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Several studies with optical coherence tomography (OCT) have demonstrated thinning of the retinal nerve fiber layer (RNFL) in patients with optic neuritis and multiple sclerosis. Similar studies have not been performed with scanning laser polarimetry (SLP), which relies on different physical phenomena. This study was designed to use SLP to measure axonal loss following a single episode of optic neuritis and to determine if there is a relationship between the degree of axonal loss and the degree of residual visual dysfunction.Twenty-five patients with a single episode of optic neuritis and 15 control subjects were studied with SLP using the GDxVCC device to determine RNFL thickness in relation to visual acuity, visual fields, color vision, visual evoked potentials (VEPs), and previously published OCT data.SLP detected significant RNFL thinning in affected eyes compared to clinically unaffected fellow eyes in patients and in control eyes (P < 0.001). Reduced RNFL thickness was associated with significantly worse logMAR visual acuity, visual field mean deviation, and color vision. RNFL thinning correlated with reduced whole visual field and central visual field measures and VEP amplitudes. Superior and inferior quadrant RNFL thinning was related to corresponding regional visual field loss. There was a scaling factor between SLP and OCT RNFL measurements but only modest agreement.SLP detected functionally relevant axonal loss in eyes affected by optic neuritis. There was a scaling factor between RNFL measurements obtained with SLP and OCT but only modest agreement. Care should therefore be taken when comparing RNFL data from studies using these different devices. [ABSTRACT FROM AUTHOR]

Background: Standard-of-care biomarkers for renal allograft rejection are lagging indicators, signaling existing organ injury. This precludes early intervention, when immunological cascades leading to rejection are most susceptible. Donor-derived cell-free DNA (dd-cfDNA) shows promise as an early indicator of rejection, allowing earlier and possibly more effective treatment. This analysis was designed to assess this promise using real-world dd-cfDNA testing evidence., Methods: This retrospective analysis of the prospective, observational ProActive registry study (NCT04091984) assessed dd-cfDNA and serum creatinine levels before biopsy in 424 patients with ≥1 dd-cfDNA test (n = 1013) in the 6 mo before biopsy., Results: Of 4667 enrolled patients, 1631 patients had ≥18 mo of follow-up data, of which 424 had a biopsy and were included in this analysis. Twenty-six biopsies showed antibody-mediated rejection (ABMR), 62 showed T cell-mediated rejection, and 336 showed nonrejection; each from a unique patient. dd-cfDNA fractions were significantly elevated 5 mo before ABMR biopsies, and 2 mo before T cell-mediated rejection biopsies, compared with nonrejection biopsies. In contrast, serum creatinine did not discriminate between rejection and nonrejection in advance, or concurrent with biopsy. Among patients with nonrejection biopsies, estimated glomerular filtration rate was significantly lower in cases with ≥2 increased dd-cfDNA results (≥1%), compared with those with 0 or 1 increased dd-cfDNA result., Conclusions: These data indicate that dd-cfDNA is an early indicator of biopsy-proven rejection, especially ABMR, suggesting a greater role for dd-cfDNA in surveillance to identify patients at high risk of ongoing or future rejection, thus requiring closer monitoring, biopsy, or other management changes., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The purpose of this study was twofold: (1) to examine the prevalence of postpartum depression and anxiety symptomatology among fathers of Asian descent living in North America during the COVID-19 pandemic, and (2) to identify the occurrences of online racial discrimination., Study Design and Methods: Using a cross-sectional design and convenience sampling methods, we recruited fathers online via social media sites (Facebook, Instagram) between March 12 and July 31, 2022. The Edinburgh Postnatal Depression Scale, General Anxiety Scale, and the Online Victimization Scale assessed mental health well-being and discrimination outcomes. Data were analyzed using descriptive statistics, two sample t-test, chi-square test of independence, and Pearson's correlation analysis., Results: Our sample included 61 fathers within 6 months postpartum living in the United States and Canada. Participants were on average 34 years old, married, and represented 17 Asian ethnic groups, including Asian Indian (41%), Filipino (11.3%), and Korean (8.1%). One-third of our participants (31.1%, n = 19) were at high risk of developing postpartum depression and scores of three (4.9%) fathers indicated they had clinically significant anxiety. Overall, 26.3% reported experiencing direct online racial discrimination and 65% reported occurrences of indirect online racial discrimination., Clinical Implications: There was a high rate of depressive symptoms and occurrences of online racial discrimination among fathers of Asian descent living in North America. These rates are higher than the general perinatal population and further research is warranted to examine risk factors and preventive strategies among this unique paternal ethnic group., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Geographically localized areas with a high prevalence of kidney disease exist currently in several regions of the world. Although the exact cause is unclear, environmental exposures accelerated by climate change, particularly heat exposure and ground water contamination, are hypothesized as putative risk factors. Aiming to inform investigations of water-related exposures as risk factors for kidney disease, we excavate the history of major water sources in three regions that are described as hotspots of kidney disease: the low-lying coastal regions in El Salvador and Nicaragua, the dry central region in Sri Lanka, and the Central Valley of California., Recent Findings: Historic data indicate that these regions have experienced water scarcity to which several human-engineered solutions were applied; these solutions could be hypothesized to increase residents' exposure to putative kidney toxins including arsenic, fluoride, pesticides, and cyanobacteria. Combined with heat stress experienced in context of climate change, there is potential for multistressor effects on kidney function. Climate change will also amplify water scarcity, and even if regional water sources are not a direct risk factor for development of kidney disease, their scarcity will complicate the treatment of the relatively larger numbers of persons with kidney disease living in these hotspots., Summary: Nephrologists and kidney disease researchers need to engage in systematic considerations of environmental exposures as potential risk factors for kidney disease, including water sources, their increasing scarcity, and threats to their quality due to changing climate., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There is ongoing debate about whether the oculomotor (III), trochlear (IV), or abducens (VI) nerve paresis in patients with migraine is directly attributable to migraine (ophthalmoplegic migraine [OM]) or is due to an inflammatory neuropathy (recurrent painful ophthalmoplegic neuropathy [RPON]). As migraine is associated with elevated serum calcitonin gene-related peptide (CGRP) levels, we studied serum CGRP levels among patients with OM/RPON to determine whether they are elevated during and between attacks. This is the first study assessing CGRP levels in the serum of patients with OM/RPON., Methods: The aim of this case-control study was to assess serum CGRP levels in patients with ophthalmoplegia and a headache consistent with migraine according to ICHD-3 criteria. Serum CGRP levels were measured during the ictal and interictal phases in 15 patients with OM/RPON and compared with age-matched and sex-matched controls without migraine (12 patients)., Results: The median serum CGRP levels were significantly elevated ( P = 0.021) during the ictal phase (37.2 [36.4, 43.6] ng/L) compared with controls (32.5 [30.1, 37.3] ng/L). Serum CGRP levels during the attack correlated with the total duration of ophthalmoplegia. A CGRP level of 35.5 ng/L in the ictal phase of the attack had a sensitivity of 86.7% and specificity of 75.0% in diagnosing a patient with OM/RPON., Conclusions: Elevated serum CGRP levels during the ictal phase of OM/RPON favor migraine as the underlying cause of episodic headache with ophthalmoplegia., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by North American Neuro-Ophthalmology Society.)

