Barium sulfate and pigment admixture for photoacoustic and x-ray contrast imaging of the gut.

Significance: X-ray imaging is frequently used for gastrointestinal imaging. Photoacoustic imaging (PAI) of the gastrointestinal tract is an emerging approach that has been demonstrated for preclinical imaging of small animals. A contrast agent active in both modalities could be useful for imaging applications. Aim: We aimed to develop a dual-modality contrast agent comprising an admixture of barium sulfate with pigments that absorb light in the second near-infrared region (NIR-II), for preclinical imaging with both x-ray and PAI modalities. Approach: Eleven different NIR-II dyes were evaluated after admixture with a 40% w/v barium sulfate mixture. The resulting NIR-II absorption in the soluble fraction and in the total mixture was characterized. Proof-of-principle imaging studies in mice were carried out. Results: Pigments that produced more uniform suspensions were assessed further for photoacoustic contrast signal at a wavelength of 1064 nm that corresponds to the output of the Nd:YAG laser used. Phantom imaging studies demonstrated that the pigment-barium sulfate mixture generated imaging contrast in both x-ray and PAI modalities. The optimal pigment selected for further study was a cyanine tetrafluoroborate salt. Ex-vivo and whole-body mouse imaging demonstrated that photoacoustic and x-ray contrast signals co-localized in the intestines for both imaging modalities. Conclusion: These data demonstrate that commercially-available NIR-II pigments can simply be admixed with barium sulfate to generate a dual-modality contrast agent appropriate for small animal gastrointestinal imaging.

Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma.

PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Complementary administration of curcumin in PCOS: a systematic review.

INTRODUCTION: The clinical benefit of curcumin, the active ingredient in turmeric, among women diagnosed with polycystic ovarian syndrome (PCOS) is unclear. In this systematic review, we aim to provide a brief review of the existing literature on the association between curcumin supplementation and PCOS. EVIDENCE ACQUISITION: Published articles relevant to the topic was obtained through extensive search using relevant keywords such as "polycystic ovarian syndrome," "PCOS," "turmeric," and "curcumin." Inclusion criteria included studies that investigated PCOS and turmeric/curcumin, while studies that investigated the use of curcumin in other gynecological disorders, infertility, rodent studies, and non-RCTs were excluded. EVIDENCE SYNTHESIS: A total of 14 articles were found and only five studies were incorporated based on the exclusion criteria. The main findings were that curcumin supplementation aids in improvement of lipid and glycemic profiles, Body Mass Index (BMI) and lowers androgen levels associated with PCOS. CONCLUSIONS: We shed light on additional therapeutic management for PCOS other than the conventional treatment. Further studies are required with larger sample sizes and diverse patient population to derive definitive conclusions regarding benefits of curcumin supplementation in PCOS.

Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans.

BACKGROUND: α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans. METHODS: We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with vehicle or senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q). FINDINGS: We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence. INTERPRETATION: Senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials. FUNDING: This work was supported by National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K., S.K.), AG044271 (N.M.), AG013319 (N.M.), and the Translational Geroscience Network (AG061456: J.L.K., T.T., N.M., S.B.K., S.K.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Noaber Foundation (J.L.K.). The previous IPF clinical trial was supported by the Claude D. Pepper Older Americans Independence Centers at WFSM (AG021332: J.N.J., S.B.K.), UTHSCA (AG044271: A.M.N.), and the Translational Geroscience Network.

The role of precision medicine in interstitial lung disease.

The management of interstitial lung disease (ILD) may benefit from a conceptual shift. Increased understanding of this complex and heterogeneous group of disorders over the past 20 years has highlighted the need for individualised treatment strategies that encompass diagnostic classification and disease behaviour. Biomarker-based approaches to precision medicine hold the greatest promise. Robust, large-scale biomarker-based technologies supporting ILD diagnosis have been developed, and future applications relating to staging, prognosis and assessment of treatment response are emerging. Artificial intelligence may redefine our ability to base prognostic evaluation on both diagnosis and underlying disease processes, sharpening individualised treatment algorithms to a level not previously achieved. Compared with therapeutic areas such as oncology, precision medicine in ILD is still in its infancy. However, the heterogeneous nature of ILD suggests that many relevant molecular, environmental and behavioural targets may serve as useful biomarkers if we are willing to invest in their identification and validation.

