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.

A Research Agenda to Improve Outcomes in Patients with Chronic Obstructive Pulmonary Disease and Cardiovascular Disease. An Official American Thoracic Society Research Statement.

BACKGROUND: Individuals with chronic obstructive pulmonary disease (COPD) are often at risk for or have comorbid cardiovascular disease and are likely to die of cardiovascular-related causes. OBJECTIVES: To prioritize a list of research topics related to diagnosis and management of patients with COPD and comorbid cardiovascular diseases (heart failure, atherosclerotic vascular disease and atrial fibrillation) by summarizing existing evidence and using consensus-based methods. METHODS: A literature search was performed. References were reviewed by committee co-chairs. An international, multidisciplinary committee, including a patient advocate, met virtually to review evidence and identify research topics. A modified Delphi approach was used to prioritize topics in real-time based on their potential for advancing the field. RESULTS: Gaps spanned the translational science spectrum from basic science to implementation: 1) disease mechanisms, 2) epidemiology, 3) subphenotyping, 4) diagnosis and management, 5) clinical trials, 6) care delivery, 7) medication access, adherence and side effects, 8) risk factor mitigation, 9) cardiac and pulmonary rehabilitation, and 10) health equity. Seventeen experts participated and quorum was achieved for all votes (>80%). Of 17 topics, ≥70% agreement was achieved for 12 topics after 2 rounds of voting. Range of summative Likert score was -15 to 25. Highest priority was "Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements." Health equity was identified as an important topic that should be embedded within all research. CONCLUSIONS: We propose a prioritized research agenda with the purpose of stimulating high-impact research that will hopefully improve outcomes among people with COPD and cardiovascular disease.

Efficacy and Safety of Vedolizumab and Tumor Necrosis Factor Inhibitors in the Treatment of Steroid-refractory Microscopic Colitis: A Systematic Review and Meta-analysis.

BACKGROUND: Tumor necrosis factor (TNF-α) inhibitors and the α4ß7 integrin antagonist, vedolizumab, have been investigated as treatment options for patients with steroid-refractory microscopic colitis. AIMS: To evaluate the benefit of vedolizumab and TNF-α inhibitors in patients with steroid-refractory microscopic colitis. METHODS: Retrospective studies and case series involving patients with steroid-refractory MC who either received vedolizumab, adalimumab, or infliximab were eligible for inclusion. Pooled proportional meta-analyses were used to calculate the rate of clinical remission at induction, clinical response, maintenance of remission, histologic remission, and overall medication related adverse effects. Statistical analysis was performed in R using the metafor and meta packages. RESULTS: A total of 14 studies involving 164 patients were included. Pooled analysis showed a clinical remission rate of 63.5% [95% CI (0.483; 0.776), I2=43% P=0.08], 57.8% [95% CI (0.3895; 0.7571), I2=0%, P=0.7541], and 39.3% [95% CI (0.0814; 0.7492), I2=66%, P=0.02] for vedolizumab, infliximab, and adalimumab, respectively. The maintenance of remission rates were 65.9% [95% CI (0.389; 0.889), I2=67%, P=0.02], 45.3% [95% CI (0.1479; 0.7747), I2=0%, P=0.36] and 32.5% [95% CI (0.000; 0.8508), I2=53%, P=0.14] in patients who received vedolizumab, infliximab, and adalimumab, respectively. Rate of biological-related adverse events warranting discontinuation of therapy was 12.2%, 32.9%, and 23.0% for the vedolizumab, infliximab, and adalimumab groups, respectively. CONCLUSION: Vedolizumab and anti-TNF-α agents demonstrated a clinical benefit in the treatment of steroid-refractory microscopic colitis and with a tolerable safety profile. Future randomized controlled trials are needed to compare vedolizumab with TNF-α inhibitors and examine treatment effect on patients' quality of life.

Evaluation of clinical performance and safety for the rechargeable InterStim Micro device in overactive bladder subjects: 6-month results from the global postmarket ELITE study.

