Finding Needles in the Haystack: Strategies for Uncovering Noncoding Regulatory Variants.

Despite accumulating evidence implicating noncoding variants in human diseases, unraveling their functionality remains a significant challenge. Systematic annotations of the regulatory landscape and the growth of sequence variant data sets have fueled the development of tools and methods to identify causal noncoding variants and evaluate their regulatory effects. Here, we review the latest advances in the field and discuss potential future research avenues to gain a more in-depth understanding of noncoding regulatory variants.

Optimization of Catalysts and Conditions in Gold(I) Catalysis-Counterion and Additive Effects.

Gold catalysis has proven to be an important breakthrough for organic synthesis. The tunable nature of gold catalysts, the unique properties of gold, and the mild reaction conditions required in many gold-catalyzed reactions have all contributed substantially to this metal's popularity in catalysis. However, gold-catalyzed reactions still suffer from limitations such as low turnover numbers (TON). Optimization of the catalysts and reaction conditions may significantly improve the efficiency of gold-catalyzed reactions. In this review, we will present leading examples of counterion or additive-regulated gold catalysis from a mechanistic perspective. We will pay special attention to the physical properties of counterion/additive, such as gold affinity and hydrogen bond basicity, and discuss their effects on the reactivity of gold catalysts.

Improvement in International Prostate Symptom Score after prostatic urethral lifts is dependent on prostatic volume.

INTRODUCTION: Prostatic urethral lifts (PUL) provide improvement in urinary symptoms for men with benign prostatic hyperplasia (BPH). The aim of this study is to determine operative factors associated with improvement in urinary symptoms after PUL in men with bothersome BPH. MATERIALS AND METHODS: Men with BPH undergoing PUL at a single, tertiary center were identified from 2019 to 2022. Inclusion criteria included documented prostate volume as well as preoperative and postoperative cystoscopic images of the prostatic urethra. Multivariate regression modeling was performed to determine the predictive factors-including prostate volume, number of implants, and degree of unobstructed prostatic urethral channel-for improvement in International Prostate Symptom Score (IPSS) after PUL. RESULTS: Of the 47 men, the distribution of prostate volume was 1 patient with < 30 grams, 33 patients with 30-79 grams, five patients with 80-100 grams, and six patients with > 100 grams. The mean number of implants used was six implants. The mean preoperative and postoperative IPSS were 23 and 14, respectively. The mean (standard error (SE)) change and percent change in IPSS score following PUL was 14 and 60%, respectively. The mean percent improvement in prostatic urethral channel after anterior clip placements was 67%. On multivariate analysis, larger prostate volume was associated with greater change in IPPS follow surgery (p = 0.0091) while number of implants and percent of prostatic urethral opening were not associated with change in IPSS (p = 0.3094 and p = 0.2249, respectively). CONCLUSION: Men with larger prostates are associated with greater improvement in urinary symptom after PUL regardless of number of implants utilized and degree of prostatic urethral channel opening after prostatic implants.

Risk Factors Associated with Adverse Outcomes after Ablative Surgery for Lymphedema.

