Real-world effectiveness of airway clearance techniques in children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is commonly characterised by thick respiratory mucus. From diagnosis, people with CF are prescribed daily physiotherapy, including airway clearance techniques (ACTs). ACTs consume a large proportion of treatment time, yet the efficacy and effectiveness of ACTs are poorly understood. This study aimed to evaluate associations between the quality and quantity of ACTs and lung function in children and young people with CF. METHODS: Project Fizzyo, a longitudinal observational cohort study in the UK, used remote monitoring with electronic pressure sensors attached to four different commercial ACT devices to record real-time, breath-by-breath pressure data during usual ACTs undertaken at home over 16 months in 145 children. ACTs were categorised either as conformant or not with current ACT recommendations based on breath pressure and length measurements, or as missed treatments if not recorded. Daily, weekly and monthly associations between ACT category and lung function were investigated using linear mixed effects regression models adjusting for clinical confounders. RESULTS: After exclusions, 45 224 ACT treatments (135 individuals) and 21 069 days without treatments (141 individuals) were analysed. The mean±sd age of participants was 10.2±2.9 years. Conformant ACTs (21%) had significantly higher forced expiratory volume in 1 s (FEV1) (mean effect size 0.23 (95% CI 0.19-0.27) FEV1 % pred per treatment) than non-conformant (79%) or missed treatments. There was no benefit from non-conformant or missed treatments and no significant difference in FEV1 between them (mean effect size 0.02 (95% CI -0.01-0.05) FEV1 % pred per treatment). CONCLUSIONS: ACTs are beneficial when performed as recommended, but most people use techniques that do not improve lung function. Work is needed to monitor and improve ACT quality and to increase the proportion of people doing effective airway clearance at home.

Direct Oral Anticoagulants and Coronary Artery Disease.

Coronary artery disease is a leading cause of morbidity and mortality worldwide. Acute coronary syndrome as a first presentation is common and patients with established disease have a high rate of recurrent ischemic events, despite antiplatelet therapy. Over the past several years, direct oral anticoagulants have become available and have been studied in patients with coronary artery disease. These medications directly inhibit either thrombin or factor Xa which contribute to atherothrombosis. This review will summarize the clinical data regarding the use of direct oral anticoagulants in different patient populations with coronary disease and the balance between protection against ischemia and bleeding. Additionally, the review will summarize the available data on the use of direct oral anticoagulants periprocedurally in patients undergoing percutaneous coronary intervention. The future direction of coronary artery disease and the role of direct oral anticoagulants will rely on further studies determining the optimal combination of antiplatelet and oral anticoagulant regimens that derive ischemic benefit without increased rates of bleeding. Additional upstream blockade of the coagulation cascade with factor XIIa and factor XIa inhibitors may also improve treatment in the future.

Presence and activation of pro-inflammatory macrophages are associated with CRYAB expression in vitro and after peripheral nerve injury.

BACKGROUND: Inflammation constitutes both positive and negative aspects to recovery following peripheral nerve injury. Following damage to the peripheral nervous system (PNS), immune cells such as macrophages play a beneficial role in creating a supportive environment for regrowing axons by phagocytosing myelin and axonal debris. However, a prolonged inflammatory response after peripheral nerve injury has been implicated in the pathogenesis of negative symptoms like neuropathic pain. Therefore, the post-injury inflammation must be carefully controlled to prevent secondary damage while allowing for regeneration. CRYAB (also known as alphaB-crystallin/HSPB5) is a small heat shock protein that has many protective functions including an immunomodulatory role in mouse models of multiple sclerosis, spinal cord injury, and stroke. Because its expression wanes and rebounds in the early and late periods respectively after PNS damage, and CRYAB null mice with sciatic nerve crush injury display symptoms of pain, we investigated whether CRYAB is involved in the immune response following PNS injury. METHODS: Sciatic nerve crush injuries were performed in age-matched Cryab knockout (Cryab-/-) and wildtype (WT) female mice. Nerve segments distal to the injury site were processed by immunohistochemistry for macrophages and myelin while protein lysates of the nerves were analyzed for cytokines and chemokines using Luminex and enzyme-linked immunosorbent assay (ELISA). Peritoneal macrophages from the two genotypes were also cultured and polarized into pro-inflammatory or anti-inflammatory phenotypes where their supernatants were analyzed for cytokines and chemokines by ELISA and protein lysates for macrophage antigen presenting markers using western blotting. RESULTS: We report that (1) more pro-inflammatory CD16/32+ macrophages are present in the nerves of Cryab-/- mice at days 14 and 21 after sciatic nerve crush-injury compared to WT counterparts, and (2) CRYAB has an immunosuppressive effect on cytokine secretion [interleukin (IL)-ß, IL-6, IL-12p40, tumor necrosis factor (TNF)-α] from pro-inflammatory macrophages in vitro. CONCLUSIONS: CRYAB may play a role in curbing the potentially detrimental pro-inflammatory macrophage response during the late stages of peripheral nerve regeneration.

