A multi-institutional update on surgical outcomes after penile silicone sleeve implantation.

Background: The increasing popularity of the silicone sleeve penile implant has been accompanied by concerns over potential risks and adverse events. Objectives: To provide multi-institutional data on safety outcomes in patients undergoing silicone sleeve penile implant surgery across high-volume implant surgeons. In addition, we discuss preventative techniques to minimize postoperative complications and the management of these events. Design and methods: We performed a retrospective analysis of men undergoing penile silicone sleeve implants between November 2020 and November 2022 with four surgeons, each from a separate institution. Perioperative and postoperative adverse events, including unsatisfactory cosmetic outcomes requiring revision, were determined by physician follow-up. Flaccid penile length and girth were measured preoperatively and postoperatively. Results: A total of 299 male patients underwent silicone sleeve implant surgery, with an average age of 42.5 ± 10.5 years and an average body mass index of 28.5 ± 4.0. The patient cohort exhibited minimal comorbidities, with 5% having hyperlipidemia, 2% being smokers, 2% having cardiovascular disease, and 1% having diabetes. Patients experienced an average increase of 4.1 ± 1.5 cm in their flaccid penile length (a 50% increase) and an average increase of 3.4 ± 1.5 cm in their flaccid girth (a 37% increase) (p < 0.01). Complication rates included new-onset postoperative erectile dysfunction (0%), infection (1.3%), seroma (2.0%), and erosion (5.0%). The average follow-up time was 11.6 months. Notably, our rates of infection and seroma were lower than those reported in a previous single-center review, while erosion rates were higher. Conclusion: This is the largest study to characterize the safety of the penile silicone sleeve implant across multiple institutions. In men who desire cosmetic size augmentation, silicone sleeve implant surgery is associated with significantly increased flaccid penile length and girth. Complications are mainly cosmetic and may be corrected; however, patients should be appropriately counseled on the risk of erosion, which appears to be higher than previously reported.

Outcomes for penile silicone sleeve surgery This is the largest study to characterize the safety of the penile silicone sleeve implant across multiple institutions. In men who desire cosmetic penile size improvement, the silicone sleeve implant surgery is associated with significantly increased flaccid penile length and girth. Complications are mainly cosmetic and may be corrected, however, patients should be appropriately counseled on the risk of erosion, which appears to be higher than previously reported.

Low-Dose Infigratinib Increases Bone Growth And Corrects Growth Plate Abnormalities In An Achondroplasia Mouse Model.

Achondroplasia, the most common form of disproportionate short stature, is caused by gain-of-function point mutations in fibroblast growth factor receptor 3 (FGFR3). Abnormally elevated activation of FGFR3 modulates chondrocyte proliferation and differentiation via multiple signaling pathways, such as the MAPK pathway. Using a mouse model mimicking achondroplasia (Fgfr3Y367C/+), we have previously shown that daily treatment with infigratinib (BGJ398), a selective and orally bioavailable FGFR1-3 inhibitor, at a dose of 2 mg/kg, significantly increased bone growth. In this study, we investigated the activity of infigratinib administered at substantially lower doses (0.2 and 0.5 mg/kg, given once daily) and using an intermittent dosing regimen (1 mg/kg every 3 days). Following a 15-day treatment period, these low dosages were sufficient to observe significant improvement of clinical hallmarks of achondroplasia such as growth of the axial and appendicular skeleton and skull development. Immunohistological labeling demonstrated the positive impact of infigratinib on chondrocyte differentiation in the cartilage growth plate and the cartilage end plate of the vertebrae. Macroscopic and microcomputed analyses showed enlargement of the foramen magnum area at the skull base, thus improving foramen magnum stenosis, a well-recognized complication in achondroplasia. No changes in FGF23 or phosphorus levels were observed, indicating that the treatment did not modify phosphate homeostasis. This proof-of-concept study demonstrates that infigratinib administered at low doses has the potential to be a safe and effective therapeutic option for children with achondroplasia.

