Mechanical Failure of SIGMA Total Condylar-III Revision Total Knee System Modular Femoral Component Due to Bolt Screw Breakage - Our Experience in Overcoming Broken Component Incarceration.

Introduction: The rising use of modular implants in revision total knee arthroplasty offers surgeons greater flexibility in addressing bone defects and achieving uniform gaps compared to monoblock counterparts. However, this enhanced functionality brings specific complications such as loosening and breakage at component coupling sites, leading to challenges due to mechanical failures and suboptimal fixation. Extracting broken components during revision surgery poses a significant challenge, prompting innovative techniques to facilitate extraction. Case Report: We present a rare case of modular femoral component mechanical failure in a 69-year-old male, manifesting as left knee instability and acute pain while walking 4 years following revision of total knee replacement due to infection. Radiographs revealed mechanical failure of the Sigma Total Condylar-III Revision prosthesis bolt, with intra-operative extraction efforts complicated by a lodged broken bolt. Despite initial challenges, successful extraction was achieved using mosquito forceps and a universal nail extractor. Conclusion: This case highlights the importance of documenting rare instances of mechanical failure in modular implants, emphasizing the need to understand prevalence rates and various surgical techniques for implant extraction. Our experience underscores the utility of the universal nail extractor as a valuable tool in managing difficult implant removal during revision surgery. Surgeons must remain vigilant and innovative in addressing challenges encountered during modular implant revisions.

Orthostatic hypotension and subjective symptomatic orthostasis in Parkinson's disease: Associations and correlations.

Background: Both measured orthostatic hypotension and symptomatic orthostasis are common in PD but their relationship is unclear. Objective: We aim to determine clinical predictors of both measured orthostatic hypotension and reported symptomatic orthostasis in PD, including the impact of "on"/"off" status and seasons, and to determine the correlation between measured OH and subjective orthostasis. Methods: We analyzed BP readings, demographic and disease state predictors for both 1. Measured blood pressure OH criteria and 2. The subjective report of orthostatic symptoms, using logistic regression analyses from an initial "on" motor state clinical visit in all PD patient visits. We then correlated subjective orthostasis symptoms with BP measurements. We also compared intra-subject BP measures in PD patients seen in both "on" and "off" states, and when seen "on" in both summer and winter. Results: 723 consecutive visits over 2 years identified 250 unique PD individuals. Subjective orthostasis was reported by 44 % and "on" measured OH (>20 drop in SBP or 10 DBP upon standing) was seen in 30 %. Measured OH did not significantly correlate with any assessed clinical feature or specific medicine. Subjective orthostasis correlated most with older age, dementia, and L-dopa use. Subjective orthostasis correlated equally with absolute lower measured standing SBP and the drop in SBP from sitting to standing. Compared to the "off" state, "on" state showed lower sitting and standing SBP, more than DBP, but no significant change in BP drop upon standing. Seasons did not impact measured BP. Conclusions: Both OH and symptomatic orthostasis are common. Dopaminergic medications did not cause traditionally defined OH but lowered all SBP (sitting and standing) and thus reduced pulse pressure, possibly by increasing arteriole compliance simply by reducing motor tone, as this BP-lowering effect may be specific to Parkinsonism.

Greater Postoperative Biceps Tendon Migration Following Biceps Tenodesis Correlates with Lower Patient Reported Outcomes Scores.