Purpose: The aim of this study was to describe the safe use of repeated intracameral amphotericin B for anterior chamber reactivations after therapeutic penetrating keratoplasty for Fusarium solani keratitis., Methods: A 49-year-old woman monthly soft contact lens wearer with a history of overuse and swimming in her lenses presented with a red painful left eye. Her vision was 0.5 logMAR and there was a poorly demarcated corneal infiltrate. Although corneal scrapes and a corneal biopsy were negative, confocal microscopy showed fungal hyphae. After failure of medical treatment, therapeutic penetrating keratoplasty was performed. Fusarium solani sensitive to amphotericin was isolated. There was pan-azole resistance. The patient was managed with topical amphotericin B, and repeated anterior chamber reactivations were managed with intracameral amphotericin B 5 µg in 0.1 mL on 9 occasions over 5 months after sensitivities were known. Topical cyclosporine was used as the sole immunomodulator postoperatively, with no topical steroid use over the 4-year follow-up period., Results: There were no episodes of graft rejection and no endothelial, lenticular, or retinal toxicity. The best-corrected visual acuity is -0.1 logMAR and the endothelial cell count is 2160/mm 2 ., Conclusion: This report describes the safe and effective use of repeated intracameral amphotericin (cumulative 45 µg) in anterior chamber reactivations after therapeutic penetrating keratoplasty and highlights the role of fungal sensitivity in guiding treatment in refractory cases. It also demonstrated the successful use of topical cyclosporin as the sole postoperative immunomodulatory therapy despite repeated recurrence of infection and consequent increased inflammation in the postoperative period., Competing Interests: The authors have no conflict of interest and no financial declarations, (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We aimed to examine associations between the oral, fecal, and mucosal microbiome communities and adenoma formation., Summary Background Data: Data are limited regarding the relationships between microbiota and preneoplastic colorectal lesions., Methods: Individuals undergoing screening colonoscopy were prospectively enrolled and divided into adenoma and nonadenoma formers. Oral, fecal, nonadenoma and adenoma-adjacent mucosa were collected along with clinical and dietary information. 16S rRNA gene libraries were generated using V4 primers. DADA2 processed sequence reads and custom R-scripts quantified microbial diversity. Linear regression identified differential taxonomy and diversity in microbial communities and machine learning identified adenoma former microbial signatures., Results: One hundred four subjects were included, 46% with adenomas. Mucosal and fecal samples were dominated by Firmicutes and Bacteroidetes whereas Firmicutes and Proteobacteria were most abundant in oral communities. Mucosal communities harbored significant microbial diversity that was not observed in fecal or oral communities. Random forest classifiers predicted adenoma formation using fecal, oral, and mucosal amplicon sequence variant (ASV) abundances. The mucosal classifier reliably diagnosed adenoma formation with an area under the curve (AUC) = 0.993 and an out-of-bag (OOB) error of 3.2%. Mucosal classifier accuracy was strongly influenced by five taxa associated with the family Lachnospiraceae, genera Bacteroides and Marvinbryantia, and Blautia obeum. In contrast, classifiers built using fecal and oral samples manifested high OOB error rates (47.3% and 51.1%, respectively) and poor diagnostic abilities (fecal and oral AUC = 0.53)., Conclusion: Normal mucosa microbial abundances of adenoma formers manifest unique patterns of microbial diversity that may be predictive of adenoma formation., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Estimate agricultural work's effect on hemoglobin (Hgb) level in men. A negative effect may indicate presence of chronic kidney disease of uncertain etiology., Methods: We use Demographic and Health Surveys data from seven African and Asian countries and use matching to control for seven confounders., Results: On average, Hgb levels were 0.09 g/dL lower among agricultural workers compared with matched controls. Significant effects were observed in Ethiopia, India, Lesotho, and Senegal, with effects from 0.07 to 0.30 g/dL lower Hgb level among agricultural workers. The findings were robust to multiple control groups and a modest amount of unmeasured confounding., Conclusions: Men engaged in agricultural work in four of the seven countries studied have modestly lower Hgb levels. Our data support integrating kidney function assessments within Demographic and Health Surveys and other population-based surveys., Competing Interests: Conflict of Interest: None declared., (Copyright © 2022 American College of Occupational and Environmental Medicine.)