Platypnea-orthodeoxia syndrome (POS) in a patient who had undergone partial liver resection.

A South Asian male in his early 60s presented with acute-onset dyspnoea on postoperative day 4 after undergoing middle hepatic vein sacrificing partial liver resection for epithelioid angiomyolipoma. The patient's SpO2 on presentation was 65% in standing position which improved to 90% in left lateral decubitus. He was suspected of having platypnea-orthodeoxia syndrome (POS) which was confirmed on echocardiogram with microbubble contrast showing a large intracardiac right-to-left shunt. The patient was taken up for transcatheter closure of patent foramen ovale (PFO). A 30 mm Amplatzer PFO Occluder was deployed across the PFO which reduced the intracardiac shunt resulting in an improved arterial saturation as well as immediate relief of patient's symptoms. This case illustrates the importance of suspecting and recognising POS clinically as well as the efficacy of transcatheter closure of PFO in such cases leading to resolution of hypoxaemia in a short span of time.

The 'qRBBB myocardial infarction': Unwrapping an old enigma.

This single-center, prospective, observational study was conducted at a tertiary-care center over a span of two years. Patients presenting with acute Anterior-Wall STEMI were included as a study population. The subgroups included qRBBB pattern on ECG and non-qRBBB group. Among 1128 patients included in the study, 100 (11.28 %) patients presented with qRBBB pattern. Increased risk of cardiogenic shock, increased hospital-stay, a higher Killip class on presentation, high incidence of recanalized IRA, remarkably depressed LVEF were significantly associated with qRBBB-MI, which is a menacing form of ACS that leads not only to a high mortality but also to a long-term morbidity.

Endomyocardial fibrosis: a tragic conundrum or a mere negligence?

Often termed as 'vanishing mystery' epidemiologically, endomyocardial fibrosis (EMF) continues to be the the most common cause of restrictive cardiomyopathy in Africa and some parts of the Indian subcontinent, where it is considered a significant public health problem. On the other hand, in developed countries, it is considered a rare phenomenon. This entity is considered incurable due to lack of targeted therapies, even after 75 years since its discovery. The authors describe here a case of an Indian male, in his early 30s who presented with complaints of dyspnoea on minimal daily activities, swelling of both legs and abdominal fullness for 3 months. The clinical features were suggestive of isolated right heart failure. He was diagnosed with EMF on echocardiography and the findings were confirmed on cardiac MRI. The patient has progressed to develop biventricular dysfunction and is being managed symptomatically with diuretics due to unavailability of targeted treatment options at present.

Role of endoscopic ultrasound-guided tissue acquisition for the diagnosis of gastric wall thickening: a retrospective study with meta-analysis.

Background: Tissue acquisition from a thickened gastric wall using biopsy forceps may not always lead to diagnosis, given the submucosal location of the pathology. Endoscopic ultrasound (EUS)-guided tissue acquisition (TA) may serve as a minimally invasive diagnostic tool in such cases. Hence, we aimed to assess the diagnostic outcome and safety of EUS-TA from thickened gastric walls. Methods: Data from patients with gastric wall thickening undergoing EUS-TA at 5 tertiary care centers from August 2020 to August 2022 were retrospectively analyzed. These data were pooled with studies obtained from a comprehensive search of Medline, Embase and Scopus from January 2000 to November 2022 and a meta-analysis was performed. Pooled event rates were calculated using an inverse variance model. Results: The search strategy yielded 13 studies that were combined with data from 30 patients from our centers; a total of 399 patients were included in the analysis. The pooled rate of sample adequacy was 94.1% (95% confidence interval [CI] 90.0-98.2), while the pooled rate of diagnostic accuracy was 91.3% (95%CI 87.0-95.5). The pooled sensitivity and specificity for diagnosing malignant lesions with EUS-TA from gastric wall thickening were 94.8% (95%CI 91.3-97.2) and 100% (95%CI 93.6-100), respectively. There were no reported adverse events in any of the studies. Conclusions: EUS-TA offers a safe and accurate diagnostic modality for the etiological diagnosis of thickened gastric walls. Further research is required to identify the needle type and optimal technique for improving outcomes.