Immunocytochemical detection of minichromosome maintenance protein 2 as a potential urinary-based marker of bladder cancer: A prospective observational study.

INTRODUCTION: Numerous biomarkers have been investigated for the diagnosis and follow-up of patients with bladder cancer, but none has achieved desirable acceptability. In the search of biomarkers, minichromosome maintenance protein 2 (MCM2), a cell cycle regulatory protein, was investigated and the preliminary results were promising. Hence, we conducted a study to investigate the role of immunocytochemical (ICC) detection of MCM2 in voided urinary samples of patients with bladder cancer in an Indian population. MATERIALS AND METHODS: A prospective comparative observational study was performed. One hundred and fifty patients with a mass lesion in the bladder and 100 controls were enrolled in this prospective study from June 2017 to-December 2018. Fifty-milliliter of voided urine sample was collected and processed for ICC staining of MCM2. RESULTS: Fifty, 100, and 200 positive MCM2 cells as a cutoff value has shown a sensitivity of 87.33% (80.93%-92.20%), 84.67% (77.89%-90.02%), and 80.67% (73.43%-86.65%), respectively. The specificity of 50, 100, and 200 positive MCM2 cells was 97% (91.48%-99.38%), 99% (94.55%-99.97%), and 100% (96.38%-100.0%), respectively. CONCLUSION: ICC detection of MCM2 in voided urinary samples has good sensitivity and specificity for the detection of bladder cancer. Hence, it can be used as a potential marker for the detection of bladder cancer.

PARP inhibitor, olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice.

We have previously shown that PARP-1 inhibition provides protection against lung inflammation in the context of asthma and acute lung injury. Olaparib is a potent new generation PARP inhibitor that has been approved for human testing. The present work was designed to evaluate its beneficial potential against LPS-induced acute lung injury and acute kidney injury upon intratracheal administration of the endotoxin in mice. Administration of olaparib at different doses, 30 min after LPS treatment showed that single intraperitoneal injection of the drug at 5 mg/kg b.wt. reduced the total number of inflammatory cells particularly neutrophils in the lungs. This was associated with reduced pulmonary edema as the total protein content in the bronchoalveolar fluid was found to be decreased substantially. Olaparib provided strong protection against LPS-mediated secondary kidney injury as reflected by restoration of serum levels of urea, creatinine, and uric acid toward normal. The drug restored the LPS-mediated redox imbalance toward normal in lung and kidney tissues as assessed by measuring malondialdehyde and GSH levels. Finally, RT-PCR data revealed that olaparib downregulates the LPS-induced expression of NF-κB-dependent genes namely TNF-α, IL-1ß, and VCAM-1 in the lungs without altering the expression of total p65NF-κB. Overall, the data suggest that olaparib has a strong potential to protect against LPS-induced lung injury and associated dysfunctioning of kidney in mice. Given the fact that olaparib is approved by FDA for human testing, our findings can pave the way for testing of the drug on humans inflicted with acute lung injury.

Quantity and quality of airway clearance in children and young people with cystic fibrosis.