AIMS: Sacral neuromodulation (SNM) is an advanced therapy option for the treatment of overactive bladder (OAB), nonobstructive urinary retention, and fecal incontinence. The aim of this ongoing prospective, multicenter, global, postmarket study is to confirm safety and clinical performance of the InterStimTM Micro system for SNM in all indications. Reported here are the results for the OAB cohort through 6-month follow-up. METHODS: Eligible OAB subjects that had a successful therapy evaluation were enrolled after implant of an InterStim Micro implantable pulse generator (IPG). Subjects completed voiding diaries and the Overactive Bladder Quality of Life questionnaire (OAB-q) at baseline and follow-up visits occurring at 3 months and 6 months postimplant. Safety was evaluated as device-, procedure-, or therapy-related adverse events. The primary objective for the OAB cohort was to demonstrate an improvement in OAB-q Health Related Quality of Life (HRQL) total score at 3 months postimplant compared to baseline. RESULTS: Sixty-eight OAB subjects were enrolled and implanted with an InterStim Micro IPG. Of those, 67 and 66 subjects completed the 3- and 6-month follow-up visits, respectively. The OAB-q HRQL demonstrated a statistically significant improvement from baseline to 3-month follow-up with an average increase of 33 ± 24 points (n = 67, p < 0.001). The change was also observed at 6-months with an average increase of 31 ± 23 points (n = 65) compared to baseline. Eighty-two percent of subjects achieved the minimally important difference in HRQL score at 3- and 6-month, respectively, with a change of 10 points or greater. The majority of subjects reported that their bladder condition was better at 3-month (92.5%, 62/67) and 6-month (89%, 59/66) compared to before they were treated with SNM therapy delivered by the InterStim Micro system. For subjects with urgency urinary incontinence (UUI), the average change from baseline to follow-up in UUI episodes/day was -3.6 (95% CI: -4.7, -2.6; n = 62) at 3-month and -3.7 (95% CI: -4.7, -2.7; n = 61) at 6-month. Among subjects with urgency-frequency (UF), the average change from baseline to follow up in voids/day was -4.5 (95% CI: -6.3, -2.7; n = 52) at 3-months and -4.4 (95% CI: -6.0, -2.7; n = 52) at 6-month. The cumulative incidence of device-, procedure-, or therapy- related adverse events was 7.4% (5/68). Out of these five related adverse events, there was one serious adverse event (1.5%, implant site pain) at the time of database snapshot. CONCLUSIONS: These data confirm the safety and clinical performance of the InterStim Micro device for subjects with OAB by demonstrating a significant improvement in OAB-q HRQL score at 3-month. Similar improvements were observed at 6 months in addition to an incidence of adverse events that is comparable to previously reported rates for SNM.

Association between obstructive sleep apnea and gastroesophageal reflux disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: We aim to conduct a systematic review and determine the association between obstructive sleep apnea (OSA) and gastroesophageal reflux disease (GERD). METHODS: Literature search for eligible studies was performed across major databases. The main endpoint was to assess the association between GERD and OSA. Subgroup analyses were performed to determine this strength of the association stratified by the diagnostic tools used for OSA (nocturnal polysomnogram or Berlin questionnaire) and GERD (validated reflux questionnaire or esophagogastroduodenoscopy). We also compared sleep efficiency, apnea hypopnea index, oxygen desaturation index, and Epworth Sleepiness Scale in OSA patients with or without GERD. Results were pooled together using Reviewer Manager 5.4. RESULTS: Six studies involving 2950 patients with either GERD or OSA were included in the pooled analysis. Our findings suggest that there was a statistically significant unidirectional association between GERD and OSA (odds ratio [OR] = 1.53, P = 0.0001). Subgroup analyses redemonstrated an OSA-GERD association irrespective of the tools used for diagnosing either GERD or OSA (P = 0.24 and P = 0.82, respectively). Sensitivity analyses demonstrated the same association after controlling for gender (OR = 1.63), BMI (OR = 1.81), smoking (OR = 1.45), and alcohol consumption (OR = 1.79). In patients with OSA, there were no statistically significant differences between patients with or without GERD in terms of apnea hypopnea index (P = 0.30), sleep efficiency (P = 0.67), oxygen desaturation index (P = 0.39), and Epworth Sleepiness Scale (P = 0.07). CONCLUSION: There exists an association between OSA and GERD that is independent of the modalities used for screening or diagnosing both disorders. However, the presence of GERD did not affect the severity of OSA.

Effect of computer-aided colonoscopy on adenoma miss rates and polyp detection: A systematic review and meta-analysis.