PURPOSE: To assess the relationship between tendon migration, as measured by radiostereometric analysis (RSA), and patient-reported outcome measures (PROMs) following biceps tenodesis (BT); to determine the likelihood of achieving clinically significant outcomes (CSOs) following BT; and to identify factors that impact CSO achievement. METHODS: Patients undergoing arthroscopic suprapectoral or open subpectoral BT at a single, high-volume academic medical center were prospectively enrolled. A tantalum bead sutured to the tenodesis construct was utilized as a radio-opaque marker. Biceps tendon migration was measured on calibrated radiographs at 12 weeks postoperatively. PROMs (Constant-Murley score [Constant], Single Assessment Numeric Evaluation [SANE], and Patient-Reported Outcomes Measurement Information Systemic-Upper Extremity [PROMIS-UE]) were collected preoperatively and at ≥2 years follow-up. RESULTS: Of 115 patients enrolled, 94 (82%) patients were included (median age=52 years and BMI=31.4 kg/m2). At a mean follow-up of 2.9 years, median Constant, SANE, and PROMIS-UE were 33 (interquartile range [IQR]=26-35), 90 (IQR=80-99), and 47 (IQR=42-58), respectively. Median tantalum bead migration was 6.5 mm (IQR 1.8-13.8). There was a significant correlation between migration and Constant (r2 = 0.222, beta= -0.554, 95% CI -1.027- [-0.081], P=0.022), SANE (r2 = 0.238, beta= -0.198, 95% CI -0.337 - [-0.058], P=0.006) and PROMIS-UE (r2 = 0.233, beta= -0.406, 95% CI -0.707 - [-0.104], P=0.009). In univariable analysis, higher BMI was associated with achievement of substantial clinical benefit (SCB, unadj-OR=1.078, 95%CI 1.007-1.161, P=0.038). Greater bead migration was negatively associated with achievement of minimal clinically important difference (MCID, unadj-OR=0.969, 95% CI 0.943-0.993, P=0.014) and patient acceptable symptomatic state (PASS, unadj-OR 0.965, 95% CI 0.937-0.989, P=0.008) on all 3 instruments. CONCLUSION: A 1 cm-increase in tenodesed biceps tendon migration was associated with a decrease in Constant, SANE, and PROMIS-UE of 6, 2, and 4 points, respectively, at a mean of 2.9 years after surgery. Most patients achieved clinically significant outcomes (CSOs) for these PROMs by latest follow-up, and greater biceps tendon construct migration was negatively associated with the likelihood of CSO achievement. LEVEL OF EVIDENCE: IV, retrospective case series.

Visualizing Multilayer Spatiotemporal Epidemiological Data with Animated Geocircles.

OBJECTIVE: The COVID-19 pandemic emphasized the value of geospatial visual analytics for both epidemiologists and the general public. However, systems struggled to encode temporal and geospatial trends of multiple, potentially interacting variables, such as active cases, deaths, and vaccinations. We sought to ask (1) how epidemiologists interact with visual analytics tools, (2) how multiple, time-varying, geospatial variables can be conveyed in a unified view, and (3) how complex spatiotemporal encodings affect utility for both experts and non-experts. MATERIALS AND METHODS: We propose encoding variables with animated, concentric, hollow circles, allowing multiple variables via color encoding and avoiding occlusion problems, and we implement this method in a browser-based tool called CoronaViz. We conduct task-based evaluations with non-experts, as well as in-depth interviews and observational sessions with epidemiologists, covering a range of tools and encodings. RESULTS: Sessions with epidemiologists confirmed the importance of multivariate, spatiotemporal queries and the utility of CoronaViz for answering them, while providing direction for future development. Non-experts tasked with performing spatiotemporal queries unanimously preferred animation to multi-view dashboards. DISCUSSION: We find that conveying complex, multivariate data necessarily involves trade-offs. Yet, our studies suggest the importance of complementary visualization strategies, with our animated multivariate spatiotemporal encoding filling important needs for exploration and presentation. CONCLUSION: CoronaViz's unique ability to convey multiple, time-varying, geospatial variables makes it both a valuable addition to interactive COVID-19 dashboards and a platform for empowering experts and the public during future disease outbreaks. CoronaViz is open-source and a live instance is freely hosted at http://coronaviz.umiacs.io.

Burden of rare genetic disorders in India: twenty-two years' experience of a tertiary centre.

BACKGROUND: Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. RESULTS: Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of ß-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), ß-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29-13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. CONCLUSION: The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Early Recanalization after Tenecteplase versus Alteplase: Experience in a Large Stroke Network.