Children and young people with CF (CYPwCF) get advice about using positive expiratory pressure (PEP) or oscillating PEP (OPEP) devices to clear sticky mucus from their lungs. However, little is known about the quantity (number of treatments, breaths, or sets) or quality (breath pressures and lengths) of these daily airway clearance techniques (ACTs) undertaken at home. This study used electronic pressure sensors to record real time breath-by-breath data from 145 CYPwCF (6-16y) during routine ACTs over 2 months. ACT quantity and quality were benchmarked against individual prescriptions and accepted recommendations for device use. In total 742,084 breaths from 9,081 treatments were recorded. Individual CYPwCF maintained consistent patterns of ACT quantity and quality over time. Overall, 60% of CYPwCF did at least half their prescribed treatments, while 27% did fewer than a quarter. About 77% of pre-teens did the right number of daily treatments compared with only 56% of teenagers. CYPwCF usually did the right number of breaths. ACT quality (recommended breath length and pressure) varied between participants and depended on device. Breath pressures, lengths and pressure-length relationships were significantly different between ACT devices. PEP devices encouraged longer breaths with lower pressures, while OPEP devices encouraged shorter breaths with higher pressures. More breaths per treatment were within advised ranges for both pressure and length using PEP (30-31%) than OPEP devices (1-3%). Objective measures of quantity and quality may help to optimise ACT device selection and support CYPwCF to do regular effective ACTs.

Catheter ablation using pulmonary vein isolation with versus without left atrial posterior wall isolation for persistent atrial fibrillation: an updated systematic review and meta-analysis.

BACKGROUND: Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation of atrial fibrillation (AF); however, the results are suboptimal for persistent AF. The left atrial posterior wall (LAPW) is thought to be a major additional area in initiation and perpetuation of persistent AF. Therefore, adjunctive ablation of the posterior wall may reduce AF recurrence in patients with persistent AF. OBJECTIVE: The objective of this study was to compare outcomes of catheter ablation in patients with persistent AF using PVI alone versus a combination of PVI and LAPW isolation. METHODS: Literature search was conducted in PubMed, PubMed Central, Scopus, and Embase since inception to February 2023. Screening of studies was done via Covidence software. Risk of bias assessment was done using appropriate tools. Data extraction and a narrative synthesis were carried out accordingly. RESULTS: Ten studies were included, of which five were randomized controlled trials. PVI with LAPW ablation group had significantly lower recurrence of overall atrial tachyarrhythmia (OR 0.47, CI 0.32-0.70) and AF (OR 0.39, CI 0.23-0.69). In sensitivity analysis, freedom from atrial arrhythmias was noted to be significantly higher in the PVI with LAPW ablation group (OR 2.22, CI 1.36-3.64). However, there was no significant difference in occurrence of atrial flutter (OR 1.36, CI 0.86-2.14) or with periprocedural adverse events (OR 1.10, CI 0.60-1.99). CONCLUSION: LAPW ablation, in addition to PVI, significantly improves the rates of arrhythmia freedom and reduces the recurrence of overall atrial tachyarrhythmia. There was no significant difference in atrial flutter or periprocedural adverse events.

Case report: paradoxically reversible perfusion defects on vasodilator stress imaging in a case of metastatic coronary compression.

Background: Patients with malignancy who experience metastasis to cardiac structures may exhibit ST-segment elevations and acute coronary syndrome (ACS) through poorly understood pathophysiologic mechanisms. We present a case in which vasodilator stress cardiovascular magnetic resonance provides unique insight into one such patient who suffered from recurrent episodes resembling ACS. Case summary: A 58-year-old male with metastatic lung adenocarcinoma presented with refractory angina and dynamic inferior electrocardiogram changes. The patient was referred for adenosine stress cardiovascular magnetic resonance, revealing multiple territories of abnormal perfusion during rest with improvement during adenosine infusion. Subsequent computed tomography displayed tumour encasement of the right coronary artery. Taken together, vasodilator-responsive extrinsic compression of multiple epicardial coronary arteries was suspected. Outpatient oncology follow-up for chemoimmunotherapy initiation was arranged with the hope that reducing tumour burden might alleviate coronary compression. However, in the ensuing months, the patient's disease advanced beyond the point of which his symptoms could be controlled medically, and he was ultimately enrolled in hospice care. Discussion: Encasement of coronary arteries can result in anginal symptoms if their position impairs coronary arterial flow. The presented case highlights the unique manner in which these lesions might behave on stress cardiac magnetic resonance imaging. Clinicians who encounter such unusual findings on vasodilator stress imaging should consider metastatic lesions to the cardiac structures on the differential diagnosis.