BACKGROUND AND AIM: Multiple computer-aided techniques utilizing artificial intelligence (AI) have been created to improve the detection of polyps during colonoscopy and thereby reduce the incidence of colorectal cancer. While adenoma detection rates (ADR) and polyp detection rates (PDR) are important colonoscopy quality indicators, adenoma miss rates (AMR) may better quantify missed lesions, which can ultimately lead to interval colorectal cancer. The purpose of this systematic review and meta-analysis was to determine the efficacy of computer-aided colonoscopy (CAC) with respect to AMR, ADR, and PDR in randomized controlled trials. METHODS: A comprehensive, systematic literature search was performed across multiple databases in September of 2022 to identify randomized, controlled trials that compared CAC with traditional colonoscopy. Primary outcomes were AMR, ADR, and PDR. RESULTS: Fourteen studies totaling 10 928 patients were included in the final analysis. There was a 65% reduction in the adenoma miss rate with CAC (OR, 0.35; 95% CI, 0.25-0.49, P < 0.001, I2  = 50%). There was a 78% reduction in the sessile serrated lesion miss rate with CAC (OR, 0.22; 95% CI, 0.08-0.65, P < 0.01, I2  = 0%). There was a 52% increase in ADR in the CAC group compared with the control group (OR, 1.52; 95% CI, 1.39-1.67, P = 0.04, I2  = 47%). There was 93% increase in the number of adenomas > 10 mm detected per colonoscopy with CAC (OR 1.93; 95% CI, 1.18-3.16, P < 0.01, I2  = 0%). CONCLUSIONS: The results of the present study demonstrate the promise of CAC in improving AMR, ADR, PDR across a spectrum of size and morphological lesion characteristics.

Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer.

Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions. Here, we explore an approach to identify potential synthetic-lethal interactions by screening mutually exclusive deletion patterns in cancer genomes. We sought to identify 'synthetic-essential' genes: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumour-suppressor deficiency. We also posited that such synthetic-essential genes would be therapeutic targets in cancers that harbour specific tumour-suppressor deficiencies. In addition to known synthetic-lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic-essential gene in PTEN-deficient cancers. In PTEN-deficient prostate and breast cancers, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential. Mechanistically, functional PTEN stimulates the GSK3ß-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the ß-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 modification to activate transcription of the pro-tumorigenic TNF-NF-κB gene network. This study identifies a novel PTEN pathway in cancer and provides a framework for the discovery of 'trackable' targets in cancers that harbour specific tumour-suppressor deficiencies.

Combination Topical Epinephrine and Non-steroidal Inflammatory Drugs in the Prevention of Post-ERCP Pancreatitis: A Systematic Review.

BACKGROUND: The utility of combination rectal NSAID and topical epinephrine (EI) or rectal NSAID and normal saline (SI) sprayed on duodenal papilla in the prevention of post-ERCP pancreatitis (PEP) has been studied but results have been conflicting. AIMS: To evaluate the benefit of using combination prophylaxis in preventing PEP. METHODS: A literature search was performed using Scopus, PubMed/MEDLINE, and Cochrane databases in May 2021. Randomized controlled trials (RCTs) involving adults patients who underwent ERCP and received EI versus SI were eligible for inclusion. The pooled effect was expressed as odds ratio (OR) to assess the rate of PEP, severity of PEP, and specific adverse events. The results were pooled using Reviewer Manager 5.4 software. RESULTS: Six RCTs involving 4016 patients were included in the final analysis. The EI group did not demonstrate any significant benefit over SI group in preventing PEP (OR = 1.00, 95% CI [0.68, 1.45], P = 0.98), irrespective of gender or the epinephrine concentration used. The tests for subgroup differences were not statistically significant with P-values of 0.66 and 0.28, respectively. The addition of topical epinephrine to rectal NSAID did not improve the rate of moderate to severe PEP (OR = 0.94, P = 0.86) or PEP in high-risk patients (OR = 1.14, 95%, P = 0.73). The rates of infection, including cholangitis and sepsis (OR = 0.63, P = 0.07), gastrointestinal bleeding (OR = 1.25, P = 0.56) and procedure-related death (OR = 0.71, P = 0.59) were similar between both groups. CONCLUSION: The addition of topical epinephrine did not demonstrate any benefit over rectal NSAID alone in preventing PEP or reducing other procedure-related adverse events.

Accurate predictions of thermoset resin glass transition temperatures from all-atom molecular dynamics simulation.