Children with neuroblastoma (NB) and opsoclonus-myoclonus-ataxia syndrome (OMAS) have a favorable oncologic outcome and overall survival. In contrast, despite intensive multidrug immunomodulation, the neurologic outcome is complicated by the relapsing nature of the neurologic symptoms and long-term neurobehavioral sequelae. Being associated with low-risk NB, there exists an ambiguity in the current literature regarding the administration of chemotherapy in these children. We reviewed our archives for children with NB-OMAS over a 22-year (January 1996 to January 2018) period. Eighteen children (10 female) with a median age at diagnosis of 23 months had NB-OMAS and were included. They had stage 1 (9/18; 50%), 2 (1/18; 5.5%), 3 (7/18; 39%), and 4 (1/18; 5.5%) disease according to the International Neuroblastoma Staging System. Multimodality therapy included surgery (16/18; 89%), chemotherapy (11/18; 61%), and immunomodulatory therapy (10/18; 55%). Complete oncologic remission was achieved in all children. Relapse of OMAS and presence of neurologic sequelae were observed in 1 (5.5%) and 5 (28%) cases, respectively. Presence of neurologic sequelae was significantly associated with low-tumor stage (P=0.036) and treatment without chemotherapy (P=0.003). Chemotherapy administration was the only variable significantly predicting a favorable neurologic outcome (95% confidence interval: 0.26-1.40, P=0.01). To conclude, our study including a limited cohort of patients highlights a favorable neurologic outcome associated with chemotherapy administration in children with NB-OMAS. However, further studies with larger sample size need to be conducted before drawing any definite conclusions., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We evaluated whether identification of undiagnosed HIV-infected people who inject drugs (PWID) via respondent-driven sampling (RDS) can be enhanced through a precision RDS (pRDS) approach., Design/methods: First, using prior RDS data from PWID in India, we built a prediction algorithm for recruiting undiagnosed HIV-infected PWID. pRDS was tested in Morinda, Punjab where participants were randomly assigned to standard or pRDS. In the standard RDS approach, all participants received two recruitment coupons. For pRDS, the algorithm determined an individual's probability of recruiting an undiagnosed PWID, and individuals received either two (low probability) or five (high probability) coupons. Efficiency in identifying undiagnosed HIV-infected PWID for the RDS approaches was evaluated in two ways: the number needed to recruit (NNR) and identification rate/week., Results: Predictors of recruiting undiagnosed PWID included HIV/HCV infection, network size, syringe services utilization, and injection environment. 1631 PWID were recruited in Morinda. From the standard RDS approach, 615 were recruited, including 39 undiagnosed; from pRDS, 1012 were recruited, including 77 undiagnosed. In pRDS, those with higher predicted probability were more likely to recruit others with HIV/HCV co-infection, undiagnosed and viremic HIV, and who utilized services. pRDS had a significantly higher identification rate of undiagnosed PWID (1.5/week) compared with the standard (0.8/week). The NNR for pRDS (13.1) was not significantly lower than the standard approach (15.8)., Conclusion: pRDS identified twice as many undiagnosed and viremic PWID significantly faster than the standard approach. Leveraging RDS or similar network-based strategies should be considered alongside other strategies to ensure meeting UNAIDS targets., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Implantable cardiac sensors have shown promise in reducing rehospitalization for heart failure (HF), but the efficacy of noninvasive approaches has not been determined. The objective of this study was to determine the accuracy of noninvasive remote monitoring in predicting HF rehospitalization., Methods: The LINK-HF study (Multisensor Non-invasive Remote Monitoring for Prediction of Heart Failure Exacerbation) examined the performance of a personalized analytical platform using continuous data streams to predict rehospitalization after HF admission. Study subjects were monitored for up to 3 months using a disposable multisensor patch placed on the chest that recorded physiological data. Data were uploaded continuously via smartphone to a cloud analytics platform. Machine learning was used to design a prognostic algorithm to detect HF exacerbation. Clinical events were formally adjudicated., Results: One hundred subjects aged 68.4±10.2 years (98% male) were enrolled. After discharge, the analytical platform derived a personalized baseline model of expected physiological values. Differences between baseline model estimated vital signs and actual monitored values were used to trigger a clinical alert. There were 35 unplanned nontrauma hospitalization events, including 24 worsening HF events. The platform was able to detect precursors of hospitalization for HF exacerbation with 76% to 88% sensitivity and 85% specificity. Median time between initial alert and readmission was 6.5 (4.2-13.7) days., Conclusions: Multivariate physiological telemetry from a wearable sensor can provide accurate early detection of impending rehospitalization with a predictive accuracy comparable to implanted devices. The clinical efficacy and generalizability of this low-cost noninvasive approach to rehospitalization mitigation should be further tested. Registration: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03037710.

An unexplained increase in the incidence of oral cavity squamous cell carcinoma (oSCC) has been observed despite decreasing smoking rates, particularly in younger patients. Links to defects in the DNA mismatch repair (MMR) system are well established in early onset colorectal, urothelial and gynaecological malignancies. MMR deficient patients treated with immune checkpoint inhibitors have demonstrated improved response rates. Studies exploring MMR status in head and neck squamous cell carcinoma (HNSCC) demonstrate conflicting results. This study explores the incidence of MMR protein loss and its association with clinicopathological features and outcome in oSCC. Immunohistochemical staining using tissue microarrays to assess the expression of MMR proteins (hMLH1, hMSH2, hMSH6, and hPMS2) was performed on 285 consecutive oSCC cases between 2000 and 2016. Data on smoking, alcohol and metachronous malignancies were retrospectively collected. Proportional hazards regression models were used to compare survival in MMR intact and deficient patients. MMR deficiency was seen in 21 patients (7.4%). MMR deficient tumours were associated with bone invasion (52% vs 32%, p=0.05), higher pT stage (pT4 in 57% vs 35%, p<0.001) and a higher number of metachronous malignancies (p=0.05). MMR deficiency was not associated with younger age at presentation or absence of smoking or alcohol. There was no significant association between MMR status and survival (overall survival hazard ratio 1.36; p=0.32). The incidence of MMR loss in oSCC is low and is not associated with young age at presentation. MMR deficiency in oSCC is associated with an increase in the number of metachronous malignancies and more advanced primary tumours., (Copyright © 2019 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background and Purpose- The aims of this study were to investigate the effect of an intervention to unblind data on r-tPA (recombinant tissue-type plasminogen activator) administration and sharing data with chief executive officers of participating hospitals, on r-tPA administration rates postintervention and on potential healthcare cost savings implemented at 26 Southeast Texas Regional Advisory Council hospitals. Methods- Retrospective analysis of prospective data on thrombolytic therapy from 26 Southeast Texas Regional Advisory Council hospitals, collected between April 2014 and June 2016. The control (blinded) period (Q2-2014 to Q2-2015) was followed by unblinding (Q3-2015). Results- Intervention was associated with 21.1% increase in r-tPA administration rates, with 38.5% increase in r-tPA administration with door-to-needle time ≤60 minutes. An absolute increase in r-tPA administration of 2.1% was seen with an average lifetime cost savings of $3.6 million. Conclusions- Transparent regional data sharing was associated with improved r-tPA administration and healthcare cost savings.