QT Prolongation and In-Hospital Ventricular Arrhythmic Complications in Patients With Apical Ballooning Takotsubo Syndrome.

BACKGROUND: Takotsubo syndrome is associated with life threatening arrhythmias, and the apical ballooning pattern is characterized by a peculiar QT prolongation and particularly high-risk of arrhythmias. OBJECTIVES: The aim of the study was to determine the association of QT interval on electrocardiogram for ventricular arrhythmic complications in patients with apical ballooning Takotsubo syndrome in a diverse population at a large urban hospital in the U.S. METHODS: We reviewed 105 cases of apical ballooning Takotsubo syndrome in patients admitted between 2011 and 2017. Two cardiologists reviewed the electrocardiograms to measure QT interval, adjusted for rate using the Fridericia formula (QTCF), and ventricular arrhythmic complications during the hospitalization. Data are reported as median and interquartile range or number and percentage. RESULTS: Of the 105 patients, 86 (82%) were female, and 34 (32%) were self-reported Black or African American. The mean age was 65 years (range: 58-72 years). Left ventricular ejection fraction was 25% (range: 25%-35%). Heart rate was 101 beats/min (range: 83-121 beats/min). Ten (11%) patients experienced a ventricular arrhythmic complication and had significantly longer QTCF (470 [range: 422-543] milliseconds) than did those without complications (417 [range: 383-456] milliseconds, P = 0.031). The area under the curve for QTCF was 0.708 (95% CI: 0.536-0.880; P = 0.031). Twenty-eight (27%) patients had a QTCF ≥460 milliseconds and significantly more arrhythmic complications (21% vs 5%, odds ratio 4.997 [95% CI: 1.288-19.237], P = 0.021). QTCF was an independent predictor of ventricular arrhythmias: odds ratio 1.090 for each 10-millisecond increase in QTCF (95% CI: 1.004-1.183; P = 0.040, corrected for sex). CONCLUSIONS: In a diverse population of patients with apical ballooning Takotsubo syndrome admitted to a large urban hospital in the United States, QTCF at admission ≥460 milliseconds identifies patients at high risk for in-hospital arrhythmic complications. Further studies are needed to determine strategies aimed at shortening QT interval to potentially prevent life-threatening arrhythmic events.

Impact of intrarectal chromofungin treatment on dendritic cells-related markers in different immune compartments in colonic inflammatory conditions.

BACKGROUND: Chromofungin (CHR: chromogranin-A 47-66) is a chromogranin-A derived peptide with anti-inflammatory and anti-microbial properties. Ulcerative colitis (UC) is characterized by a colonic decrease of CHR and a dysregulation of dendritic CD11c+ cells. AIM: To investigate the association between CHR treatment and dendritic cells (DCs)-related markers in different immune compartments in colitis. METHODS: A model of acute UC-like colitis using dextran sulphate sodium (DSS) was used in addition to biopsies collected from UC patients. RESULTS: Intrarectal CHR treatment reduced the severity of DSS-induced colitis and was associated with a significant decrease in the expression of CD11c, CD40, CD80, CD86 and interleukin (IL)-12p40 in the inflamed colonic mucosa and CD11c, CD80, CD86 IL-6 and IL-12p40 within the mesenteric lymph nodes and the spleen. Furthermore, CHR treatment decreased CD80 and CD86 expression markers of splenic CD11c+ cells and decreased NF-κB expression in the colon and of splenic CD11c+ cells. In vitro, CHR decreased CD40, CD80, CD86 IL-6 and IL-12p40 expression in naïve bone marrow-derived CD11c+ DCs stimulated with lipopolysaccharide. Pharmacological studies demonstrated an impact of CHR on the NF-κB pathway. In patients with active UC, CHR level was reduced and showed a negative linear relationship with CD11c and CD86. CONCLUSION: CHR has protective properties against intestinal inflammation via the regulation of DC-related markers and CD11c+ cells. CHR could be a potential therapy of UC.

Deceased Donor Renal Transplantation: A Single Center Experience.