To enable the design and development of the next generation of high-performance composite materials, there is a need to establish improved computational simulation protocols for accurate and efficient prediction of physical, mechanical, and thermal properties of thermoset resins. This is especially true for the prediction of glass transition temperature (Tg), as there are many discrepancies in the literature regarding simulation protocols and the use of cooling rate correction factors for predicting values using molecular dynamics (MD) simulation. The objectives of this study are to demonstrate accurate prediction the Tg with MD without the use of cooling rate correction factors and to establish the influence of simulated conformational state and heating/cooling cycles on physical, mechanical, and thermal properties predicted with MD. The experimentally-validated MD results indicate that accurate predictions of Tg, elastic modulus, strength, and coefficient of thermal expansion are highly reliant upon establishing MD models with mass densities that match experiment within 2%. The results also indicate the cooling rate correction factors, model building within different conformational states, and the choice of heating/cooling simulation runs do not provide statistically significant differences in the accurate prediction of Tg values, given the typical scatter observed in MD predictions of amorphous polymer properties.

Endoscopic ultrasound-guided portal pressure gradient with liver biopsy: 6 years of endo-hepatology in practice.

BACKGROUND AND AIM: The portal pressure gradient (PPG) is a useful predictor of portal hypertension (PH) related complications. We previously showed the feasibility and safety of endoscopic ultrasound guided PPG measurement (EUS-PPG). Now EUS-guided liver biopsy (EUS-bx) has been shown to be a safe and effective alternative to percutaneous or Interventional Radiology-guided liver biopsy for the diagnosis of chronic liver disease (CLD). We aimed to evaluate the correlation between PPG and clinical markers of PH, and assess the feasibility and safety of concomitant, single session EUS-PPG and EUS-bx. METHODS: This was a retrospective study of patients undergoing EUS-PPG for CLD at a single tertiary endoscopy center between February 2014 and March 2020. EUS-PPG was performed using a 25-gauge needle and compact manometer. Data analysis was performed with SAS version 9.4. RESULTS: Eighty-three patients underwent EUS-PPG with 100% technical success. The mean PPG was 7.06 mmHg (SD 6.09, range 0-27.3). PPG was higher in patients with (vs without) clinical features of cirrhosis (9.46 vs 3.61 mmHg, P < 0.0001), esophageal or gastric varices (13.88 vs 4.34 mmHg, P < 0.0001), and thrombocytopenia (9.25 vs 4.71 mmHg, P = 0.0022). In the 71 patients (85.5%) who underwent EUS-bx, 70 (98.6%) specimens were deemed adequate by the pathologist for histologic diagnosis. There were no early or late major adverse events. CONCLUSION: EUS-PPG correlates well with clinical markers of PH. EUS-bx can be performed safely during the same session as EUS-PPG, providing a comprehensive endoscopic evaluation of the patient with CLD.

High Return to Play and Low Reinjury Rates in National Collegiate Athletic Association Division I Football Players Following Anterior Cruciate Ligament Reconstruction Using Quadrupled Hamstring Autograft.

PURPOSE: The purpose of this study was to examine the outcomes of anterior cruciate ligament (ACL) reconstruction using quadrupled hamstring (QH) autograft in a cohort of National Collegiate Athletic Association (NCAA) Division I football players. METHODS: A retrospective analysis was performed on NCAA Division I football players at a single institution who had transtibial ACL reconstruction using QH autograft between 2001 and 2016. Primary outcomes were ACL reinjury and return to play (RTP). Secondary outcomes were position, percent of eligibility used after surgery, graft diameter, Tegner-Lysholm scores, concomitant injuries/surgeries, and postcollegiate professional play. RESULTS: Between 2001 and 2016, 34 players had QH autograft ACL reconstruction, and 29 players achieved RTP. Of the 29, 2 (6.9%) sustained ACL reinjuries. The average RTP was 318 days (range 115-628) after surgery. Players used 79.5% of their remaining collegiate eligibility after surgery. Nine players sustained multiligamentous knee injuries. This did not have a significant effect on RTP (P = 0.709; mean 306±24 days for isolated ACL, mean of 353±51 for 2 ligaments, mean of 324±114 for 3 + ligaments) and none sustained reinjury. Associated meniscal injuries were sustained by 28, and 8 sustained chondral injuries. The mean postoperative Tegner-Lysholm score was 90.7 of 100, with mean follow-up of 102 months. Of these players, 18 went on to play professionally, with 17 joining National Football League rosters and 1 an arena team roster. CONCLUSION: QH demonstrated an ACL reinjury and RTP rates similar to those in previously published, predominantly bone-patella tendon-bone ACL reinjury data in elite athletes. This study demonstrates that QH autograft may be a viable option in elite athletes. LEVEL OF EVIDENCE: IV, case series.