INTRODUCTION: Previously published data are conflicting regarding the ability of tenecteplase versus alteplase to produce early recanalization of an intracranial large vessel occlusion. We compared the performance of each thrombolytic in a stroke network. METHODS: We queried our prospectively collected code stroke registry for basilar, internal carotid, or proximal middle cerebral artery occlusion patients treated with intravenous thrombolysis from 11/17/2021-9/16/2023. The primary outcome was early recanalization, defined using angiographic or clinical criteria. Secondary and safety outcomes included 90-day functional independence and symptomatic intracranial hemorrhage. A multivariable regression analysis was performed to determine independent associations with the primary outcome. RESULTS: 233 patients, with mean age 66.9 (16.6) years and median National Institutes of Health Stroke Scale score 15 (10-21), were included. One-hundred twenty-four of 233 (53.2%) patients were treated with alteplase while 109/233 (46.8%) were treated with tenecteplase. Endovascular thrombectomy was performed in 82% of subjects. Early recanalization rates were similar between the groups (alteplase 22.6%, tenecteplase 14.7%; p=0.14), as were rates of 90-day independent neurological function, symptomatic intracranial hemorrhage, and mortality. Patients with an internal carotid artery occlusion or with higher presenting stroke severity were less likely to achieve early recanalization. CONCLUSIONS: Tenecteplase and alteplase have similar rates of early recanalization, 90-day functional independence, and safety outcomes in large vessel occlusion patients. Occlusion site and stroke severity predict response to thrombolysis. Future studies may investigate other factors associated with a positive response to thrombolytics as expanded treatment indications are explored.

A Neuroendocrine Tumor of Unknown Primary Origin: A Case Report and Review of the Literature.

Neuroendocrine tumors (NETs) are uncommon malignancies that develop from neuroendocrine cells which most commonly occur in the GI tract, lung, and pancreas. Treatment courses for these tumors are largely dictated by the primary origin site, which can present diagnostic and therapeutic challenges in NETs of unknown primary origin. Herein, we present a case of an NET of unknown primary origin with significant liver metastases. Our aim is to highlight the key components of the workup of NETs of unknown primary origin and detail the biochemical, histopathological, and imaging modalities as recommended by current literature. We highlight the importance of a multidisciplinary approach to both diagnosis and treatment of these patients as well as touch upon therapeutic options.

Dostarlimab in the treatment of mismatch repair deficient recurrent or advanced endometrial cancer.

Dostarlimab, a programmed death receptor-1 (PD-1)-blocking IgG4 humanized monoclonal antibody, gained accelerated approval from the US Food and Drug Administration (FDA) in April 2021, and received a full approval in February 2023. Dostarlimab was approved for treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (EC) that progressed during or after prior treatment who have no other suitable treatment options. Herein, we review the structure-based mechanism of action of dostarlimab and the results of a clinical study (GARNET; NCT02715284) to comprehensively clarify the efficacy and toxicity of the drug. The efficacy and safety of dostarlimab as monotherapy was assessed in a non-randomized, multicenter, open-label, multi-cohort trial that included 209 patients with dMMR recurrent or advanced solid tumors after receiving systemic therapy. Patients received 500 mg of dostarlimab intravenously every three weeks until they were given four doses. Then, patients received 1000 mg dostarlimab intravenously every six weeks until disease progression or unacceptable toxicity. The overall response rate, as determined by shrinkage in tumor size, was 41.6% (95% confidence interval [CI]; 34.9, 48.6), with 34.7 months as the median response duration. In conclusion, dostarlimab is an immunotherapy-based drug that has shown promising results in adult patients with recurrent or advanced dMMR EC. However, its efficacy in other cancer subtypes, the development of resistance to monotherapy, and efficacy and safety in combination with other immunotherapeutic drugs have not yet been studied.

Ammonium oxidation from concentrated synthetic wastewater and landfill leachate using partial nitritation in sequencing batch reactor.