Diagnostic efficacy of endoscopic ultrasound-guided liver biopsy for diffuse liver diseases and its predictors - a multicentric retrospective analysis.

Aim of the study: Endoscopic ultrasound (EUS)-guided liver biopsy (LB) has become an increasingly popular method of tissue acquisition for evaluating liver diseases. Despite its advantages, EUS-LB has not been widely adopted in clinical practice due to concerns regarding efficacy and safety. Present data on EUS-LB from India are scarce. We aimed to study the diagnostic outcome and safety of EUS-guided liver biopsy. Material and methods: This is a retrospective analysis of prospectively maintained data from January 2021 to October 2022 of consecutive patients undergoing EUS-LB at four tertiary care centers in India. The primary outcome was sample adequacy, while secondary outcomes were rate of successful pathological diagnoses and incidence of adverse events (AE). Results: A total of 74 patients (median age: 44.5 years, 50.0% males) were included. The majority of the patients underwent left-lobe biopsy (62/74, 83.7%), and a 19-G Franseen FNB needle was most commonly used (61/74, 82.4%). Wet heparin suction was used in most cases (60/74, 81.1%). There were five mild AEs observed (one case of self-limited bleeding and four cases of post-procedural pain). Adequate and optimal samples were obtained in 71 (95.9%) and 49 (66.2%) cases, with a conclusive diagnosis being made in 97.3% (72/74) of the patients. On multivariate analysis, the presence of ascites was a negative predictor of optimal sample (odds ratio [OR] = 0.128, 95% CI: 0.017-0.96). Conclusions: EUS-LB is a safe and viable alternative to percutaneous liver biopsy, achieving diagnosis in > 95% of cases. EUS-LB can be performed safely even in patients with mild ascites, although ascites reduces the chances of getting an optimal sample.

Safety of Xiaflex® (Collagenase Clostridium histolyticum) Treatment for Adult Anterior Urethral Stricture Disease.

Male urethral stricture disease is highly prevalent and difficult to treat due to potential complications. Minimally invasive treatments tend to have high recurrence rates, keeping urethroplasty as the gold standard. Collagenase Clostridium histolyticum (CCH) has been used in humans to treat fibrosis in a minimally invasive manner. Herein, we present the preliminary results from treatments of three males with urethral stricture as a feasibility and safety evaluation of the first-in-human CCH treatment for male urethral stricture disease.

Safety outcomes of the first Rigi10™ malleable penile prostheses implanted worldwide.

Implantation of penile prosthesis is considered when conservative measures fail or are unacceptable to patients' wishing treatment for erectile dysfunction. In the United States (US), inflatable penile prostheses are more often used than malleable penile prostheses (MPP). Outside the US, the reverse is true because third-party reimbursement is not available, and MPP is considerably cheaper. Two American manufacturers make MPP; presently, a new manufacturer, Rigicon (Ronkonkoma NY), has recently begun to sell its MPP worldwide. Patient information forms submitted to the manufacturer between March 1, 2019, and December 8, 2022, were used to conduct an initial safety study for 605 first-time patients implanted with Rigicon10® by 46 physicians in 15 countries with a mean follow-up of 21.6 months. It has the same configuration of trimmable, paired silicone rods containing a twisted stainless-steel wire for bendability. However, it is available in six widths with hydrophilic coating compared to three widths offered by competitors. Revision or explantation was needed in 6 of 605 patients (0.99%) with half of those being removed for dissatisfaction (0.50%). Two (0.33%) suffered device infection and one (0.16%) required removal for erosion. Kaplan-Meier's statistical analysis showed three-year implant survival from revision = 99.2%. It demonstrated a comparable safety record with less than 1.00% of patients requiring reoperation.

Functional characterization of all missense variants in LEPR, PCSK1, and POMC genes arising from single-nucleotide variants.