Purpose: Cardiac imaging expenditures have come under scrutiny, and a focus on appropriate use criteria (AUC) has arisen to ensure cost-effective resource utilization. Although AUC has been developed by clinical experts, it has not undergone rigorous quality assurance testing to ensure that inappropriate indications for testing yield little clinical benefit. The objective of the study was to evaluate the potential incremental prognostic value of coronary computed tomographic angiography (CCTA) in the different AUC categories., Materials and Methods: Consecutive patients enrolled into a cardiac CT Registry were collated. Patient indications were reviewed and based on the 2010 AUC (appropriate, uncertain, and inappropriate). Patients were followed-up for death, myocardial infarction (MI), and late revascularization, with the primary composite endpoint being cardiac death, nonfatal MI, and late revascularization. The prognostic value of CCTA over clinical variables in each of the AUC categories was assessed., Results: Indications for CCTA were appropriate, uncertain, and inappropriate in 1284 (66.5%), 312 (16.2%), and 334 (17.3%) patients, respectively. Rates of all-cause of death, cardiac death, nonfatal MI, and late revascularization were similar across patients with appropriate, uncertain, and inappropriate indications for CCTA. Moreover, in each AUC category, CCTA had incremental prognostic value over a routine clinical risk score (National Cholesterol Education Program) with hazard ratios of 9.98, 7.39, and 5.61., Conclusions: CCTA has incremental prognostic value in all AUC categories, even when the reason for the study was deemed "inappropriate." This suggests that CCTA may still have clinical value in "inappropriate" indications and that further quality assurance AUC studies are needed.

Objective: The aim of the study was to explore specific microRNAs (miRs) in rectal cancer that would predict response to radiation and identify target pathways that may be exploited for neoadjuvant therapies., Summary Background Data: Chemoradiotherapy (CRT) response is a predictor of survival in rectal cancer. Studies have demonstrated changes in RNA expression correlate with chemoradiation sensitivity across cancers., Methods: Forty-five rectal cancer patients, partial responders (PR = 18), nonresponders (NR = 13), and complete responders (CR = 14) to CRT, as defined by a tumor regression score, were examined. miRs differentially expressed, using NanoString microArray profiling, were validated with qPCR. We quantified 1 miR and its downstream targets in patient samples. Chemosensitivity was measured in HCT-116, a human colorectal carcinoma cell line, using inhibitors of SHP2 and RAF., Results: miR-451a, 502-5p, 223-3p, and 1246 were the most upregulated miRs (>1.5-fold change) in a NanoString profiling miR panel. qPCR revealed a decrease in expression of miR-451a in NRs. EMSY and CAB39, both downstream targets of miR-451a and involved in carcinogenesis (shown in TCGA) were increased in NRs (qPCR). Both targets are associated with worse survival in colorectal cancer. Inhibition of miR-451a in HCT-116 cells significantly decreased cell proliferation with treatment of SHP2 and RAF inhibitors., Conclusions: An integrated analysis of rectal cancer miRs may yield biomarkers of radioresistance and offer treatment targets for resensitization.

Background: Appropriate Use Criteria (AUC) guidelines for cardiac computed tomography (CCT) were developed to limit testing to reasonable clinical settings. However, significant testing is still done for inappropriate indications. This study investigates the impact of AUC on evaluability of CCT to determine if inappropriate tests result in a greater proportion of nondiagnostic results., Methods: Investigators reviewed the medical records of 2417 consecutive patients who underwent CCT at the University of Ottawa Heart Institute. We applied the 2010 AUC and classified them as appropriate, inappropriate, or uncertain. Unclassifiable tests, as well as those with uncertain appropriateness, were excluded from the final analysis. Cardiac computed tomography results were classified as diagnostic if (1) all coronary segments were visualized, evaluable, and without obstructive stenosis; or (2) obstructive coronary artery disease with greater than 50% diameter stenosis in at least 1 coronary artery. All other test results were considered nondiagnostic., Results: Of the 1984 patients included in the final analysis, 1522 patients (76.7%) had indications that were appropriate, whereas the remaining 462 (23.3%) were inappropriate. Inappropriate tests resulted in a higher rate of nondiagnostic results compared with appropriate CCT (9.0% vs 6.2%, P = 0.034). Inappropriate tests also had significantly more studies with nonevaluable segments than appropriate tests (24.5% vs 16.4%, P < 0.001) and were more likely to reveal obstructive coronary disease than appropriate CCT (50.5% vs 32.7%, P < 0.001)., Conclusions: Cardiac computed tomography done for inappropriate indications may be associated with lower diagnostic yield and could impact future downstream resource utilization and health care costs.