Partial nitritation (PN) is a novel treatment for nitrogen removal using aerobic ammonium oxidation with reduced oxygen requirements compared to conventional nitrification. This study evaluated the performance of the PN process and the factors influencing nitrogen removal from landfill leachate. During the reactivation of biomass, the results showed 70% ammonium removal, but only 20% total nitrogen removal. Further analysis showed that low nitrite accumulation and high nitrate production promoted the growth of nitrite-oxidizing bacteria (NOB). The ammonium removal activity after soaking the cultivated biomass in synthetic water and leachate was measured to be 0.57, 0.1, 0.17, and 0.25 g N•g VSS-1•d-1 for synthetic wastewater and leachate soaking for synthetic wastewater, 12 h, 3 days, and 7 days, respectively. The study found abundant ammonium-oxidizing bacteria (AOB) and NOBs in biomass soaked in synthetic wastewater. However, soaking in leachate promoted AOB growth and inhibited NOB growth making leachate suitable for PN. PRACTITIONER POINTS: The study found that with a longer leachate-soaking period for biomass, ammonium removal activity increases, which in turn increases ammonium conversions during the PN process. Ammonium-oxidizing bacteria (AOB) can acclimate to landfill leachate substrate and grow with a longer soaking period. Nitrite-oxidizing bacteria (NOB) were inhibited by landfill leachate substrate, which is beneficial for nitrite accumulation. Anabolized DO can convert nitrite to nitrate rapidly, which results in higher nitrate accumulation compared to nitrite accumulation. Hence, the DO level has to be sufficiently low to prevent nitrite oxidation and nitrate accumulation.

Neurological outcomes for patients meeting radiographic criteria for DEFUSE 3 and SELECT2.

BACKGROUND: The DEFUSE 3 and SELECT2 thrombectomy trials included some patients with similar radiographic profiles, although the rates of good functional outcomes differed widely between the studies. OBJECTIVE: To report neurological outcomes for patients who meet CT and CT perfusion (CTP) inclusion criteria common to both DEFUSE 3 and SELECT2. METHODS: Retrospective study of thrombectomy patients, presenting between November 2016 and December 2023 to a large health system, with Alberta Stroke Program Early CT score ≥6, core infarction 50-69 mL, mismatch ratio ≥1.8, and mismatch volume ≥15 mL. The primary outcome was 90-day modified Rankin Scale score 0-2. A logistic regression analysis was performed to identify independent predictors of the primary outcome. RESULTS: 85 patients, with mean age 64.6 (16.6) years and median National Institutes of Health Stroke Scale score 18 (15-23), were included. Thirty-eight of 85 patients (44.7%) were functionally independent at 90 days. Predictors of functional independence included age (OR=0.943, 95% CI 0.908 to 0.980; P=0.003), initial glucose (OR=0.989, 95% CI 0.978 to 1.000; P=0.044), and time last known well to skin puncture (OR=0.997, 95% CI 0.994 to 1.000; P=0.028). The area under the curve for the multivariable model predicting the primary outcome was 0.82 (95% CI 0.73 to 0.92). CONCLUSION: Nearly half of patients meeting radiographic criteria common to DEFUSE 3 and SELECT2 are functionally independent at 90 days, similar to rates reported for the treated DEFUSE 3 cohort. This might be due to their moderate core volumes and large ischemic penumbra.

Utilizing human cerebral organoids to model breast cancer brain metastasis in culture.

BACKGROUND: Metastasis, the spread, and growth of malignant cells at secondary sites within a patient's body, accounts for over 90% of cancer-related mortality. Breast cancer is the most common tumor type diagnosed and the leading cause of cancer lethality in women in the United States. It is estimated that 10-16% breast cancer patients will have brain metastasis. Current therapies to treat patients with breast cancer brain metastasis (BCBM) remain palliative. This is largely due to our limited understanding of the fundamental molecular and cellular mechanisms through which BCBM progresses, which represents a critical barrier for the development of efficient therapies for affected breast cancer patients. METHODS: Previous research in BCBM relied on co-culture assays of tumor cells with rodent neural cells or rodent brain slice ex vivo. Given the need to overcome the obstacle for human-relevant host to study cell-cell communication in BCBM, we generated human embryonic stem cell-derived cerebral organoids to co-culture with human breast cancer cell lines. We used MDA-MB-231 and its brain metastatic derivate MDA-MB-231 Br-EGFP, other cell lines of MCF-7, HCC-1806, and SUM159PT. We leveraged this novel 3D co-culture platform to investigate the crosstalk of human breast cancer cells with neural cells in cerebral organoid. RESULTS: We found that MDA-MB-231 and SUM159PT breast cancer cells formed tumor colonies in human cerebral organoids. Moreover, MDA-MB-231 Br-EGFP cells showed increased capacity to invade and expand in human cerebral organoids. CONCLUSIONS: Our co-culture model has demonstrated a remarkable capacity to discern the brain metastatic ability of human breast cancer cells in cerebral organoids. The generation of BCBM-like structures in organoid will facilitate the study of human tumor microenvironment in culture.