BACKGROUND: Postmastectomy breast cancer lymphedema poses an important health threat. Historically, physical therapy was the exclusive treatment option. More recently, lymphedema surgery has revolutionized care. As a first-in-kind, multicenter report, the postmastectomy breast cancer patients' risk factors associated with postlymphedema ablative surgical outcomes were documented. METHODS: Using the New York Statewide Planning and Research Cooperative System database from 2010 to 2018, multivariable models identified the postmastectomy breast cancer lymphedema surgical patients' characteristics associated with major adverse outcomes and mortality. RESULTS: Of 65,543 postmastectomy breast cancer patients, 1,052 lymphedema surgical procedures were performed including 393 (37.4%) direct excisions and 659 (63.6%) liposuctions. Direct excision and liposuction surgical patients had median ages of 58 and 52 years, respectfully (p < 0.001). Although a 30-day operative mortality was rare (0.3%, all direct excisions), major adverse outcomes occurred in 154 patients (28.5% direct excision; 6.4% liposuction; p < 0.0001). Multivariable clinical outcomes model identified that patients with higher Elixhauser's score, renal disease, emergent admissions, and direct excision surgery had higher incidences of adverse outcomes (all p < 0.01). For those patients with 30-day readmissions (n = 60), they were more likely to have undergone direct excision versus liposuction (12.5 vs. 1.7%; p < 0.0001). The important risk factors predictive of future cellulitis/lymphangitis development included diabetes mellitus, Medicaid insurance, renal disease, prior cellulitis/lymphangitis, chronic obstructive pulmonary disease (COPD), and chronic steroid use (all p < 0.01). CONCLUSION: Lymphedema surgery carries a favorable risk profile, but better understanding the "high-risk" patients is critical. As this new era of lymphedema surgery progresses, evaluating the characteristics for adverse postoperative outcomes is an important step in our evolution of knowledge.

Management of mammalian bites to the external genitalia: a scoping review.

OBJECTIVE: To review existing publications to determine the approaches for the medical and operative management of mammalian bites to the external genitalia. MATERIALS AND METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Scoping Review guidelines were followed. Four databases were searched. Articles were independently screened and analysed by two reviewers. Publications were included if detailed summaries of genitalia bites and management were documented. Discrepancies were resolved by a third reviewer. Data were extracted from the final article cohort. RESULTS: A total of 42 articles were included in this scoping review with 67 cases of mammalian bites to the genitalia reported in the cohort. The most common injury site was the penis (44.9%). Dog and human bites were the most common type of mammalian bites (61.2% and 26.9%, respectively). In all, 13.4% of cases were managed with medical therapy while 86.6% of cases required surgical intervention. The most common intervention was wound irrigation, debridement, and primary closure (32.8%). Although uncommon, other operative approaches included skin flaps (7.5%) and grafts (4.5%), re-implantation (4.5%), urethroplasty/repair (7.5%), penectomy (3.0%), scrotoplasty (3.0%), and perineal urethrostomy (1.5%). The reported complication rate was 19.4%. The mean follow-up time was 39.9 months. CONCLUSION: Trauma related to mammalian bites is associated with high utilisation of healthcare resources and cost. Although management of such bites to the genitalia is controversial, surgical intervention is often warranted ranging from simple debridement of devitalised tissue to complex reconstructive surgery. This review underscores the need for further investigation of mammalian bites to the genitalia to improve surgical options and monitor for long-term complication rates.

The Microbiome and Urolithiasis: Current Advancements and Future Challenges.

PURPOSE OF REVIEW: The aim of this review is to explore the effect of the microbiome on urolithiasis and explore recent advances and challenges in microbiome research for urolithiasis. RECENT FINDINGS: Lack of standardization and shortcomings in study design for urinary microbiome research on urolithiasis has hampered the generalizability of results and weakened the impact of findings on clinical practice. Important study limitations include sample heterogenicity, specimen contamination, poor culture yields, and lack of shared datasets for meta-analysis. Contrary to traditional teaching, the genitourinary tract is not a sterile environment. This urinary microbiome may influence the pathogenesis of urolithiasis, although the specific mechanisms are still currently being explored. Successful investigation will depend on consistency in study design and analysis, as well as sharing data and protocols across institutions. Developing an understanding of the relationship between the urinary microbiome and urolithiasis may lead to novel approaches to mitigate stone risk.

Risk Factors Associated With Postmastectomy Breast Cancer Lymphedema: A Multicenter Retrospective Analysis.