Lung Microbiome in Idiopathic Pulmonary Fibrosis and Other Interstitial Lung Diseases.

Interstitial lung diseases represent a heterogeneous and wide group of diseases in which factors leading to disease initiation and progression are not fully understood. Recent evidence suggests that the lung microbiome might influence the pathogenesis and progression of interstitial lung diseases. In recent years, the utilization of culture-independent methodologies has allowed the identification of complex and dynamic communities of microbes, in patients with interstitial lung diseases. However, the potential mechanisms by which these changes may drive disease pathogenesis and progression are largely unknown. The aim of this review is to discuss the role of the altered lung microbiome in several interstitial lung diseases. Untangling the host-microbiome interaction in the lung and airway of interstitial lung disease patients is a research priority. Thus, lung dysbiosis is a potentially treatable trait across several interstitial lung diseases, and its proper characterization and treatment might be crucial to change the natural history of these diseases and improve outcomes.

Monitoring and management of fibrosing interstitial lung diseases: a narrative review for practicing clinicians.

Close monitoring of patients with fibrosing interstitial lung diseases (ILDs) is important to enable prompt identification and management of progressive disease. Monitoring should involve regular assessment of physiology (including pulmonary function tests), symptoms, and, when appropriate, high-resolution computed tomography. The management of patients with fibrosing ILDs requires a multidisciplinary approach and should be individualized based on factors such as disease severity, evidence of progression, risk factors for progression, comorbidities, and the preferences of the patient. In this narrative review, we discuss how patients with fibrosing ILDs can be effectively monitored and managed in clinical practice.

Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial.

Importance: Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. Objective: To assess the effect of antimicrobial therapy on clinical outcomes. Design, Setting, and Participants: Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020). Interventions: Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group. Main Outcomes and Measures: The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. Results: Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%). Conclusions and Relevance: Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease. Trial Registration: ClinicalTrials.gov Identifier: NCT02759120.

HACE1 Prevents Lung Carcinogenesis via Inhibition of RAC-Family GTPases.

HACE1 is an E3 ubiquitin ligase with important roles in tumor biology and tissue homeostasis. Loss or mutation of HACE1 has been associated with the occurrence of a variety of neoplasms, but the underlying mechanisms have not been defined yet. Here, we report that HACE1 is frequently mutated in human lung cancer. In mice, loss of Hace1 led to enhanced progression of KRasG12D -driven lung tumors. Additional ablation of the oncogenic GTPase Rac1 partially reduced progression of Hace1-/- lung tumors. RAC2, a novel ubiquitylation target of HACE1, could compensate for the absence of its homolog RAC1 in Hace1-deficient, but not in HACE1-sufficient tumors. Accordingly, ablation of both Rac1 and Rac2 fully averted the increased progression of KRasG12D -driven lung tumors in Hace1-/- mice. In patients with lung cancer, increased expression of HACE1 correlated with reduced levels of RAC1 and RAC2 and prolonged survival, whereas elevated expression of RAC1 and RAC2 was associated with poor prognosis. This work defines HACE1 as a crucial regulator of the oncogenic activity of RAC-family GTPases in lung cancer development. SIGNIFICANCE: These findings reveal that mutation of the tumor suppressor HACE1 disrupts its role as a regulator of the oncogenic activity of RAC-family GTPases in human and murine lung cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/14/3009/F1.large.jpg.

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.

BACKGROUND: Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice. METHODS: A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored. FINDINGS: Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50). INTERPRETATION: Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases. ClinicalTrials.gov identifier: NCT02874989 (posted 2016-2018).

Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases.

Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype. Progressive fibrosis is associated with worsening respiratory symptoms, lung function decline, limited response to immunomodulatory therapies, decreased quality of life and, potentially, early death. Idiopathic pulmonary fibrosis may be regarded as a model for other progressive-fibrosing ILDs. Here we focus on other ILDs that may present a progressive-fibrosing phenotype, namely idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-associated ILDs (e.g. rheumatoid arthritis-related ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and ILDs related to other occupational exposures. Differential diagnosis of these ILDs can be challenging, and requires detailed consideration of clinical, radiological and histopathological features. Accurate and early diagnosis is crucial to ensure that patients are treated optimally.