High-throughput characterization of functional variants highlights heterogeneity and polygenicity underlying lung cancer susceptibility.

Genome-wide association studies (GWASs) have identified numerous lung cancer risk-associated loci. However, decoding molecular mechanisms of these associations is challenging since most of these genetic variants are non-protein-coding with unknown function. Here, we implemented massively parallel reporter assays (MPRAs) to simultaneously measure the allelic transcriptional activity of risk-associated variants. We tested 2,245 variants at 42 loci from 3 recent GWASs in East Asian and European populations in the context of two major lung cancer histological types and exposure to benzo(a)pyrene. This MPRA approach identified one or more variants (median 11 variants) with significant effects on transcriptional activity at 88% of GWAS loci. Multimodal integration of lung-specific epigenomic data demonstrated that 63% of the loci harbored multiple potentially functional variants in linkage disequilibrium. While 22% of the significant variants showed allelic effects in both A549 (adenocarcinoma) and H520 (squamous cell carcinoma) cell lines, a subset of the functional variants displayed a significant cell-type interaction. Transcription factor analyses nominated potential regulators of the functional variants, including those with cell-type-specific expression and those predicted to bind multiple potentially functional variants across the GWAS loci. Linking functional variants to target genes based on four complementary approaches identified candidate susceptibility genes, including those affecting lung cancer cell growth. CRISPR interference of the top functional variant at 20q13.33 validated variant-to-gene connections, including RTEL1, SOX18, and ARFRP1. Our data provide a comprehensive functional analysis of lung cancer GWAS loci and help elucidate the molecular basis of heterogeneity and polygenicity underlying lung cancer susceptibility.

Correlation of non-invasive parameters with upper gastrointestinal endoscopy findings for presence and grading of gastroesophageal varices in liver cirrhosis patients.

Background: Development of esophageal varices is one of the major complications of liver cirrhosis, and endoscopy is used to see the presence, grading, and long-term monitoring of esophageal varices which is an invasive and unpleasant procedure. There is no adequate data available showing noninvasive methods can be used for the same. Methods: Seventy patients with liver cirrhosis participated in the study. Factors like portal vein diameter, spleen size, platelet count, serum bilirubin, Child-Pugh score, prothrombin time (PT), and PT INR were observed and correlated endoscopically with the presence and grading of esophageal varices in all patients. Results: The platelet count, portal vein diameter, serum bilirubin, spleen bipolar diameter, and PT had statistically significant correlations with the presence of varices. Among them, platelet count, portal vein diameter, and serum bilirubin also had statistically significant correlations with the grading of varices. Monitoring of these noninvasive parameters can help in monitoring variceal growth. Conclusions: Noninvasive parameters can be used effectively to predict the presence and grading of esophageal varices and at the same time keep the rate of undiagnosed varices acceptably low. By using noninvasive parameters, patients can be benefited by decreasing the requirement of repeated endoscopic evaluation which is an unpleasant procedure and availability is also limited.

Cyproheptadine in serotonin syndrome: A retrospective study.

Objective: Serotonin syndrome (SS) is an iatrogenic life-threatening condition caused by serotonergic agents. The treatment for SS involves the administration of a serotonin antagonist (cyproheptadine). However, the dosing schedule for cyproheptadine is not uniform in the literature. Methods: We retrospectively evaluated 23 adult patients (>18 years) admitted to the Neurology Department and met the Hunter criteria for SS. Results: The mean age was 35.2 years, and 52% were female. Ten patients were managed in the intensive care unit (ICU), whereas thirteen patients were admitted to the ward. Hyperreflexia was the most common clinical feature (100%), followed by clonus (91%), tachycardia (83%), and tremor (83%). Other common clinical features were rigidity (65%), increased bowel sound (61%), diaphoresis (48%), fever (43%), hypertension (39%), and myoclonus (30%). All but one patient received two or more serotonergic drugs. Tramadol was the most common serotonergic agent (39%), followed by sodium valproate (21%), and amitriptyline (21%). Cyproheptadine was administered to all patients. All patients admitted in the ICU received a loading dose of 12 mg followed by 2 mg every 2 h for at least 24 h. All patients admitted to the ward were given 4 mg of cyproheptadine three times each day. Every patient showed at least some response to cyproheptadine within 24 h. The total doses of cyproheptadine and the length of treatment differed between patients. Conclusion: Any response to cyproheptadine at a therapeutic dose within 24 h, even a partial one, could be a diagnostic indicator of the existence of SS.