BACKGROUND: Lymphedema is an edematous condition that afflicts the postmastectomy breast cancer population, with diminished quality of life with substantial financial costs. The factors predictive of postmastectomy lymphedema development in breast cancer patients are unknown. The objective was to evaluate the trends over time in lymphedema development and the risk factors predictive of lymphedema-related events within 2 years of mastectomy. METHODS: Using the New York Statewide Planning and Research Cooperative System multicenter deidentified database from 2010 to 2016, a total of 65,543 breast cancer postmastectomy female patients (mean age, 59 ± 20 years) were identified across 177 facilities. The breast cancer patients were followed for any 2-year postmastectomy lymphedema-related events. A multivariable model identified predictors of 2-year lymphedema using eligible variables involving demographics, comorbidities, and complications. Elixhauser score was defined as a comorbidity index based on International Classification of Diseases codes used in hospital settings. RESULTS: Overall, 5.2% (n = 3409) of the breast cancer postmastectomy patients experienced a lymphedema-related event within 2 years of initial surgery. Over time, 2-year postmastectomy lymphedema rates have more than doubled from 4.62% in 2010 to 9.75% in 2016 (P < 0.001). Two-year postmastectomy lymphedema rates varied significantly by mastectomy procedure type: 5.69% of the mastectomy-only procedures, 5.96% of the mastectomies with lymph node biopsies, and 7.83% of the mastectomies with lymph node dissections (P < 0.0001). Full mastectomies had a greater 2-year lymphedema rate of 7.31% when compared with partial mastectomies with 2.79% (P < 0.0001). The top predictive risk factors for a lymphedema-related event included higher Elixhauser score, prolonged hospitalization for mastectomy, more recent mastectomy procedure, obesity, younger age, non-Asian race, Medicaid insurance, and hypertension (all P's < 0.01). CONCLUSIONS: Although more recent postmastectomy lymphedema rates may not be as high as historical estimates, the 2-year postmastectomy lymphedema rates have more than doubled from 2010 to 2016 requiring further elucidation as well as continued focus on treatment. Furthermore, risk factors were identified that predispose postmastectomy breast cancer patients to developing lymphedema. Given these findings, perioperative screening seems warranted to proactively identify, educate, and monitor postmastectomy patients at greatest risk of future lymphedema development.

Synthesis and applications of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (Umemoto reagent IV).

A new, powerful, and easy-to-handle electrophilic trifluoromethylating agent, S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (Umemoto reagent IV), was developed. Due to the extraordinary electronic effect of trifluoromethoxy group, Umemoto reagent IV was easily synthesized by a one-pot method from readily available 3,3'-bis(trifluoromethoxy)biphenyl. It was shown that Umemoto reagent IV was more powerful than Umemoto reagent II and could trifluoromethylate many kinds of nucleophilic substrates more effectively. In addition, Umemoto reagent IV was successfully utilized for the preparation of trifluoromethyl nonaflate, a useful trifluoromethoxylating agent. The direct conversion of 2,8-bis(trifluoromethoxy)dibenzothiophene to Umemoto reagent IV with triflic anhydride was achieved, albeit in low yield.

Clinical Presentation of Cases with Upper Gastro - Intestinal Bleeding.