Possible UIP pattern on high-resolution computed tomography is associated with better survival than definite UIP in IPF patients.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease of unknown etiology. Inter-society consensus guidelines on IPF diagnosis and management outline radiologic patterns including definite usual interstitial pneumonia (UIP), possible UIP, and inconsistent with UIP. We evaluate these diagnostic categories as prognostic markers among patients with IPF. METHODS: Included subjects had biopsy-proven UIP, a multidisciplinary team diagnosis of IPF, and a baseline high-resolution computed tomography (HRCT). Thoracic radiologists assigned the radiologic pattern and documented the presence and extent of specific radiologic findings. The outcome of interest was lung transplant-free survival. RESULTS: IPF patients with a possible UIP pattern on HRCT had significantly longer Kaplan-Meier event-free survival compared to those with definite UIP pattern (5.21 and 3.57 years, respectively, p = 0.002). In a multivariable Cox proportional hazards model adjusted for baseline age, gender, %-predicted FVC, and %-predicted DLCO via the GAP Stage, extent of fibrosis (via the traction bronchiectasis score) and ever-smoker status, possible UIP pattern on HRCT (versus definite UIP) was associated with reduced hazard of death or lung transplant (HR = 0.42, CI 95% 0.23-0.78, p = 0.006). CONCLUSIONS: Radiologic diagnosis categories outlined by inter-society consensus guidelines is a widely-reported and potentially useful prognostic marker in IPF patients, with possible UIP pattern on HRCT associated with a favorable prognosis compared to definite UIP pattern, after adjusting for relevant covariates.

Effectiveness and safety of mycophenolate mofetil in idiopathic pulmonary fibrosis.

BACKGROUND: Currently available antifibrotic treatments may slow down disease progression in idiopathic pulmonary fibrosis (IPF), but are associated with potentially significant side effects and are costly. Mycophenolate mofetil (MMF) is well known for its potent immunosuppressive properties and possesses important antiproliferative and antifibrotic effects. The safety and effectiveness of MMF in IPF is unknown. METHODS: We performed a retrospective multicohort analysis of IPF patients treated with MMF compared to those treated with either ineffective/harmful treatments or no treatment. Longitudinal change in forced vital capacity (FVC) between the groups was analyzed using a mixed model with random intercept and slope allowing for repeated measures within subjects. Categorical change in FVC, median overall survival, and adverse events were also assessed. RESULTS: Forty-one IPF patients were included: 11 treated with MMF, 20 treated with ineffective/harmful agents (such as prednisone, azathioprine, and/or NAC), and 10 did not receive any specific treatment for their IPF. After one year, there was a trend towards reduced FVC decline in the MMF-treated group (-76.3 mL, -2.4% of predicted) compared to the non-MMF-treated (-165 mL, -8.9% of predicted) and the no-treatment (-239 mL, -11.5% of predicted) groups, respectively. By categorical change, there was a trend towards greater FVC stability in the MMF-treated group (87.5%) compared to the non-MMF-treated (57%) and the no-treatment groups (50%), respectively. MMF-treated IPF patients had a trend towards improved median overall survival (40.3 months) compared to the non-MMF-treated (25.5 months) and the no-treatment (29.3 months) groups, respectively. Treatment-related adverse events were not different between groups; however, very few adverse events were reported overall. CONCLUSIONS: MMF treatment was associated with potentially clinically important trends toward reduced annual FVC decline (similar to approved antifibrotics), greater FVC stability and improved overall survival in IPF patients. MMF was generally safe, well tolerated, and relatively inexpensive. Future prospective studies of MMF in combination with antifibrotic therapy in IPF are needed.

Spectrum of hepatobiliary cystic lesions: A 7-year experience at a tertiary care referral center in North India and review of literature.