INTRODUCTION: Deceased donor kidney transplant are still not common across India. This study was done to assess various measures taken at a single center level to increase organ donation rate and to analyse the outcomes of transplants performed from these donors. METHODS: All deceased donor renal transplants performed from November 2011 to February 2017 were analysed for patient and death censored graft survival, rate of delayed graft function, rate of rejection and mortality. Kaplan Meir analysis for Survival Curves was used. RESULTS: Organ donation rate at our center improved from one donation every alternate year in 2004 to a peak of 44 donations in 2017. Patient survival was 93.42%, 89.44%, 85.53%, and death censored graft survival was 94.07%, 88.21%, and 82.86% at 1, 2 and 3 years respectively. Mean duration of hemodialysis pre transplantation was 34.6 ± 27.43 months. CONCLUSIONS: This study has shown that steps taken at a single center level alone can also significantly improve organ donation rates. Employment of dedicated professionals including transplant surgeons and coordinators, developing a protocol-based approach for referral, and early counseling in triage along with regular audits can help to establish deceased donor program with acceptable outcomes elsewhere in the country.

Cardiovascular disease and prevention among people living with HIV in South Florida.

ABSTRACT: Antiretroviral therapy (ART) has improved survival of patients living with HIV (PLWH); however, this has been accompanied by an increase in cardiovascular disease (CVD). Although preventative measures for CVD among the general population are well described, information is limited about CVD prevention among PLWH. The goal of this study was to characterize the prevalence of CVD in our population and to assess the use of primary and secondary prevention.We performed a retrospective review of PLWH receiving primary care at a large academic center in Miami, Florida. We characterized the prevalence of CVD, CVD risk, and the use of aspirin and statins for primary and secondary CVD prevention.A total of 985 charts were reviewed (45% women, 55% men). Average age was 52.2 years. Average CD4 count was 568 cells/microL. 92.9% were receiving ART, and 71% were virologically suppressed. The median 10-year ASCVD risk was 7.3%. The prevalence of CVD was 10.4% (N = 102). The odds of having CVD was lower in patients on ART (OR 0.47, 95% CI: 0.25-0.90, P = .02). The use of medications for primary and secondary prevention of CVD based on current guidelines was low: 15% and 37% for aspirin respectively, and 25% and 44% for statins.CVD risk and rates of CVD are high among PLWH and receiving ART could protect against CVD. However, the use of medications for primary and secondary prevention is low. Increased awareness of CVD risk-reduction strategies is needed among providers of PLWH to decrease the burden of CVD.

Transcatheter aortic valve replacement in low risk patients: a review of PARTNER 3 and Evolut low risk trials.

Transcatheter aortic valve replacement (TAVR) has become a mainstay in treatment for patients with severe aortic stenosis who are considered high-risk surgical candidates. The use of TAVR in low-risk patients with severe aortic stenosis is being explored as an alternative to surgical aortic valve replacement (SAVR). Recent results from the Medtronic Evolut Low Risk trial and the Placement of Aortic Transcatheter Valves (PARTNER) 3 trial shed light on the use of TAVR in low-risk surgical candidates. The Evolut Low Risk trial compared TAVR with a self-expanding supra-annular bioprosthesis to SAVR in 1468 patients with severe aortic stenosis who were low surgical risk. Patients with a mean age of 74 and a mean Society of Thoracic Surgeons (STS) risk score of 1.9% were randomized to either TAVR or SAVR groups. Using the composite end point of death or disabling stroke at 24 months, the study found an incidence of 5.3% in the TAVR arm and 6.7% in the surgical arm. The Evolut Low Risk trial thus concluded that TAVR was statistically noninferior but not superior to SAVR (difference, -1.4 percentage points; 95% Bayesian credible interval for the difference, -4.9 to 2.1; posterior probability of noninferiority, >0.999). The PARTNER 3 trial assigned 1,000 patients with severe aortic stenosis and low surgical risk to either TAVR with transfemoral placement of balloon expandable valve or SAVR. Patients with a mean age of 73 and a mean STS score of 1.9% were randomized to either TAVR or SAVR groups. With respect to the primary endpoint of composite death from any cause, stroke, or rehospitalization, the study found an occurrence of 8.5% in TAVR and 15.1% in SAVR, confirming both noninferiority and superiority in the TAVR group [absolute difference, -6.6 percentage points; 95% confidence interval (CI), -10.8 to -2.5; P<0.001 for noninferiority; hazard ratio, 0.54; 95% CI, 0.37 to 0.79; P=0.001 for superiority]. Both the Evolut low risk trial and the PARTNER 3 trial provide evidence that the use of TAVR extends beyond the scope of high and intermediate risk surgical patients and is at the very least equivalent to SAVR in the treatment low-risk surgical candidates when using a transfemoral approach in patients without bicuspid aortic valves. In this article we provide an extensive review on the Evolute low risk and PARTNER 3 trials, including a discussion on clinically relevant outcomes.