A Single-center Comparison of Surgical Outcomes following Prepectoral and Subpectoral Implant-based Breast Reconstruction.

Background: Prepectoral implant placement continues to gain widespread acceptance as a safe and effective option for breast reconstruction. Current literature demonstrates comparable rates of complications and revisions between prepectoral and subpectoral placement; however, these studies are underpowered and lack long-term follow-up. Methods: We performed a retrospective cohort study of patients who underwent immediate two-staged tissue expander or direct-to-implant breast reconstruction at a single center from January 2017 to March 2021. Cases were divided into prepectoral and subpectoral cohorts. The primary outcomes were postoperative complications, aesthetic deformities, and secondary revisions. Descriptive statistics and multivariable regression models were performed to compare the demographic characteristics and outcomes between the two cohorts. Results: We identified 996 breasts (570 patients), which were divided into prepectoral (391 breasts) and subpectoral (605 breasts) cohorts. There was a higher rate of complications (P < 0.001) and aesthetic deformities (P = 0.02) with prepectoral breast reconstruction. Secondary revisions were comparable between the two cohorts. Multivariable regression analysis confirmed that prepectoral reconstruction was associated with an increased risk of complications (odds ratio 2.39, P < 0.001) and aesthetic deformities (odds ratio 1.62, P = 0.003). Conclusions: This study evaluated outcomes in patients undergoing prepectoral or subpectoral breast reconstruction from a single center with long-term follow-up. Prepectoral placement was shown to have an inferior complication and aesthetic profile compared with subpectoral placement, with no difference in secondary revisions. These findings require validation with a well-designed randomized controlled trial to establish best practice for implant-based breast reconstruction.

ECRG2/SPINK7 Tumor Suppressor as Modulator of DNA Damage Response.

Esophageal Cancer-Related Gene 2 (ECRG2), also known as Serine Peptidase Inhibitor Kazal type 7 (SPINK7), is a novel tumor suppressor gene from the SPINK family of genes that exhibits anticancer potential. ECRG2 was originally identified during efforts to discover genes involved in esophageal tumorigenesis. ECRG2 was one of those genes whose expression was absent or reduced in primary human esophageal cancers. Additionally, absent or reduced ECRG2 expression was also noted in several other types of human malignancies. ECRG2 missense mutations were identified in various primary human cancers. It was reported that a cancer-derived ECRG2 mutant (valine to glutamic acid at position 30) failed to induce cell death and caspase activation triggered by DNA-damaging anticancer drugs. Furthermore, ECRG2 suppressed cancer cell proliferation in cultured cells and grafted tumors in animals and inhibited cancer cell migration/invasion and metastasis. ECRG2 also was identified as a negative regulator of Hu-antigen R (HuR), an oncogenic RNA-binding protein that is known to regulate mRNA stability and the expression of transcripts corresponding to many cancer-related genes. ECRG2 function is important also for the regulation of inflammatory responses and the maintenance of epithelial barrier integrity in the esophagus. More recently, ECRG2 was discovered as one of the newest members of the pro-apoptotic transcriptional targets of p53. Two p53-binding sites (BS-1 and BS-2) were found within the proximal region of the ECRG2 gene promoter; the treatment of DNA-damaging agents in cancer cells significantly increased p53 binding to the ECRG2 promoter and triggered a strong ECRG2 promoter induction following DNA damage. Further, the genetic depletion of ECRG2 expression significantly impeded apoptotic cell death induced by DNA damage and wild-type p53 in cancer cells. These findings suggest that the loss of ECRG2 expression, commonly observed in human cancers, could play important roles in conferring anticancer drug resistance in human cancers. Thus, ECRG2 is a novel regulator in DNA damage-induced cell death that may also be a potential target for anticancer therapeutics.