CONTEXT: Cysts arising from the hepatobiliary tree are a group of heterogeneous lesions with regard to pathogenesis, clinical presentation, and radiological finding. They can be intrahepatic or extrahepatic, developmental, secondary to infective/inflammatory etiologies, as well as neoplastic. This study was conducted to determine the spectrum of hepatobiliary cysts in surgically intervened cases, with regard to their prevalence, histological spectrum, and clinicoradiological correlation, wherever possible. METHODS: In this retrospective observational study, hematoxylin and eosin stained slides of all cases of hepatobiliary cystic lesions, operated between 2009 and 2016 were reviewed. Special stains as reticulin, Masson's trichrome, and periodic acid Schiff were done wherever necessary. Overall prevalence, age-sex distribution, clinical presentation and histopathological patterns were studied. Relevant imaging findings were correlated wherever possible. RESULTS: A total of 312 cases of hepatobiliary cysts were identified, the majority in females. Choledochal cysts (CCs) were the most common type (n = 198,63.5%), followed by hydatid cysts (n = 73,23.3%), simple hepatic cysts (n = 10,3.2%), congenital hepatic fibrosis (n = 10,3.2%), biliary cystadenomas (n = 4,1.2%) hepatic mesenchymal hamartomas (n = 7,2.2%), and cavernous hemangiomas (n = 3,0.9%). Fibropolycystic liver disease (n = 2,0.6%), Caroli's disease (n = 1, 0.3%), liver abscess (n = 2, 0.6%), infantile hemangioendothelioma (n = 1,0.3%), and biliary cystadenocarcinomas (n = 1,0.3%) were rare. Lesions noted mostly in 1st decade of life were: CCs, fibrocystic liver disease, Caroli's syndrome, cystic mesenchymal hamartoma, and infantile hemangioendotheliomas. CONCLUSION: In our cohort of surgically intervened cases of hepatobiliary cystic lesions from a tertiary care hospital in North India, the CCs, followed by hydatid cyst were the most common lesions. Histology can play vital role in characterization, as often clinical findings and radiology can overlap.

Diagnosis and Management of Sarcoidosis.

Sarcoidosis is a systemic disease of unknown etiology characterized by the presence of noncaseating granulomas in any organ, most commonly the lungs and intrathoracic lymph nodes. A diagnosis of sarcoidosis should be suspected in any young or middle-aged adult presenting with unexplained cough, shortness of breath, or constitutional symptoms, especially among blacks or Scandinavians. Diagnosis relies on three criteria: (1) a compatible clinical and radiologic presentation, (2) pathologic evidence of noncaseating granulomas, and (3) exclusion of other diseases with similar findings, such as infections or malignancy. An early and accurate diagnosis of sarcoidosis remains challenging, because initial presentations may vary, many patients are asymptomatic, and there is no single reliable diagnostic test. Prognosis is variable and depends on epidemiologic factors, mode of onset, initial clinical course, and specific organ involvement. The optimal treatment for sarcoidosis remains unclear, but corticosteroid therapy has been the mainstay of therapy for those with significantly symptomatic or progressive pulmonary disease or serious extrapulmonary disease. Refractory or complex cases may require immunosuppressive therapy. Despite aggressive treatment, some patients may develop life-threatening pulmonary, cardiac, or neurologic complications from severe, progressive disease. End-stage disease may ultimately require lung or heart transplantation for eligible patients.

Outcomes of transcatheter aortic valve replacement in patients with chronic liver disease.

OBJECTIVE: Transcatheter aortic valve replacement (TAVR) has emerged as an alternative to high-risk surgery in patients with comorbid conditions. The role of TAVR in patients with liver disease has not been examined. METHODS: We examined the procedural and intermediate to long-term follow-up outcomes of patients with severe symptomatic aortic valve stenosis and chronic liver disease, identified by liver biopsy or from a combination of clinical findings. All patients were treated with balloon-expandable transfemoral (TF) or transapical (TA) TAVR between November 2007 and February 2014. RESULTS: A total of 17 of 706 (2.41%) patients treated at our institution with TF [n=14] or TA [n=3] TAVR had chronic liver disease (mean age 77.65±9.06 years, 7 women, mean STS score 8.37, mean Charlson score 5.00, mean MELD score 11.35, Child-Turcotte-Pugh (CTP) Class A [n=11], B [n=6], C [n=0], biopsy proven liver disease [n=5]). Median follow-up was 466 days (range=12-1,403 days). The mean post-procedure length of hospital stay was 5.88±3.08 days. Procedural success was achieved in all cases. In-hospital mortality was 5.88% and 90-day mortality was 17.65%. Safety and efficacy endpoints as defined by the valve academic research consortium (VARC) were significant for one perioperative death from a proximate cardiac cause (post-operative day 14), one death after hospital discharge of unknown cause (post-operative day 12), two late deaths from non-cardiac causes (post-operative days 50 and 487, respectively), and one late death of unknown cause (post-operative day 1,005). There were no life-threatening or major bleeding complications. One patient had an MI, one had a transient ischemic attack, four had transient, Stage I, acute kidney injury and one had transient, Stage II, acute kidney injury. CONCLUSION: TF and TA TAVR are feasible methods for treating aortic stenosis in patients with chronic liver disease. In patients with mild to moderate chronic liver disease there are acceptable rates of early and late complications, however, outcomes in patients with advanced liver disease (MELD>20 or CTP class C) warrant further study.