Acute upper gastrointestinal bleeding (UGIB) is a common emergency and can be a serious condition that requires hospitalization, rapid evaluation and management. The usual presentation is hematemesis (vomiting of blood or coffee ground-like material) and/or melena (black, tarry stools) 1. UGIB occurs more commonly in men and older subjects. PUD is the most common cause of UGIB in the US accounting for about 50% of the cases, whereas in tropical country like India, esophageal varices attribute to half the cases. Esophago-Gastro-Duodenoscopy [EGD] is a primary diagnostic and therapeutic modality in the setting of UGIB. MATERIAL: Prospective study. Forty patients who have presented with frank blood or coffee ground color vomitus and/or melena were considered for this study. All patients greater than 18 years of age were included. Their clinical presentation, hemogram and endoscopic findings were analyzed. Descriptive statistical analysis has been applied. OBSERVATION: In our study, the age distribution was between 23 and 87 years. There is a male preponderance with 65 % males and 35%females. Among 40 patients,42.5%had varices, 17.5% had Peptic Ulcer Disease and12.5% had Erosive Gastritis. The other causes of UGIB include Pangastritis(10%), Mallory Weiss Tear(7.5%), Polyp(5%), Esophagitis(2.5%), Coagulopathy induced bleed(2.5%) and Carcinoma stomach(2.5%). Of the 40 cases admitted, only 3 patients (7.5%) had massive Upper GI Bleed.10 patients (25%) had moderate bleed and 27 patients (67.5%) had mild bleed. Amongst the patients with massive bleed, an important cause is esophageal varices(66.7%). A total of 21 (52.5%) patients have recovered. There was one death(2.5%) amongst the cases which was not attributed to UGIB. 14 patients(45%) has residual disease of which 42.5% were of variceal bleed. Patients with variceal bleed have undergone banding and have been asked to regularly follow up for check endoscopy and banding till their eradication. There was 1 patient of residual disease with Carcinoma stomach(2.5%) who has been initiated on chemotherapy. CONCLUSION: Hematemesis is much commoner than melena in the presentation of upper GI bleed. EGD has a diagnostic as well as therapeutic role in UGIB .In this study endoscopy provided diagnosis in 97.5% of patients. In this cross sectional study, the most common cause of upper GI bleed was esophageal varices, with alcoholic cirrhosis being the main cause of portal hypertension. Varices remain to be the most common cause of UGIB in both males and females, however, the percentage is more in males as compared to females. Varices are an important cause of massive variceal bleed.

Gold (I/III)-Catalyzed Trifluoromethylthiolation and Trifluoromethylselenolation of Organohalides.

The first C-SCF3 /SeCF3 cross-coupling reactions using gold redox catalysis [(MeDalphos)AuCl], AgSCF3 or Me4 NSeCF3 , and organohalides as substrates are reported. The new methodology enables a one-stop shop synthesis of aryl/alkenyl/alkynyl trifluoromethylthio- and selenoethers with a broad substrate scope (>60 examples with up to 97 % isolated yield). The method is scalable, and its robustness is evidenced by the late-stage functionalization of various bioactive molecules, which makes this reaction an attractive alternative in the synthesis of trifluoromethylthio- and selenoethers for pharmaceutical and agrochemical research and development.

Antiplatelet therapies in diabetes.

Cardiovascular complications remain the main cause of mortality and morbidity in diabetes. This is related to advanced vascular pathology in this population, together with an enhanced thrombotic environment. The increased risk in thrombosis is secondary to platelet hyper-reactivity and increased levels and/or altered activity of coagulation factors. The current review is focused on the role of antiplatelet agents in modulating the thrombotic milieu in diabetes and improving vascular outcome in this high-risk population. We review the latest evidence for the use of aspirin in primary vascular prevention together with long-term treatment with this agent for secondary prevention. We also discuss the effects of the various P2Y12 inhibitors, including clopidogrel, prasugrel and ticagrelor, on both short- and long-term secondary vascular prevention. Moreover, we briefly review antiplatelet therapies in special groups of people including those intolerant to aspirin, individuals with peripheral vascular disease and those with cerebrovascular pathology. The overall aim of this review is to provide the healthcare professional with a pragmatic guide for the management of thrombotic risk using established antiplatelet therapies to improve vascular outcome in persons with diabetes.

Responses of diversity, productivity, and stability to the nitrogen input in a tropical grassland.

Atmospheric nitrogen (N) deposition is a matter of serious concern for the structure and functioning of global ecosystems, but the effect of N application of species diversity (D), primary productivity (P), and stability (S) of tropical grassland ecosystems is not known. The present study reports the effects of different levels of N application on species composition, and the D, P, S, and their relationships in a tropical grassland. Within the experimental grassland, 72 1 × 1 m plots with 6 N-input levels and with 12 replicates, were established in 2013. For 3 yr, different doses of urea as a source of N were applied to the plots. Data on individuals and biomass of each species were recorded and statistically analyzed. The study revealed that the N applied caused variations in species composition, D, P, and S. Below the 90 kg N dose, D was positively related to P and S while, above this level, the relations were negative due to N-induced responses of species and functional group composition as well as biomass distribution among them. The optimum applied N levels for maximum D (50-60 kg N), P (120 kg N), and a positive relationship of S with D (up to 90 kg N treatment) suggested that the 90-kg N dose could be the maximum dose of N that the grassland can tolerate. Hence, N application should not exceed the 90-kg level for sustainability of the structure and functioning of tropical grassland ecosystems.