Experience With 15 Years of Laparoscopic Donor Nephrectomy: Review of 2500 Cases.

BACKGROUND: Laparoscopic donor nephrectomy (LDN) is considered the gold standard for live donor nephrectomies owing to lesser pain, shorter hospitalization, and earlier return to normal activities, yet it remains a technically challenging surgery. Repetition of a highly skilled task such as LDN should lead to improved performance reflected in shorter surgery times and a decrease in adverse events. METHODS: The records of over 2524 LDNs from February 2004 to June 2019 were evaluated for duration of surgery (from incision time to clamping of the renal artery) and occurrence of complications. RESULTS: The mean duration of surgery ± SD from incision to clamp time for the first 100 cases at the inception of LDN was 166.13 ± 33.28 minutes whereas it was 124.59 ± 35.91 minutes for the best 100 consecutive cases in 2015 with a decrease of 41 minutes duration of surgery from incision to artery clamping. The adverse events were accessory renal artery injury (n = 10), splenic laceration (n = 2), bowel and mesocolon injuries (n = 12), venous or arterial clip slippage (n = 4), inferior vena cava tear (n = 2) pneumothorax (during stapler application, n = 1), missing gauze counts (n = 1), chylous ascites (n = 1), ureteric thermal injury (n = 2), and renal parenchyma injury (n = 3). CONCLUSIONS: LDN is a technically demanding surgery where surgeon experience appears to affect operative metrics such as operative time. The occurrence of intraoperative complications appears to be acceptably low, although serious complications are a possibility.

Denosumab Regulates Gut Microbiota Composition and Cytokines in Dinitrobenzene Sulfonic Acid (DNBS)-Experimental Colitis.

The pro-inflammatory mediator receptor activator of nuclear factor-kappa B ligand (RANKL) plays a significant role in the development of rheumatoid arthritis; however, its role in inflammatory bowel disease is unknown. Genome-wide association meta-analysis for Crohn's disease (CD) identified a variant near the TNFSF11 gene that encodes RANKL and CD risk allele increased expression of RANKL in specific cell lines. This study aims to elucidate if the RANKL inhibitor denosumab can reduce the severity of experimental colitis and modify the gut microbiota composition using murine dinitrobenzenesulfonic acid (DNBS)-experimental model of colitis mimicking CD. In colitic conditions, denosumab treatment significantly decreased the pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α within the colonic mucosa. Moreover, colitis was accompanied by disruption of gut microbiota, and preventative treatment with denosumab modulated this disruption. Denosumab treatment also modified the alpha- and beta diversity of colonic mucosa and fecal microbiota. These results provide a rationale for considering denosumab as a future potential therapy in CD; however, more detailed experimental and clinical studies are warranted.

Protocol for Project Fizzyo, an analytic longitudinal observational cohort study of physiotherapy for children and young people with cystic fibrosis, with interrupted time-series design.