Single-stage renal transplantation-urinary diversion: a novel surgical approach.

INTRODUCTION: This article reports outcomes of 2 patients who received a single-stage renal transplantation and concomitant urinary-diversion procedure. TECHNICAL CONSIDERATIONS: We followed the clinical diagnosis and outcome of 2 patients who underwent renal transplantation and urinary diversion as a single-stage procedure by retrospectively reviewing a Hartford Hospital Institutional Review Board-approved kidney database. Patient demographics, renal function, and surgical outcomes were examined. CONCLUSION: Two patients underwent a simultaneous renal transplantation-ileal conduit creation to surgically manage their end-stage renal disease. One patient did not have any surgical complications, whereas the other suffered from a postoperative ileus (Clavien grade 3a), atrial fibrillation (Clavien grade 2), hypertension (Clavien grade 2), methicillin-resistant Staphylococcus aureus at the incisional site (Clavien grade 2), and a positive urine culture managed using antibiotics (Clavien grade 2). No major complications were observed and both have favorable outcomes at 23 and 19 months after surgery, respectively. This report demonstrates the feasibility and safety of single-stage renal transplantation and urinary diversion in select patients with end-stage renal disease status after cystectomy. To our knowledge, this is the first report of this novel technique.

Clinical effectiveness and safety of cetirizine versus rupatadine in chronic spontaneous urticaria: a randomized, double-blind, 6-week trial.

BACKGROUND: Urticaria is a distressing condition associated with diverse clinical presentations. Chronic spontaneous urticaria (CsU) is characterized by wheals and angioedema. Its treatment requires an algorithmic approach to identify the optimum medication. OBJECTIVES: Cetirizine is commonly used in the treatment of urticaria. Rupatadine is a selective non-sedating H1 -antihistamine approved for the treatment of CsU. This trial was conducted to ascertain whether the properties of rupatadine offer advantages over cetirizine. METHODS: Seventy patients with CsU were enrolled. Parameters assessed included: (i) mean number of wheals (MNW); (ii) pruritus; (iii) mean total symptom score (MTSS); (iv) size of wheal; (v) interference of wheals with sleep; and (vi) sedation. Patients with CsU were divided randomly into two groups. Routine investigations were performed at baseline and at the end of the study. RESULTS: Evaluations of MTSS, MNW, and pruritus revealed statistically significant differences at week 3 compared with baseline in the cetirizine group. However, greater reductions in these parameters were obtained with rupatadine. In patients receiving rupatadine, reductions in the MNW, size of wheals, and intensity of erythema were also significant at six weeks (P < 0.001) and were significantly greater than those in the cetirizine group (P < 0.05). CONCLUSIONS: Improvements in MTSS, MNW, size of wheals, intensity of erythema, and differential eosinophil count imply that rupatadine is a particularly attractive therapeutic modality compared with cetirizine for the treatment of CsU.

An unusual case of "renal failure".

Myopathy is common in hypothyroidism, but a very high creatinine kinase (CK) level in the range commonly seen with inflammatory myopathy is rare. Reversible elevation of creatinine is known to occur in hypothyroidism due to a decrease in the glomerular filtration rate, but it can also occur rarely due to enhanced creatinine production. We present a case of severe hypothyroidism with massively elevated CK levels and high creatinine levels, both of which reversed on treatment of hypothyroidism.