Public Health Representation on Active Transportation Bodies Across US Municipalities.

CONTEXT: Municipal bodies such as planning or zoning commissions and active transportation advisory committees can influence decisions made by local governments that support physical activity through active transportation. Public health professionals are encouraged to participate in and inform these processes. However, the extent of such collaboration among US municipalities is currently unknown. OBJECTIVE: To estimate the prevalence of active transportation bodies among US municipalities and the proportion with a designated public health representative. DESIGN: A cross-sectional survey administered from May through September 2014. SETTING: Nationally representative sample of US municipalities with populations of 1000 or more people. PARTICIPANTS: Respondents were the city or town manager, planner, or person with similar responsibilities (N = 2018). MAIN OUTCOME MEASURES: The prevalence of planning or zoning commissions and active transportation advisory committees among municipalities and whether there was a designated public health representative on them. RESULTS: Approximately 90.9% of US municipalities have a planning or zoning commission, whereas only 6.5% of these commissions have a designated public health representative. In contrast, while 16.5% of US municipalities have an active transportation advisory committee, 22.4% of them have a designated public health representative. These active transportation bodies are less common among municipalities that are smaller, rural, located in the South, and where population educational attainment is lower. Overall, few US municipalities have a planning or zoning commission (5.9%) or an active transportation advisory committee (3.7%) that also has a designated public health representative. CONCLUSIONS: Approximately 9 in 10 US municipalities have a planning or zoning commission, whereas only 1 in 6 has an active transportation advisory committee. Public health representation on active transportation bodies across US municipalities is low. Increasing the adoption of active transportation advisory committees and ensuring a designated public health representative on active transportation bodies may help promote the development of activity-friendly communities across the United States.

Mental Health Indices of Intensive Care Unit and Emergency Room Frontliners during the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic in India.

BACKGROUND: The contagious coronavirus disease-2019 (COVID-19) pandemic has had a significant psychological impact on healthcare workers. Intensive care unit (ICU) and emergency room (ER) providers have functioned in an environment of fear for their health as well as their family well-being. AIM AND OBJECTIVE: The aim and objective of the article was to study mental health disorders (anxiety, depression, stress, post-traumatic stress disorder (PTSD), and sleep quality) in frontliners and to identify factors affecting mental health indices. MATERIALS AND METHODS: A survey of 153 doctors and nurses working in ICU and ER was conducted from December 2020 to January 2021 using questionnaire with clinically validated scales: Acute Stress Disorder Scale, Perceived Stress Scale, Beck's Depression Inventory (BDI), Zung Self-rating Anxiety Scale (SAS), Global Pittsburgh Sleep Quality Index (PSQI), Multidimensional Scale of Perceived Social Support (MSPS), and New General Self-efficacy (NGSE) Scale. Analysis was performed to identify of gender, age, place of work, self-efficacy, and social support using logistic regression. RESULTS: Of the 153 participants, 21.6% had PTSD, 88.6% had moderate to high stress, 16.3% had anxiety, and 59.5% had poor sleep. Of these, the majority were females and those aged ≤30 years. Males had lesser depression, anxiety, and poor sleep compared to females (p <0.05). Participants working in ER reported higher stress as compared to those working in ICU (p <0.05). PTSD, perceived stress, depression, anxiety, and poor sleep were higher in participants with low-to-moderate perceived self-efficacy as compared to participants with high self-efficacy (p <0.05). CONCLUSION: This study reveals significant psychological distress among ER and ICU frontliners during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a typical high-acuity environment during the nonpandemic times. HOW TO CITE THIS ARTICLE: Vadi S, Shah S, Bajpe S, George N, Santhosh A, Sanwalka N, et al. Mental Health Indices of Intensive Care Unit and Emergency Room Frontliners during the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic in India. Indian J Crit Care Med 2022;26(1):100-107.

Underwater versus conventional EMR for colorectal polyps: systematic review and meta-analysis.