OBJECTIVE: Hyperphagia and early-onset, severe obesity are clinical characteristics of rare melanocortin-4 receptor (MC4R) pathway diseases due to loss-of-function (LOF) variants in genes comprising the MC4R pathway. In vitro functional characterization of 12,879 possible exonic missense variants from single-nucleotide variants (SNVs) of LEPR, POMC, and PCSK1 was performed to determine the impact of these variants on protein function. METHODS: SNVs of the three genes were transiently transfected into cell lines, and each variant was subsequently classified according to functional impact. We validated three assays by comparing classifications against functional characterization of 29 previously published variants. RESULTS: Our results significantly correlated with previously published pathogenic categories (r = 0.623; P = 3.03 × 10-4) of all potential missense variants arising from SNVs. Of all observed variants identified through available databases and a tested cohort of 16,061 patients with obesity, 8.6% of LEPR, 63.2% of PCSK1, and 10.6% of POMC variants exhibited LOF, including variants currently classified as a variant of uncertain significance (VUS). CONCLUSIONS: The functional data provided here can assist in the reclassification of several VUS in LEPR, PCSK1, and POMC and highlight their impact in MC4R pathway diseases.

Glucose-6-Phosphate Dehydrogenase, ZwfA, a Dual Cofactor-Specific Isozyme Is Predominantly Involved in the Glucose Metabolism of Pseudomonas bharatica CSV86T.

Glucose-6-phosphate dehydrogenase (Zwf) is an important enzyme in glucose metabolism via the Entner-Doudoroff pathway and the first enzyme in the oxidative pentose-phosphate pathway. It generates NAD(P)H during the conversion of glucose-6-phosphate (G6P) to 6-phosphogluconolactone, thus aiding in anabolic processes, energy yield, and oxidative stress responses. Pseudomonas bharatica CSV86T preferentially utilized aromatic compounds over glucose and exhibited a significantly lower growth rate on glucose (0.24 h-1) with a prolonged lag phase (~10 h). In strain CSV86T, glucose was metabolized via the intracellular phosphorylative route only because it lacked an oxidative (gluconate and 2-ketogluconate) route. The genome harbored three genes zwfA, zwfB, and zwfC encoding three Zwf isozymes. The present study aimed to understand gene arrangement, gene expression profiling, and molecular and kinetic properties of the purified enzymes to unveil their physiological significance in the strain CSV86T. The zwfA was found to be a part of the zwfA-pgl-eda operon, which was proximal to other glucose transport and metabolic clusters. The zwfB was found to be arranged as a gnd-zwfB operon, while zwfC was present independently. Among the three, zwfA was transcribed maximally, and the purified ZwfA displayed the highest catalytic efficiency, cooperativity with respect to G6P, and dual cofactor specificity. Isozymes ZwfB and ZwfC were NADP+-preferring and NADP+-specific, respectively. Among other functionally characterized Zwfs, ZwfA from strain CSV86T displayed poor catalytic efficiency and the further absence of oxidative routes of glucose metabolism reflected its lower growth rate on glucose compared to P. putida KT2440 and could be probable reasons for the unique carbon source utilization hierarchy. IMPORTANCE Pseudomonas bharatica CSV86T metabolizes glucose exclusively via the intracellular phosphorylative Entner-Doudoroff pathway leading the entire glucose flux through Zwf as the strain lacks oxidative routes. This may lead to limiting the concentration of downstream metabolic intermediates. The strain CSV86T possesses three isoforms of glucose-6-phosphate dehydrogenase, ZwfA, ZwfB, and ZwfC. The expression profile and kinetic properties of purified enzymes will help to understand glucose metabolism. Isozyme ZwfA dominated in terms of expression and displayed cooperativity with dual cofactor specificity. ZwfB preferred NADP+, and ZwfC was NADP+ specific, which may aid in redox cofactor balance. Such beneficial metabolic flexibility facilitated the regulation of metabolic pathways giving survival/fitness advantages in dynamic environments. Additionally, multiple genes allowed the distribution of function among these isoforms where the primary function was allocated to one of the isoforms.

