditions are projected to increase in frequency in Ethiopia by 2-10% but the converse is true for Tanzania (2-8% reduction) and Uganda (17-20% reduction) by 2050 depending on the Shared Socioeconomic Pathway (SSP). Accordingly, by 2050, terminal drought stresses of various intensities (moderate, severe, extreme) are prevalent in 34% of Uganda, around a quarter of Ethiopia, and 40% of the bean growing environments in Tanzania. The TPEs identified in each country serve as a basis for prioritizing breeding activities in national programs. However, to optimize resource use in international breeding programs to develop genotypes that are resilient to future projected stress patterns, we argue that common bean breeding programs should focus primarily on identifying genotypes with tolerance to severe terminal drought, with co-benefits in relation to adaptation to moderate and extreme terminal drought. Little to no emphasis on heat stress is warranted by 2050s.

Harnessing artificial intelligence in radiology to augment population health.

This review article serves to highlight radiological services as a major cost driver for the healthcare sector, and the potential improvements in productivity and cost savings that can be generated by incorporating artificial intelligence (AI) into the radiology workflow, referencing Singapore healthcare as an example. More specifically, we will discuss the opportunities for AI in lowering healthcare costs and supporting transformational shifts in our care model in the following domains: predictive analytics for optimising throughput and appropriate referrals, computer vision for image enhancement (to increase scanner efficiency and decrease radiation exposure) and pattern recognition (to aid human interpretation and worklist prioritisation), natural language processing and large language models for optimising reports and text data-mining. In the context of preventive health, we will discuss how AI can support population level screening for major disease burdens through opportunistic screening and democratise expertise to increase access to radiological services in primary and community care.

IL-21/23 axis modulates inflammatory cytokines and RANKL expression in RA CD4+ T cells via p-Akt1 signaling.

Introduction: CD4+ T cells are critically involved in the pathogenesis of Rheumatoid Arthritis; an autoimmune disorder characterized by joint inflammation and bone degeneration. In this study, we focused on the critical role of cytokines, IL-21 and IL-23 in facilitating the aberrant status of RA Th17-like cells and report their significant contribution(s) in modulating the expression of inflammatory cytokines and RANKL. Methods: Blood and synovial fluid collected from a total of 167 RA patients and 25 healthy volunteers were assessed for various inflammatory markers and RANKL expression in plasma and CD4+ T cells. Subsequent ex vivo studies examined the role of specific cytokines, IL-21 and IL-23 in mediating inflammation and RANKL upregulation by blocking their expression with neutralizing antibodies in RA CD4+ T cells and terminally differentiated human Th17 cells. Further, the role of p-Akt1 as a signalling target downstream of IL-21 and IL-23 was evinced with IL-21 and IL-23 inhibition and phospho Akt-1/2 kinase inhibitor. Results: Our observations highlighted the augmented inflammatory cytokine levels in plasma and an aberrant CD4+ T cell phenotype expressing exaggerated inflammatory cytokines and membrane RANKL expression in RA as opposed to healthy controls. Neutralization of either IL-21 or IL-23 (p19 and p40) or both, resulted in downregulation of the cytokines, TNF-α, IFN-γ and IL-17 and RANKL expression in these cells, signifying the critical role of IL-21/23 axis in modulating inflammation and RANKL. Subsequent dissection of the signaling pathway found p-Akt1 as the key phosphoprotein downstream of both IL-21 and IL-23, capable of increasing inflammatory cytokines and RANKL production. Discussion: Our findings unequivocally identify IL-21/23 axis in RA CD4+ T cells as a key regulator dictating two critical processes i.e. exaggerated inflammation and higher RANKL expression and provide critical targets in their downstream signalling for therapeutic approaches.

Structure-function analysis of histone H2B and PCNA ubiquitination dynamics using deubiquitinase-deficient strains.

Post-translational covalent conjugation of ubiquitin onto proteins or ubiquitination is important in nearly all cellular processes. Steady-state ubiquitination of individual proteins in vivo is maintained by two countering enzymatic activities: conjugation of ubiquitin by E1, E2 and E3 enzymes and removal by deubiquitinases. Here, we deleted one or more genes encoding deubiquitinases in yeast and evaluated the requirements for ubiquitin conjugation onto a target protein. Our proof-of-principle studies demonstrate that absence of relevant deubiquitinase(s) provides a facile and versatile method that can be used to study the nuances of ubiquitin conjugation and deubiquitination of target proteins in vivo. We verified our method using mutants lacking the deubiquitinases Ubp8 and/or Ubp10 that remove ubiquitin from histone H2B or PCNA. Our studies reveal that the C-terminal coiled-domain of the adapter protein Lge1 and the C-terminal acidic tail of Rad6 E2 contribute to monoubiquitination of histone H2BK123, whereas the distal acidic residues of helix-4 of Rad6, but not the acidic tail, is required for monoubiquitination of PCNA. Further, charged substitution at alanine-120 in the H2B C-terminal helix adversely affected histone H2BK123 monoubiquitination by inhibiting Rad6-Bre1-mediated ubiquitin conjugation and by promoting Ubp8/Ubp10-mediated deubiquitination. In summary, absence of yeast deubiquitinases UBP8 and/or UBP10 allows uncovering the regulation of and requirements for ubiquitin addition and removal from their physiological substrates such as histone H2B or PCNA in vivo.

Impact of Mineralocorticoid Receptor Antagonists in the Treatment of Heart Failure: Targeting the Heart Failure Cascade.

Epidemiological data from the Indian subcontinent on the burden of Heart failure (HF) is scarce. Mineralocorticoid receptor antagonists (MRAs) are usually used in the management of HF and hypertension. A consortium of experts reviewed and opined on the pathophysiological role of aldosterone in HF and its cascading effects on the heart in terms of cardiac fibrosis, cardiac hypertrophy, and remodeling, increased propensity to cause arrhythmias in addition to its effect on sodium and water retention. This expert opinion document highlights the various mechanisms of action of MRAs. It provides clinical experience and practice-based expert opinion on the use of spironolactone and eplerenone in patients with HF. The role of MRAs in diabetic patients with HF has also been profiled.