Right unilateral ultrabrief-pulse electroconvulsive therapy (RUL-UB ECT) is gaining popularity and is being used for the treatment of severe major depression. Though brief pulse-width ECT has shown to have robust antimanic effects, the efficacy of UB ECT for mania has not been studied, and there are very few reports on its use in mania. A brief case series of 3 patients with manic episode of bipolar disorder who were treated with RUL-UB ECT is presented here. The successful treatment of 2 patients in this report suggests that some manic episodes can be rapidly and effectively treated with RUL-UB ECT.

A public health approach to combination HIV prevention is advocated to contain the epidemic in sub-Saharan Africa. We explore the implications of universal access to treatment along with HIV education scale-up in the region. We develop an HIV transmission model to investigate the impacts of universal access to treatment, as well as an analytical framework to estimate the effects of HIV education scale-up on the epidemic. We calibrate the model with data from South Africa and simulate the impacts of universal access to treatment along with HIV education scale-up on prevalence, incidence, and HIV-related deaths over a course of 15 years. Our results show that the impact of combined interventions is significantly larger than the summation of individual intervention impacts (super-additive property). The combined strategy of universal access to treatment and HIV education scale-up decreases the incidence rate by 74% over the course of 15 years, whereas universal access to treatment and HIV education scale up will separately decrease that by 43% and 8%, respectively. Combination HIV prevention could be notably effective in transforming HIV epidemic to a low-level endemicity. Our results suggest that in designing effective combination prevention in sub-Saharan Africa, priorities should be given to achieving universal access to treatment as quickly as possible and improving compliance to condom use.

Objective: To characterize prevalence, incidence, and associated correlates of HIV infection among MSM in 12 cities across India., Design: Cross-sectional sample using respondent-driven sampling from September 2012 to June 2013., Methods: A total 12022 MSM (~1000/city) were recruited. Participants had to be at least 18 years, self-identify as male, and report oral/anal intercourse with a man in the prior year. HIV infection was diagnosed using three rapid tests. Cross-sectional HIV incidence was estimated using a multiassay algorithm. All estimates incorporate respondent-driven sampling-II weights., Results: Median age was 25 years, 45% self-identified as 'panthi' (predominantly penetrative anal intercourse) and 30.6% reported being married to a woman. Weighted HIV prevalence was 7.0% (range: 1.7-13.1%). In multivariate analysis, significantly higher odds of HIV infection was observed among those who were older, had lower educational attainment, were practicing purely receptive anal sex or both receptive and penetrative sex, and those who were herpes simplex virus-2 positive. Of 1147 MSM who tested HIV positive, 53 were identified as recent HIV infections (annualized incidence = 0.87%; range = 0-2.2%). In multivariate analysis, injecting drugs in the prior 6 months, syphilis, and higher number of male partners and fewer female partners were significantly associated with recent HIV infection., Conclusion: We observed a high burden of HIV among MSM in India with tremendous diversity in prevalence, incidence, and risk behaviors. In particular, we observed high incidence in areas with relatively low prevalence suggesting emerging epidemics in areas not previously recognized to have high HIV burden.

Biliary endoprostheses continue to demonstrate their utility and simplicity in daily therapeutic endoscopy. However, the transient nature of these foreign bodies also underscores their potential detrimental effects even after successful deployment. Stent related factors, such as type, length and caliber offer potential avenues to minimize the risk of migration. However, a patient related factor such as the presence of prior abdominal surgeries makes it paramount for endoscopists to ascertain the location of a migrated stent. There is a ripe niche for continued research and development in biodegradable stents.

Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated and nosocomial infectious diarrhea. Presenting as clostridium difficile colitis, it is a significant cause of morbidity and mortality. Metronidazole is regarded as the agent of choice for CDl therapy and also for the first recurrence in most patients with mild to moderate CDI. Vancomycin is recommended as an initial therapy for patients with severe CDI. With recent Food and Drug Administration-approval fidaxomicin is available for clinical use and is as effective as vancomycin with lower relapse rates. Rifaximin and fecal bacteriotherapy are alternative approaches in patients with severe or refractory CDI, before surgical intervention. Antibiotic research is ongoing to add potential new drugs such as teicoplanin, ramoplanin, fusidic acid, nitazoxanide, rifampin, bacitracin to our armamentarium. Role of toxin-binding agents is still questionable. Monoclonal antibody and intravenous immunoglobulin are still investigational therapies that could be promising options. The ongoing challenges in the treatment of CDI include management of recurrence and presence of resistance strains such as NAP1/BI/027, but early recognition of surgical candidates can potentially decrease mortality in CDI.

Hepatic hydrothorax is defined as a pleural effusion in patients with liver cirrhosis in the absence of cardiopulmonary disease. The estimated prevalence among patients with liver cirrhosis is approximately 5-6%. The pathophysiology involves the passage of ascitic fluid from the peritoneal cavity to the pleural space through diaphragmatic defects. The diagnosis is made from clinical presentation and confirmed by diagnostic thoracentesis with pleural fluid analysis. The initial medical management is sodium restriction and diuretics, but liver transplantation provides the only definitive therapy. For patients who are not transplant candidates and those who await organ availability, other therapeutic modalities that are to be considered include transjugular intrahepatic portosystemic shunt placement, videoassisted thoracoscopic surgery repair, pleurodesis, and vasoconstrictors (eg, octreotide and terlipressin). The primary therapeutic goals are to reduce ascitic fluid production and improve symptoms to bridge the time for liver transplantation.