A prospective study of fully covered self-expandable metal stents for refractory benign pancreatic duct strictures.

BACKGROUND/AIMS: Fully covered self-expanding metal stents (FCSEMSs) are a relatively novel option for treating painful main pancreatic duct refractory strictures in patients with chronic pancreatitis. Herein, we aimed to assess the efficacy, feasibility, and safety of FCSEMSs in this patient group. METHODS: This prospective single-center study included patients who underwent endoscopic retrograde pancreatography with FCSEMS placement. The primary endpoints were the technical and clinical success rates. A reduction in visual analog scale pain score of >50% compared with that before stent placement was defined as clinical success. Secondary endpoints were resolution of pancreatic strictures on fluoroscopy during endoscopic retrograde pancreatography and the development of stent-related adverse events. RESULTS: Thirty-six patients were included in the analysis. The technical success rate was 100% (n=36) and the clinical success rate was 86.1% (n=31). There was a significant increase in stricture diameter from 1.7 mm to 3.5 mm (p<0.001) after stent removal. The mean visual analog scale pain score showed statistically significant improvement. At 19 months of follow-up, 55.6% of the patients were asymptomatic. Stent migration (16.7%), intolerable abdominal pain (8.3%), development of de novo strictures (8.3%), and mild pancreatitis (2.8%) were the most common adverse events. CONCLUSION: FCSEMS placement showed good technical and clinical success rates for achieving pain relief in patients with refractory main pancreatic duct strictures.

Eco-physiological portrait of a novel Pseudomonas sp. CSV86: an ideal host/candidate for metabolic engineering and bioremediation.

Pseudomonas sp. CSV86, an Indian soil isolate, degrades wide range of aromatic compounds like naphthalene, benzoate and phenylpropanoids, amongst others. Isolate displays the unique and novel property of preferential utilization of aromatics over glucose and co-metabolizes them with organic acids. Interestingly, as compared to other Pseudomonads, strain CSV86 harbours only high-affinity glucokinase pathway (and absence of low-affinity oxidative route) for glucose metabolism. Such lack of gluconate loop might be responsible for the novel phenotype of preferential utilization of aromatics. The genome analysis and comparative functional mining indicated a large genome (6.79 Mb) with significant enrichment of regulators, transporters as well as presence of various secondary metabolite production clusters, suggesting its eco-physiological and metabolic versatility. Strain harbours various integrative conjugative elements (ICEs) and genomic islands, probably acquired through horizontal gene transfer events, leading to genome mosaicity and plasticity. Naphthalene degradation genes are arranged as regulonic clusters and found to be part of ICECSV86nah . Various eco-physiological properties and absence of major pathogenicity and virulence factors (risk group-1) in CSV86 suggest it to be an ideal candidate for bioremediation. Further, strain can serve as an ideal chassis for metabolic engineering to degrade various xenobiotics preferentially over simple carbon sources for efficient remediation.

Carbazole-based semicarbazones and hydrazones as multifunctional anti-Alzheimer agents.

With the aim to combat a multi-faceted neurodegenerative Alzheimer's disease (AD), a series of carbazole-based semicarbazide and hydrazide derivatives were designed, synthesized and assessed for their cholinesterase (ChE) inhibitory, antioxidant and biometal chelating activity. Among them, (E)-2-((9-ethyl-9H-carbazol-3-yl)methylene)-N-(pyridin-2-yl)hydrazinecarbothioamide (62) and (E)-2-((9-ethyl-9H-carbazol-3-yl)methylene)-N-(5-chloropyridin-2-yl)hydrazinecarbothioamide (63) emerged as the premier candidates with good ChE inhibitory activities (IC50 values of 1.37 µM and 1.18 µM for hAChE, IC50 values of 2.69 µM and 3.31 µM for EqBuChE, respectively). All the test compounds displayed excellent antioxidant activity (reduction percentage of DPPH values for compounds (62) and (63) were 85.67% and 84.49%, respectively at 100 µM concentration). Compounds (62) and (63) conferred specific copper ion chelating property in metal chelation study. Molecular docking studies of compounds (62) and (63) indicate strong interactions within the active sites of both the ChE enzymes. Besides that, these compounds also exhibited significant in silico drug-like pharmacokinetic properties. Thus, taken together, they can serve as a starting point in the designing of multifunctional ligands in pursuit of potential anti-AD agents that might further prevent the progression of ADs.Communicated by Ramaswamy H. Sarma.