Endoscopic Submucosal Dissection and Endoscopic Mucosal Resection for Barrett's Associated Neoplasia: A Systematic Review and Meta-analysis of the Published Literature.

Introduction The role of endoscopic submucosal dissection (ESD) in the treatment of Barrett's associated neoplasia (BEN) has been evolving. We examined the efficacy and safety of ESD and EMR for BEN. Methods A database search was performed for studies reporting efficacy and safety outcomes of ESD and EMR for BEN. Pooled proportional and comparative meta-analyses were performed. Results 47 studies (23 ESD, 19 EMR, and 5 comparative) were included. Mean lesion size for ESD and EMR were 22.5 mm and 15.8 mm respectively. Majority of lesions were Paris type IIa. Pooled analysis for ESD showed en-bloc resection, R0 resection, curative resection, and local recurrence rates of 98%, 78%, 65%, and 2%, respectively. Complete eradication of dysplasia (CE-D) and complete eradication of intestinal metaplasia (CE-IM) were achieved in 94% and 59% of cases. Pooled rates of perforation, intraprocedural bleeding (IPB), delayed bleeding (DB), and stricture were 1%, 1%, 2%, and 10%, respectively. Pooled analysis for EMR showed en-bloc resection, R0 resection, curative resection, and local recurrence rates of 37%, 67%, 62%, and 6%, respectively. CE-D and CE-IM were achieved in 94% and 76% of cases. Pooled rates of perforation, IPB, DB, and stricture were 0.1%, 1%, 0.4%, and 7.7%, respectively. The mean procedure time for ESD and EMR were 111.3 and 22.3 mins respectively. Comparative analysis showed higher en-bloc and R0 resection rates with ESD compared to EMR, with comparable adverse events. Conclusion ESD and EMR both can be employed to treat BEN depending on the lesion type, size, and expertise.

Use of glucagon-like peptide-1 receptor agonists for type 2 diabetes mellitus and outcomes of inflammatory bowel disease.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) show anti-inflammatory properties. AIM: To evaluate their clinical impact on inflammatory bowel disease (IBD) outcomes. METHODS: Retrospective cohort study utilising the TriNetX database comparing IBD-specific outcomes in patients with ulcerative colitis (UC) or Crohn's disease (CD) and type 2 diabetes mellitus (T2DM) on GLP-1RA compared to oral hypoglycaemic agents. The primary outcome was hospitalisation requiring intravenous steroids and IBD-related surgery within 3 years. We performed 1:1 propensity score matching (PSM) for demographics, co-morbid conditions, BMI, laboratory values, HbA1c, and IBD medications including steroids. RESULTS: We identified 1130 patients in the UC GLP-1RA cohort (mean age: 58.9 ± 11.6 years, 56.3% female, 70.2% White, 57.2% with obesity) and 1140 patients in the CD GLP-1RA cohort (mean age: 56.7 ± 11.5, 61.9% female, 73.6% White, 56.2% with obesity). After PSM, there was no difference in the risk of intravenous steroid use (aHR: 1.21, 95% CI: 0.92-1.59) but a lower risk of colectomy (aHR: 0.37, 95% CI: 0.14-0.97) between the UC GLP-1RA and control cohort. There was no difference in the risk of intravenous steroid use (aHR: 1.04, 95% CI: 0.80-1.34) but a lower risk of surgery (aHR: 0.55, 95% CI: 0.36-0.84) between the CD GLP-1RA and CD control cohort. There was no difference in the risk of oral steroid use or advanced therapy initiation in the UC and CD GLP-1RA than control cohorts. CONCLUSIONS: We found an association between lower risk of IBD-related surgery and GLP-1RA use for T2DM in patients with UC or CD.

Development, validation and application of single molecule molecular inversion probe based novel integrated genetic screening method for 29 common lysosomal storage disorders in India.

BACKGROUND: Current clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India. RESULTS: 903 smMIPs were designed to target exon and exon-intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood. CONCLUSION: We developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.