Correction to: Twelve Hundred Consecutive Pancreato-Duodenectomies from Single Centre: Impact of Centre of Excellence on Pancreatic Cancer Surgery Across India.

The authors' affiliations are updated as reflected here.

Twelve Hundred Consecutive Pancreato-Duodenectomies from Single Centre: Impact of Centre of Excellence on Pancreatic Cancer Surgery Across India.

BACKGROUND: Pancreato-duodenectomy (PD) is a technically challenging operation with significant morbidity and mortality. Over the period of time, Tata Memorial Centre has evolved into a high-volume centre for management of pancreatic cancer. Aim of this study is to report the short- and long-term outcomes of 1200 consecutive PDs performed at single tertiary cancer centre in India. METHODS: 1200 PDs were performed from 1992 to 2017. Prospectively maintained database was used to retrospectively assess the short- and long-term outcomes. RESULTS: Study cohort was divided into periods A and B (500 and 700 patients, respectively). Both groups were comparable for demographic variables. Overall morbidity and mortality in entire cohort were 31.2% and 3.9%, respectively. Period B documented significant reduction in post-operative mortality (5.4% vs 2.8%), post-pancreatectomy haemorrhage (5.8% vs 3%) and bile leaks (3.4% vs 1.3%). However, incidence of delayed gastric emptying and clinically relevant post-operative pancreatic fistula was higher in period B. With median follow-up of 25 months, 3-year overall survival and disease-free survival for patients with pancreatic cancer were 43.7% and 38.7%, respectively, and that for periampullary tumours were 65.9% and 59.4%, respectively. Period B also corresponded with dissemination of technical expertise across diverse regions of India with specialised training of 35 surgeons. CONCLUSION: Our study demonstrates the feasibility of delivering high-quality care in a dedicated high-volume centre even in a country with low incidence of pancreatic cancer with marked disparities in medical care and socio-economic conditions. Improved outcomes underscore the need to promote regionalisation via a dedicated training programme.

Verteporfin-Loaded Polymeric Microparticles for Intratumoral Treatment of Brain Cancer.

Glioblastoma (GBMs) is the most common and aggressive type of primary brain tumor in adults with dismal prognosis despite radical surgical resection coupled with chemo- and radiotherapy. Recent studies have proposed the use of small-molecule inhibitors, including verteporfin (VP), to target oncogenic networks in cancers. Here we report efficient encapsulation of water-insoluble VP in poly(lactic- co-glycolic acid) microparticles (PLGA MP) of ∼1.5 µm in diameter that allows tunable, sustained release. Treatment with naked VP and released VP from PLGA MP decreased cell viability of patient-derived primary GBM cells in vitro by ∼70%. Moreover, naked VP treatment significantly increased radiosensitivity of GBM cells, thereby enhancing overall tumor cell killing ability by nearly 85%. Our in vivo study demonstrated that two intratumoral administrations of sustained slow-releasing VP-loaded PLGA MPs separated by two weeks significantly attenuated tumor growth by ∼67% in tumor volume in a subcutaneous patient-derived GBM xenograft model over 26 d. Additionally, our in vitro data indicate broader utility of VP for treatment for other solid cancers, including chordoma, malignant meningioma, and various noncentral nervous system-derived carcinomas. Collectively, our work suggests that the use of VP-loaded PLGA MP may be an effective local therapeutic strategy for a variety of solid cancers, including unresectable and orphan tumors, which may decrease tumor burden and ultimately improve patient prognosis.

Verteporfin-Loaded Poly(ethylene glycol)-Poly(beta-amino ester)-Poly(ethylene glycol) Triblock Micelles for Cancer Therapy.