INTRODUCTION: Daily physiotherapy is believed to mitigate the progression of cystic fibrosis (CF) lung disease. However, physiotherapy airway clearance techniques (ACTs) are burdensome and the evidence guiding practice remains weak. This paper describes the protocol for Project Fizzyo, which uses innovative technology and analysis methods to remotely capture longitudinal daily data from physiotherapy treatments to measure adherence and prospectively evaluate associations with clinical outcomes. METHODS AND ANALYSIS: A cohort of 145 children and young people with CF aged 6-16 years were recruited. Each participant will record their usual physiotherapy sessions daily for 16 months, using remote monitoring sensors: (1) a bespoke ACT sensor, inserted into their usual ACT device and (2) a Fitbit Alta HR activity tracker. Real-time breath pressure during ACTs, and heart rate and daily step counts (Fitbit) are synced using specific software applications. An interrupted time-series design will facilitate evaluation of ACT interventions (feedback and ACT-driven gaming). Baseline, mid and endpoint assessments of spirometry, exercise capacity and quality of life and longitudinal clinical record data will also be collected.This large dataset will be analysed in R using big data analytics approaches. Distinct ACT and physical activity adherence profiles will be identified, using cluster analysis to define groups of individuals based on measured characteristics and any relationships to clinical profiles assessed. Changes in adherence to physiotherapy over time or in relation to ACT interventions will be quantified and evaluated in relation to clinical outcomes. ETHICS AND DISSEMINATION: Ethical approval for this study (IRAS: 228625) was granted by the London-Brighton and Sussex NREC (18/LO/1038). Findings will be disseminated via peer-reviewed publications, at conferences and via CF clinical networks. The statistical code will be published in the Fizzyo GitHub repository and the dataset stored in the Great Ormond Street Hospital Digital Research Environment. TRIAL REGISTRATION NUMBER: ISRCTN51624752; Pre-results.

Is liquid-based cytology an alternative to conventional cytology for detection of malignant cells in urine of bladder cancer? Eastern Indian prospective observational study.

OBJECTIVE: Conventional cytology (CC) is a widely employed biomarker for the detection of bladder cancer, but due to its decreased sensitivity, liquid-based cytology (LBC) has been studied. Despite its improved cell-free background, decreased cell degeneration, and an automated slide preparation technique, it shows a variable rate of malignant cells detection. Thus, we did this study to compare the positivity of LBC with CC in eastern Indian population. MATERIAL AND METHODS: A total of 150 patients who underwent a transurethral resection of bladder tumor (June 2017 to December 2018) were enrolled. Pre-operative CC and LBC were processed from freshly voided urine samples. The malignant cells detection rate and influential factors were noted and compared. RESULTS: The detection of malignant cells by LBC was higher compared to CC (37.3% vs. 25.3%; p<0.0001). Among 59 high-grade tumors, 59% and 86% slides were positive for CC and LBC, respectively (p<0.0001). Even in the background of hematuria, LBC showed a better detection (43.33% by LBC vs. 23.66% by CC; p<0.0001). CONCLUSION: The present study concludes that LBC offers a better detection of malignant cells in the urine of patients with bladder tumor as compared to CC. The detection of malignant cells by LBC is even better in the background of hematuria.

Pain and anxiety assessment during cystourethroscopy in males using voiding instruction: A prospective, randomized controlled study.

INTRODUCTION: Office cystourethroscopy is one of the common and most frequent urological procedures. Pain and anxiety during the procedure might lead to noncompliance and incomplete cystoscopic examination. Negotiating cystoscope through external sphincter is the most painful and uncomfortable distressing part of cystoscopy. To overcome this, manual compression of irrigation bag during cystoscopy has been used and found to be helpful. Numerous other methods were also studied. Despite these, cystoscopy is still painful and causes anxiety in patients. External sphincter gets relaxed naturally during the act of micturition. Based on this principle, pain and anxiety were studied with voiding instruction during cystourethroscopy. OBJECTIVE: To study the effect of voiding instruction on anxiety and pain during cystourethroscopy using the Hamilton Anxiety Rating Scale (HAM-A) and visual analogue scale (VAS), in a well-matched Eastern Indian male patient population in a prospective, randomized pattern. METHODS: A total of 100 male patients were recruited from those who underwent cystourethroscopy examination in SSKM Hospital and were prospectively randomized into two groups: cystoscopy with or without voiding instruction. Pre- and postprocedure HAM-A score and postprocedure VAS score were recorded. RESULTS: The mean postprocedural pain (VAS) score between voiding instructed and noninstructed groups reached statistical significance: 3.06 ± 1.98 (Range, 2-5) and 5.16 ± 2.86 (Range, 4-8), respectively (P < 0.001). Preprocedure HAM-A score was similar between both groups. Postprocedure median HAM-A score was statistically significantly lower (mean 17.86 ± 2.8 vs. 19.76 ± 3.12; P < 0.001) in voiding instructed group. CONCLUSION: Pain and anxiety level during cystourethroscopy examination in males can be significantly reduced when the patient is instructed to void during cystourethroscopy examination.