Ascites that does not respond or recurs after high-dose diuresis and sodium restriction should be considered refractory ascites. As cirrhosis advances, the escaping fluid overwhelms the lymphatic return. Decrease in renal plasma flow leads to increased sodium reabsorption at the proximal tubule leading to decreased responsiveness to loop diuretics and mineralocorticoid antagonists, which work distally. These complex hemodynamic alterations lead to refractory ascites. In refractory ascites, high-dose diuresis (400 mg of spironolactone and 160 mg of furosemide) and sodium restriction (<90 mmol/d) result in inadequate weight loss and sub optimal sodium excretion (<78 mmol/d). Further use of diuretics is limited by complications such as encephalopathy, azotemia, renal insufficiency, hyponatremia, and hyperkalemia. Therapy for refractory ascites is limited. The available therapies are repeated large volume paracentesis (LVP), transjugular intrahepatic portosystemic shunts, peritoneovenous shunts, investigational medical therapies, and liver transplantation. LVP with concomitant volume expanders is the initial treatment of choice. Transjugular intrahepatic portosystemic seems to be superior to LVP in reducing the need for repeated paracentesis and improves the quality of life. Several treatments that act at different steps in the pathogenesis of ascites are investigational, and some show promising results. Splanchnic and peripheral vasoconstrictors (Octreotide, Midodrine, and Terlipressin) increase effective arterial volume and decrease activation of the renin-angiotensin system with resultant increase in renal sodium excretion. Clonidine when given with spironolactone has been shown to cause rapid mobilization of ascites by significantly decreasing the sympathetic activity and renin-aldosterone levels. Natural aquaretics and synthetic V2 receptor antagonists (satavaptan) are being evaluated for mobilization of ascites by increasing the excretion of solute-free water. Liver transplantation remains the only definitive therapy for refractory ascites. Because refractory ascites is a poor prognostic sign, liver transplantation should be considered and incorporated early in the treatment plan.

Purpose: To report the results of descemet stripping endothelial keratoplasty (DSEK) for a single-surgeon, consecutive case series., Method: All patients undergoing DSEK at our institution from 2006 to 2007 under the care of a single consultant ophthalmologist were enrolled. This was a nonrandomized, retrospective case series. Grafts were dissected manually using an artificial anterior chamber and a Morlet lamellar dissector. Data were collected for refractive error, visual acuity, endothelial cell density, graft thickness, and graft profile., Results: Twenty-one eyes of 20 patients were included. The average age at surgery was 69 ± 11 years (range, 37-88 years). The main indication for DSEK was Fuchs endothelial dystrophy. The mean preoperative best spectacle-corrected visual acuity was 1.2 logarithm of the minimum angle of resolution, improving to 0.48 logarithm of the minimum angle of resolution postoperatively (P = 0.001). Endothelial cell density decreased postoperatively compared with preoperatively, but the rate of cell loss decreased over time. No significant correlation was observed between mean graft thickness and final visual acuity or between graft profile and refractive shift., Conclusions: DSEK is a positive alternative to PK in the treatment of endothelial dysfunction. Visual function improves and the associated refractive change is negligible. Complication rates are low, and graft survival over 2 years is high. Manual preparation of tissue provides grafts of suitable thickness and profile, and endothelial cell density decline is comparable with that of donor's tissue cut via microkeratome or after PK.

Background: In clinical practice, heart failure (HF) medications are underused and prescribed at lower than recommended doses. Telephone care is an option that could help to titrate HF medication in a timely manner. We describe our experience of a nurse-run, cardiologist- or nurse practitioner-supervised clinic to up-titrate HF medications via telephone., Methods: Patients with the diagnosis of HF, New York Heart Association classes I to III, were referred to a registered nurse-run, cardiologist-/nurse practitioner-supervised HF medication titration clinic. Clinical and medication data collected at enrollment to the clinic and at 3 to 6 months after optimization of HF medications in patients who did or did not reach the target doses were compared. Effect on left ventricular (LV) function was also evaluated., Results: There were 79 patients in the evaluation: 64 with HF and LV systolic dysfunction (LVSD) and the remaining 15 with HF and preserved ejection fraction (EF). Seventy-two percent of patients with LVSD were on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and 61% were on a β-blocker at baseline, and this increased to 98% and 97%, respectively, after optimization. Target doses was achieved in 50% of patients for ACEI or ARB, and in 41% for β-blockers. The median time to optimization was 54 days (interquartile range, 20-97 days). The average number of phone calls at the time of optimization were 5.4 (SD, 3.7), and the average number of clinic visits was 1.9 (SD, 1.3). Reasons for not reaching the target doses included hypotension, hyperkalemia, and renal dysfunction for ACEI and bradycardia for β-blockers. Overall, the EF increased by 10% (SD, 10%) after 6 months, and 35% or greater in 42% of patients whose baseline EF was less than 35%. There were no adverse events related to the dose up-titration., Conclusion: Telephonic titration of HF medications was feasible and safe and was achieved in 97% patients on ACEI/ARB and β-blockers. Medication titration was associated with significant improvement in LV function, avoiding the need for device therapy in many patients.

Background: In a whole-genome scan, a single nucleotide polymorphism (SNP) (rs7566605) upstream of the insulin-induced gene 2 (INSIG2) was shown to influence body mass index and obesity in the Framingham Heart Study, with replication of these results in an additional 4 of 5 studies. However, other studies could not replicate the association. Because INSIG2 plays an important role in cholesterol biosynthesis, we hypothesized that human INSIG2 variants might play a role in the regulation of plasma lipid and lipoprotein levels., Methods and Results: We selected tagging SNPs spanning >100 kb of INSIG2 locus and sequenced 18 434 base pairs to discover novel SNPs. Thirty-two SNPs were genotyped in 645 individuals from the Quebec Family Study. Two SNPs (rs10490626 and rs12464355) were associated with plasma low-density lipoprotein cholesterol (LDL-C) (P<0.0015) and total apolipoprotein B (apoB) levels (P<0.014), whereas no association was found between any SNP and body mass index. We replicated the finding of rs10490626 for both LDL-C and total apoB in additional study samples, including 758 individuals from Saguenay-Lac St. Jean, Quebec (P=0.040 for LDL-C, P=0.044 for apoB), 3247 Europeans (P=0.028 for LDL-C, P=0.030 for apoB), and 1695 South Asians (P=0.0036 for LDL-C, P=0.034 for apoB) from the INTERHEART study (for LDL-C, the combined 2-sided P=6.2×10⁻⁵ and for total apoB, P=0.0011). Furthermore, we identified a variant in the human sorbin and SH(3)-domain-containing-1 gene that was associated with INSIG2 mRNA levels, and this SNP was shown to act in combination with rs10490626 to affect LDL-C (P=0.022) in the Quebec Family Study and in INTERHEART South Asians (P=0.019) and Europeans (P=0.052)., Conclusion: These results suggest that INSIG2 genetic variants may have a more direct role in lipid and lipoprotein metabolism than in obesity.