Kinetics of Covid-19 antibodies in terms of titre and duration among healthcare workers: A longitudinal study.

Background Most individuals with Covid-19 infection develop antibodies specific to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the dynamics of these antibodies is variable and not well-studied. We aimed to determine the titres of naturally acquired antibodies over a 12-week follow-up. Methods We recruited healthcare workers who had tested positive on a specific quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for SARS-CoV-2, and then tested for the presence of immunoglobulin G (IgG) antibody against the same virus at baseline and again at 6 and 12 weeks. The antibody titre was determined by a semi-quantitative assay based on signal/cut-off ratio. Healthcare workers with antibody positivity were divided into those with high titre (ratio ≥12) and low titre (<12). Their demographic details and risk factors were surveyed through a Google form and analysed in relation to the antibody titres at three time-points. Results Of the 286 healthcare workers, 10.48% had high antibody titres. Healthcare workers who had tested positive by qRT-PCR and those who had received the Bacille Calmette-Guérin (BCG) vaccination or other immune-boosters had a higher frequency of high antibody titres. While there was a significant decline in antibody titres at 6 and 12 weeks, 87.46% of individuals positive for IgG antibody persisted to have the antibody even at 12 weeks. Conclusion Healthcare workers who tested positive for SARS-CoV-2 on qRT-PCR had a high positivity for the specific antibody, which continued to express in them even at 12 weeks. Further follow-up is likely to enhance our understanding of antibody kinetics following SARS-CoV-2 infection.

Endoscopic ultrasonography-guided rendezvous technique for removal of a long biliary ascariasis: a challenging case.

Video 1Video demonstrating the EUS-rendezvous technique for biliary access and removal of a long biliary ascariasis.

Quantification of Liver Fat by MRI-PDFF Imaging in Patients with Suspected Non-alcoholic Fatty Liver Disease and Its Correlation with Metabolic Syndrome, Liver Function Test and Ultrasonography.

BACKGROUND: Magnetic resonance imaging (MRI)-estimated proton density fat fraction (PDFF) has emerged to be a promising tool in quantification of liver fat. Aim of this study was to quantify liver fat using MRI-PDFF in patients with suspected non-alcoholic fatty liver disease (NAFLD) and to correlate it with the presence of metabolic syndrome (MetS), ultrasonography (USG) and liver function test (LFT). METHODS: We included 111 consecutive patients who were suspected to have NAFLD on the basis of clinical, laboratory or USG findings. A 3 Tesla Phillips MRI machine was used with a software named "mDixon Quant" for quantification of the liver fat. RESULTS: MRI-PDFF revealed hepatic steatosis grading as Grade 0 in 31 patients (28%), Grade I in 40 (36%), Grade II in 19 (17.1%) and Grade III in 21 patients (18.9%). MetS patients had higher proportion of advanced steatosis (Grades II and III) as compared to those without MetS (P < 0.001). ALT (alanine transaminase) was found to be significantly elevated (>1.5 times) in the patients with advanced steatosis as compared to patients with Grades I and 0 fatty liver on MRI-PDFF (P < 0.001). The Kappa measure of agreement between USG and MRI-PDFF was found to be 0.2, which suggests a low level of agreement between the two tests. CONCLUSION: MetS patients have higher proportion of advanced steatosis (Grades II and III) at MRI-PDFF as compared to those without MetS. Patients with advanced steatosis at MRI-PDFF had higher proportion of abnormal LFTs as compared to those with Grades 0 and I hepatic steatosis. There was a dis-correlation between MRI-PDFF and USG in the evaluation of NAFLD.