Semaphorin-3E attenuates intestinal inflammation through the regulation of the communication between splenic CD11C+ and CD4+ CD25- T-cells.

BACKGROUND AND PURPOSE: An alteration in the communication between the innate and adaptive immune cells is a hallmark of ulcerative colitis (UC). Semaphorin-3E (SEMA3E), a secreted guidance protein, regulates various immune responses. EXPERIMENTAL APPROACH: We investigated the expression of SEMA3E in colonic biopsies of active UC patients and its mechanisms in Sema3e-/- mice using an experimental model of UC. KEY RESULTS: SEMA3E level was decreased in active UC patients and negatively correlated with pro-inflammatory mediators. Colonic expression of SEMA3E was reduced in colitic Sema3e+/+ mice, and recombinant (rec-) Plexin-D1 treatment exacerbated disease severity. In vivo rec-SEMA3E treatment restored SEMA3E level in colitic Sema3e+/+ mice. In Sema3e-/- mice, disease severity was increased, and rec-SEMA3E ameliorated these effects. Lack of Sema3e increased the expression of CD11c and CD86 markers. Colitic Sema3e-/- splenocytes and splenic CD11c+ cells produced more IL-12/23 and IFN-γ compared to Sema3e+/+ , and rec-SEMA3E reduced their release as much as NF-κB inhibitors, whereas an NF-κB activator increased their production and attenuated the effect of rec-SEMA3E. Colitic Sema3e-/- splenic CD11c+ /CD4+ CD25- T-cell co-cultures produced higher concentrations of IFN-γ and IL-17 when compared to colitic Sema3e+/+ splenic cell co-cultures, and rec-SEMA3E decreased these effects. In vitro, anti-IL-12p19 and -12p35 antibodies and rec-IL-12 and -23 treatment confirmed the crosstalk between CD11c+ and CD4+ CD25- T-cells. CONCLUSION AND IMPLICATIONS: SEMA3E is reduced in colitis and modulates colonic inflammation by regulating the interaction between CD11c+ and CD4+ CD25- T-cells via an NF-κB-dependent mechanism. Thus, SEMA3E could be a potential therapeutic target for UC patients.

Long-term Safety of Minimally Invasive Left Ventricular Assist Device Discontinuation for Myocardial Recovery.

BACKGROUND: Left ventricular assist devices (LVADs) play important roles in advanced heart failure (HF) management. In patients who experience myocardial recovery, the LVAD is often explanted via a resternotomy, which may negatively impact the newly recovered heart. We describe a case-series of LVAD discontinuation using a minimally invasive approach, focusing on thromboembolic phenomenon and infection rates in long-term follow-up. METHODS: Our study is a single-center, retrospective case series of patients with myocardial recovery after mechanical unloading with an LVAD. Patients underwent outflow graft ligation through a minimally invasive approach with driveline excision. Postdiscontinuation, patients obtained serial transthoracic echocardiograms for a minimum of 6 months and followed with our heart failure specialist. RESULTS: All 7 recovery patients had nonischemic cardiomyopathy and included 4 women (57%). Mean age was 44.3 ± 15.6 years. Median LVAD support duration was 454 (interquartile range, 326 to 1096) days. Intensive care unit length of stay and total length of stay were 3.4 ± 1.9 days and 6.3 ± 2.3 days, respectively. Blood transfusion rate was 0.86 ± 1.1 units. At a median follow-up of 874 (interquartile range, 864 to 1007) days, no patients developed thromboembolic phenomena despite use of aspirin only for prophylaxis. One patient experienced driveline infection, who had persistent driveline infection before procedure. CONCLUSIONS: This minimally invasive approach for LVAD discontinuation through outflow graft ligation, driveline removal, and LVAD stoppage in setting of myocardial recovery avoids resternotomy risks. Despite leaving the LVAD in situ, there was no risk of thromboembolism or infection associated with residual hardware.