Amphiphilic polymers can be used to form micelles to deliver water-insoluble drugs. A biodegradable poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE)-PEG triblock copolymer was developed that is useful for drug delivery. It was shown to successfully encapsulate and pH-dependently release a water-insoluble, small molecule anticancer drug, verteporfin. PEG-PBAE-PEG micelle morphology was also controlled through variations to the hydrophobicity of the central PBAE block of the copolymer in order to evade macrophage uptake. Spherical micelles were 50 nm in diameter, while filamentous micelles were 31 nm in width with an average aspect ratio of 20. When delivered to RAW 264.7 mouse macrophages, filamentous micelles exhibited a 89% drop in cellular uptake percentage and a 5.6-fold drop in normalized geometric mean cellular uptake compared to spherical micelles. This demonstrates the potential of high-aspect-ratio, anisotropically shaped PEG-PBAE-PEG micelles to evade macrophage-mediated clearance. Both spherical and filamentous micelles also showed therapeutic efficacy in human triple-negative breast cancer and small cell lung cancer cells without requiring photodynamic therapy to achieve an anticancer effect. Both spherical and filamentous micelles were more effective in killing lung cancer cells than breast cancer cells at equivalent verteporfin concentrations, while spherical micelles were shown to be more effective than filamentous micelles against both cancer cells. Spherical and filamentous micelles at 5 and 10 µM respective verteporfin concentration resulted in 100% cell killing of lung cancer cells, but both micelles required a higher verteporfin concentration of 20 µM to kill breast cancer cells at the levels of 80% and 50% respectively. This work demonstrates the potential of PEG-PBAE-PEG as a biodegradable, anisotropic drug delivery system as well as the in vitro use of verteporfin-loaded micelles for cancer therapy.

Identification and synthesis of novel inhibitors of mycobacterium ATP synthase.

A non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against M. smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against Mycobacterium tuberculosis (Mtb.H37Rv strain) around the identified hit 1. A scaffold hopping approach was used to identify compounds 14a, 14b and 24a with improved activity against MTb.H37Rv.

Prevalence and correlates of vitamin D deficiency in adults after traumatic brain injury.

OBJECTIVES: Traumatic brain injury (TBI) is a major cause of long-term disability with variable recovery. Preclinical studies suggest that vitamin D status influences the recovery after TBI. However, there is no published clinical data on links between vitamin D status and TBI outcomes. The aim was to determine the (i) prevalence of vitamin D deficiency/insufficiency, and associations of vitamin D status with (ii) demographic factors and TBI severity, and with (iii) cognitive function, symptoms and quality of life, in adults after TBI. DESIGN: Retrospective audit of patients seen between July 2009 and March 2015. Serum vitamin D (25-hydroxy-cholecalciferol) was categorized as deficient (<40 nmol/l), insufficient (40-70 nmol/l) or replete (>70 nmol/l). PATIENTS: A total of 353 adults seen in tertiary hospital clinic (75·4% lighter skinned, 74·8% male, age median 35·1 year, range 26·6-48·3 year), 0·3-56·5 months after TBI (74·5% moderate-severe). MEASUREMENTS: Serum vitamin D concentrations; Addenbrooke's Cognitive Examination (ACE-R), Beck Depression Inventory-II (BDI-II), SF-36 Quality of Life, Pittsburgh Sleep Quality Index. RESULTS: In total, 46·5% of patients after TBI had vitamin D deficiency and 80·2% insufficiency/deficiency. Patients with vitamin D deficiency had lower ACE-R scores than those of vitamin D replete (mean effect size ± SEM 4·5 ± 2·1, P = 0·034), and higher BDI-II scores than those of vitamin D insufficient (4·5 ± 1·6, P = 0·003), correcting for age, gender, time since TBI and TBI severity. There was no association between vitamin D status and markers of TBI severity, sleep or quality of life. CONCLUSION: Vitamin D deficiency is common in patients after TBI and associated with impaired cognitive function and more severe depressive symptoms.