BACKGROUND AND AIMS: Underwater EMR (UEMR) has emerged as an attractive alternative to conventional EMR (CEMR) for the resection of colorectal polyps. The purpose of this systematic review and meta-analysis was to compare UEMR and CEMR for the resection of colorectal polyps with respect to efficacy and safety. METHODS: A literature search was performed across multiple databases, including MEDLINE/PubMed, The Cochrane Library, CINAHL, Google Scholar, and Scopus, for studies that were published until May 2020. Only studies that compared the resection of colorectal polyps using UEMR with CEMR were included. Outcomes examined included rates of en bloc resection, recurrence, postprocedure bleeding, perforation, and resection time. RESULTS: Seven studies totaling 1237 polyps were included: 614 polyps were resected with UEMR and 623 polyps with CEMR. UEMR was associated with a significant increase in the rate of overall en bloc resection (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.42-2.39; P < .001; I2 = 38%), with subgroup analysis showing a significant increase in the rates of en bloc resection in polyps ≥20 mm (OR, 1.51; 95% CI, 1.06-2.14; P = .02; I2 = 44%) but not in polyps <20 mm (OR, 1.07; 95% CI, .65-1.76; P = .80; I2 = 27%), and with a significant reduction in the rate of recurrence (OR, .30; 95% CI, .16-.57; P = .0002; I2 = 0%), again driven by improvements in polyps ≥20 mm. There was no significant difference in postprocedure bleeding (OR, 1.11; 95% CI, .57-2.17; P = .76; I2 = 0%) or perforation (OR, .72; 95% CI, .19-2.83; P = .64; I2 = 0%). CONCLUSIONS: The results of this systematic review and meta-analysis demonstrate that UEMR is a safe and efficacious alternative to CEMR. With appropriate training, UEMR may be strongly considered as a first-line option for resection of colorectal polyps.

A prospective, multicenter, international study to explore the effect of three different amplitude settings in female subjects with urinary urge incontinence receiving interstim therapy.

AIMS: The aim of this study is to evaluate the effect of sub-sensory amplitude settings of sacral neuromodulation therapy on overactive bladder symptoms in subjects with urinary urge incontinence. METHODS: Subjects who qualified for a neurostimulator device implant were randomized to one of three amplitude settings (50% of sensory threshold [ST], 80% of ST, and ST). Subjects completed urinary voiding diaries (3-day), International consultation on incontinence modular questionnaire-overactive bladder symptoms quality of life questionnaire, and patient global impression of improvement (PGI-I) to assess change in voiding symptoms and quality of life (QoL) from baseline through 12 weeks. RESULTS: Forty-eight subjects had a successful test stimulation, 46 were implanted with a neurostimulator device and 43 completed the 12-week follow-up visit. The change from baseline to 12 weeks is -3.0 urinary incontinence (UI) episodes/day (95% confidence interval [CI]: -4.4 to -1.7) for the 50% of sensory threshold group, -2.9 UI episodes/day (95% CI: -4.7 to -1.2) for 80% of sensory threshold group, and -3.6 UI episodes/day (95% CI: -5.2 to -1.9) for the sensory threshold group. In each randomized group, improvements were observed in health-related QoL, its subscales, and symptom interference. Subjects across all three randomization groups reported on the PGI-I that their bladder condition was better at 12 weeks compared to before they were treated with InterStim therapy. CONCLUSION: These findings provide insights into possible advancements in the postimplantation phase of therapy with potential for improved patient comfort and increased device longevity.

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.

Rotational Pedicle Myocutaneous Forearm Fillet Flap Used to Fill Forequarter Amputation Defect: Indications and Uses.

A full-thickness fourth-degree burn to a large area of the upper extremity may require a forequarter amputation. Whereas our case describes a burn injury, forequarter amputations may more commonly be done in oncological surgery. In addition to the challenge of providing well-vascularized tissue coverage, the burn patient may also pose the complication of respiratory compromise in a systemically ill person. Fillet flaps have often been utilized as "spare part" reconstruction. Although previous forequarter amputations have been covered with free myocutanous forearm fillet flaps, we devised a rotational pedicle myocutaneous forearm fillet flap that might be less complex than a microvascular reconstruction. This article describes the technique and advantages of the pedicle fillet flap of the upper limb. This technique eliminates the risks of delayed warm ischemia time and avoids additional morbidity of donor sites. Although we sought to find a simpler, more rapid procedure for a burn patient, the pedicle forearm fillet flap has applications for both burn and oncological forequarter amputation defects. It provides a good combination of large tissue coverage with maximum perfusion of muscle bulk. The pedicle flap also enabled us to keep the distal part vascularized and to "bank" it for later use when the recipient area was well vascularized and free of infection.