Background: Hepatitis C virus (HCV) infection is prevalent among renal transplant recipients., Methods: Twenty-five recipients of living donor renal transplantation with HCV (group I) and without HCV (group II) were serially monitored at three time points, that is, pretransplant, day 10, and 6 months posttransplant. Phenotypic characterization of T-cell subsets and natural killer cells was performed by flow cytometric immunophenotyping. Cytometric bead array immunoassay was used to simultaneously measure six cytokines (interleukin [IL]-2, IL-4, IL-5, IL-10, tumor necrosis factor-α, and interferon-γ) from phytohemagglutin-stimulated culture supernatants, and transforming growth factor (TGF)-β1 levels were determined by ELISA. Real-time polymerase chain reaction method was used to determine the serum viral load among group I patients at three time points., Results: Group I patients on day 10 posttransplant showed a significant increase in T cells subsets with reduced interferon-γ and increased TGF-β1 levels. A significantly increased CD8 T cells and TGF-β levels were seen at 6-month posttransplant among group I patients. Multivariate linear regression analysis showed TGF-β and tumor necrosis factor-α as the most significant predictors affecting early (day 10) and late (6 months) posttransplant viral load, respectively., Conclusion: After an initial increase in the viral load immediately posttransplantation, there is a reduction in viral load. A concomitant timed dissection of the immune response shows a complex interactive environment in which, despite immunosuppression, not only the antiviral immune response persists but the virus is also able to modulate the host immune response for its survival. Per se, HCV does not adversely affect the allograft or patient outcome in this case-control study.

Background: Injection drug users (IDUs) have estimated mortality rates over 10 times higher than the general population; much of this excess mortality is HIV-associated. Few mortality estimates among IDUs from developing countries, including India, exist., Methods: IDUs (1158) were recruited in Chennai from April 2005 to May 2006; 293 were HIV positive. Information on deaths and causes was obtained through outreach workers and family/network members. Mortality rates and standardized mortality ratios were calculated; multivariate Poisson regression was used to identify predictors of mortality., Results: We observed 85 deaths over 1998 person-years (p-y) of follow-up [mortality rate (MR) 4.25 per 100 p-y; 95% confidence interval (CI) = 3.41-5.23]. The overall standardized mortality ratio was 11.1; for HIV-positive IDUs, the standardized mortality ratio was 23.9. Mortality risk among HIV-positive IDUs (MR: 8.88 per 100 p-y) was nearly three times that of negative IDUs (MR: 3.03 per 100 p-y) and increased with declining immune status (CD4 cells > 350: 5.44 per 100 p-y vs. CD4 cells < or = 200: 34.5 per 100 p-y). This association persisted after adjustment for confounders. The leading causes of mortality in both HIV negative and positive IDUs were overdose (n = 22), AIDS (n = 14), tuberculosis (n = 8) and accident/trauma (n = 9)., Conclusion: Substantial mortality was observed in this cohort with the highest rates among HIV-positive IDUs with CD4 counts of less than 350 cells/microl. Although, in these 2 years, non-AIDS deaths outnumbered 0002030-related deaths, the relative contribution of 0002030-associated mortality is likely to increase with advancing HIV disease progression. These data reinforce the need for interventions to reduce the harms associated with drug use and increase HAART access among IDUs in Chennai.

Purpose: To document the evolution of geographic atrophy in the peripherin/RDS Arg172Trp substitution, provide age-related estimates of visual acuity, and compare with other missense mutations with a similar phenotype (Arg142Trp, Arg172Gln, and Arg195Leu)., Methods: Total area of geographic atrophy in 18 affected individuals with the peripherin/RDS Arg172Trp substitution was measured from retinal photographs and plotted as a function of age. Visual acuity data from these individuals were collated with previously published cases of Arg172Trp substitution to obtain age-related estimates of visual acuity. These were compared with published series with the Arg142Trp, Arg172Gln, and Arg195Leu substitutions, using linear regression., Results: In patients with the Arg172Trp substitution, the increase in total area of chorioretinal atrophy and decline in visual acuity showed significant association with age (R2 = 0.619, P < 0.001; R2 = 0.761, P < 0.001). A trend was observed toward earlier age at onset and worse visual acuity with the Arg172Trp substitution as compared with the Arg142Trp and Arg172Gln substitutions. Linear regression analysis showed that until the age of 60 years, at any given age, visual acuity with the Arg172Trp substitution was significantly worse than the Arg142Trp (P < 0.001) and the Arg172Gln substitutions (P = 0.04). Patients above the age of 60 years were excluded as a floor effect on visual acuity was observed with visual acuity being worse than 6/60 for most patients., Conclusion: This paper demonstrates that visual prognosis in macular dystrophies associated with peripherin/RDS may be mutation specific and, for the Arg172Trp substitution, worse than the Arg142Trp and Arg172Gln substitutions.

Background: Diet is a major modifiable risk factor for cardiovascular disease, but it varies markedly in different regions of the world. The objectives of the present study were to assess the association between dietary patterns and acute myocardial infarction (AMI) globally., Methods and Results: INTERHEART is a standardized case-control study involving participants from 52 countries. The present analysis included 5761 cases and 10 646 control subjects. We identified 3 major dietary patterns using factor analysis: Oriental (high intake of tofu and soy and other sauces), Western (high in fried foods, salty snacks, eggs, and meat), and prudent (high in fruit and vegetables). We observed an inverse association between the prudent pattern and AMI, with higher levels being protective. Compared with the first quartile, the adjusted ORs were 0.78 (95% CI 0.69 to 0.88) for the second quartile, 0.66 (95% CI 0.59 to 0.75) for the third, and 0.70 (95% CI 0.61 to 0.80) for the fourth (P for trend <0.001). The Western pattern showed a U-shaped association with AMI (compared with the first quartile, the adjusted OR for the second quartile was 0.87 [95% CI 0.78 to 0.98], whereas it was 1.12 [95% CI 1.00 to 1.25] for the third quartile and 1.35 [95% CI 1.21 to 1.51] for the fourth quartile; P for trend <0.001), but the Oriental pattern demonstrated no relationship with AMI. Compared with the first quartile, the OR of a dietary risk score derived from meat, salty snacks, fried foods, fruits, green leafy vegetables, cooked vegetables, and other raw vegetables (higher score indicating a poorer diet) increased with each quartile: second quartile 1.29 (95% CI 1.17 to 1.42), third quartile 1.67 (95% CI 1.51 to 1.83), and fourth quartile 1.92 (95% CI 1.74 to 2.11; P for trend <0.001). The adjusted population-attributable risk of AMI for the top 3 quartiles compared with the bottom quartile of the dietary risk score was 30%., Conclusions: An unhealthy dietary intake, assessed by a simple dietary risk score, increases the risk of AMI globally and accounts for approximately 30% of the population-attributable risk.

Objective: The genetic determinants of severe hypertriglyceridemia (HTG; MIM 144650) in adults are poorly defined. We therefore resequenced 3 candidate genes, namely LPL, APOC2, and APOA5, to search for accumulation of missense mutations in patients with severe HTG compared with normolipidemic subjects., Methods and Results: We resequenced >2 million base pairs of genomic DNA from 110 nondiabetic patients with severe HTG and determined the prevalence of coding sequence variants compared with 472 age- and sex-matched normolipidemic controls. We found: (1) heterozygous mutations (LPL p.Q-12E >11X, p.D25H, p.W86R, p.G188E, p.I194T and p.P207L; APOC2 p.K19T and IVS2-30G>A) in 10.0% of severe HTG patients compared with 0.2% of controls (carrier odds ratio [OR] 52, 95% confidence interval [CI] 8.6 to 319); and (2) an association of the APOA5 p.S19W missense variant with severe HTG (carrier OR 5.5 95% CI 3.3 to 9.1). Furthermore, either rare mutations or the APOA5 p.S19W variant were found in 41.8% of HTG subjects compared with 8.9% of controls (carrier OR 7.4, 95% CI 4.5 to 12.0). Also, heterozygotes for rare mutations had a significantly reduced plasma triglyceride response to fibrate monotherapy., Conclusions: Both common and rare DNA variants in candidate genes were found in a substantial proportion of severe HTG patients. The findings underscore the value of candidate gene resequencing to understand the genetic contribution in complex lipoprotein and metabolic disorders.

This two-part article provides an overview of the global burden of atherothrombotic cardiovascular disease. Part I initially discusses the epidemiological transition which has resulted in a decrease in deaths in childhood due to infections, with a concomitant increase in cardiovascular and other chronic diseases; and then provides estimates of the burden of cardiovascular (CV) diseases with specific focus on the developing countries. Next, we summarize key information on risk factors for cardiovascular disease (CVD) and indicate that their importance may have been underestimated. Then, we describe overarching factors influencing variations in CVD by ethnicity and region and the influence of urbanization. Part II of this article describes the burden of CV disease by specific region or ethnic group, the risk factors of importance, and possible strategies for prevention.

This two-part article provides an overview of the global burden of atherothrombotic cardiovascular disease. Part I initially discusses the epidemiologic transition which has resulted in a decrease in deaths in childhood due to infections, with a concomitant increase in cardiovascular and other chronic diseases; and then provides estimates of the burden of cardiovascular (CV) diseases with specific focus on the developing countries. Next, we summarize key information on risk factors for cardiovascular disease (CVD) and indicate that their importance may have been underestimated. Then, we describe overarching factors influencing variations in CVD by ethnicity and region and the influence of urbanization. Part II of this article describes the burden of CV disease by specific region or ethnic group, the risk factors of importance, and possible strategies for prevention.

Background: We developed a computer model to predict lysis rates of thrombi for intravenous thrombolytic regimens based on the convective/diffusive penetration of reacting and adsorbing fibrinolytic species from the circulation into the proximal face of a dissolving clot., Methods and Results: Solution of a one-compartment plasma model provided the dynamic concentrations of fibrinolytic species that served as inlet conditions for stimulation of the one-dimensional spatiodynamics within a dissolving fibrin clot of defined composition. The model predicted the circulating levels of tissue plasminogen activator (TPA) and plasminogen levels found in clinical trials for various intravenous therapies. To test the model predictions under in vitro conditions, plasma clots were perfused with TPA (0.1 mumol/L) and plasminogen (1.0 mumol/L) delivered at constant permeation velocity of 0.1 or 0.2 mm/min. The model provided an accurate prediction of the measured lysis front movement. For TPA administration regimens used clinically, simulations predicted clot dissolution rates that were consistent with observed reperfusion times. For unidirectional permeation, the continual accumulation of adsorbing species at the moving lysis front due to prior rounds of solubilization and rebinding was predicted to provide for a marked concentration of TPA and plasmin and the eventual depletion of antiplasmin and macroglobulin in an advancing (approximately 0.25 mm thick) lysis zone., Conclusions: Pressure-driven permeation greatly enhances and is a primary determinant of the overall rate of clot lysis and creates a complex local reaction environment at the plasma/clot interface. With simulation of reaction and transport, it becomes possible to quantitatively link the administration regimen, plasminogena activator properties, and thrombolytic outcome.