Preferences and feasibility of long-acting technologies for treatment of hepatitis C virus in low- and middle-income countries: A survey of providers and policymakers.

Long-acting technologies (LATs) for hepatitis C virus (HCV) are under development as a strategy to improve linkage to care, treatment adherence and outcomes. We conducted a survey of HCV treatment prescribers and HCV policymakers in low- and middle-income countries (LMICs) regarding acceptability and feasibility of HCV LATs. We included one-time intramuscular injection, subdermal implant and transdermal patch as potential LAT options. We surveyed participants regarding optimal health system and patient characteristics, concerns, potential barriers, overall feasibility and preferences for HCV LAT as compared to daily oral medication. Overall, 122 providers and 50 policymakers from 42 LMICs completed the survey. Among providers, 93% (113/122) expressed willingness to prescribe LAT and 72% (88/120) of providers preferred LAT if provided at comparable efficacy, safety and cost as current oral treatments. Of providers preferring HCV LAT to daily oral medication, 67% (59/88) preferred injection, 24% (21/88) preferred patch and 9% (8/88) preferred implant. Only 20% (24/122) would prescribe LAT if it were more costly than oral treatment. In regression analysis, no provider characteristics were associated with preference for LAT over oral treatment. Policymakers reported high likelihood that LAT would be included in treatment guidelines (42/50; 84%) and national drug formularies (39/50; 78%) if efficacy, safety and cost were similar to oral treatment. HCV LATs could advance progress to HCV elimination in LMICs by diversifying treatment options to improve treatment coverage and outcomes. Provider preferences from LMICs are a critical consideration in the development of HCV LATs to ensure its early and equitable availability in LMICs.

Right Ventricle-Pulmonary Artery Coupling in Patients Undergoing Cardiac Interventions.

PURPOSE OF REVIEW: This review aims to summarize the fundamentals of RV-PA coupling, its non-invasive means of measurement, and contemporary understanding of RV-PA coupling in cardiac surgery, cardiac interventions, and congenital heart disease. RECENT FINDINGS: The need for more accessible clinical means of evaluation of RV-PA coupling has driven researchers to investigate surrogates using cardiac MRI, echocardiography, and right-sided pressure measurements in patients undergoing cardiac surgery/interventions, as well as patients with congenital heart disease. Recent research has aimed to validate these alternative means against the gold standard, as well as establish cut-off values predictive of morbidity and/or mortality. This emerging evidence lays the groundwork for identifying appropriate RV-PA coupling surrogates and integrating them into perioperative clinical practice.

Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4.

Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed that microbial-specific indoles regulated intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is a ligand for PXR in vivo, and IPA downregulated enterocyte TNF-α while it upregulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2(-/-)) mice showed a distinctly "leaky" gut physiology coupled with upregulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier were corrected in Nr1i2(-/-)Tlr4(-/-) mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway that involves luminal sensing and signaling by TLR4.

Bacterial Swarmers Enriched During Intestinal Stress Ameliorate Damage.

BACKGROUND AND AIMS: Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress. METHODS: We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation. From chemically induced colitis in mice, as well as humans with inflammatory bowel disease, we developed techniques to isolate the dominant swarmers. We developed swarm-deficient but growth and swim-competent mutant bacteria as isogenic controls. We performed bacterial reinoculation studies in mice with colitis, fecal 16S, and meta-transcriptomic analyses, as well as in vitro microbial interaction studies. RESULTS: We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers, in contrast to their mutant strains, abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family of Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal meta-transcriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants; however, because SM3, but not mutants, induced S24-7 in vivo, we concluded that swarming plays an essential role in disseminating SM3 in vivo. CONCLUSIONS: Overall, our work identified a new but counterintuitive paradigm in which intestinal stress allows for the emergence of swarming bacteria; however, these bacteria act to heal intestinal inflammation.

Genetic model of MS severity predicts future accumulation of disability.

No genetic modifiers of multiple sclerosis (MS) severity have been independently validated, leading to a lack of insight into genetic determinants of the rate of disability progression. We investigated genetic modifiers of MS severity in prospectively acquired training (N = 205) and validation (N = 94) cohorts, using the following advances: (1) We focused on 113 genetic variants previously identified as related to MS severity; (2) We used a novel, sensitive outcome: MS Disease Severity Scale (MS-DSS); (3) Instead of validating individual alleles, we used a machine learning technique (random forest) that captures linear and complex nonlinear effects between alleles to derive a single Genetic Model of MS Severity (GeM-MSS). The GeM-MSS consists of 19 variants located in vicinity of 12 genes implicated in regulating cytotoxicity of immune cells, complement activation, neuronal functions, and fibrosis. GeM-MSS correlates with MS-DSS (r = 0.214; p = 0.043) in a validation cohort that was not used in the modeling steps. The recognized biology identifies novel therapeutic targets for inhibiting MS disability progression.

Mutation profile of high-grade appendiceal mucinous neoplasm.

AIMS: High-grade appendiceal mucinous neoplasm (HAMN) was recently proposed as a disease entity histologically analogous to low-grade appendiceal mucinous neoplasm (LAMN), but characterised by high-grade cytological atypia. The pathogenesis and clinical features of HAMN have not been fully elucidated. METHODS AND RESULTS: Nine cases of HAMN, eight LAMN, 10 appendiceal mucinous adenocarcinomas (MACA) and five appendiceal serrated polyps resected between 2008 and 2017 contributed by three medical centres underwent targeted next-generation sequencing of 50 cancer-related genes. The patients in each category had similar profiles with respect to gender, age, tumour stage and follow-up intervals. Both LAMN and HAMN harboured mutations of KRAS [nine of nine and eight of eight (100%), respectively] and GNAS [five of eight (63%) and five of nine (56%), respectively] in significantly higher proportions than MACA [KRAS, seven of 10 (70%, P = 0.04); GNAS: one of 10 (10%, P = 0.02)] and serrated polyps [KRAS, one of five (20%, P = 0.0007); GNAS: none of five (0%, P = 0.04)]. Four cases of HAMN, but none of LAMN, harboured mutations of TP53 [four of nine (44%)] and/or ATM [two of nine (22%)]. Three cases of HAMN (33%) showed extra-appendiceal spread with retention of the same mutational profiles in the intra- and extra-appendiceal components. The 10 cases of MACA harboured a similar prevalence of TP53 mutations (n = 5, 50%) as HAMN but, unlike LAMN and HAMN, some harboured mutations in PIK3CA, APC, FBXW7, PTEN and SMAD4. CONCLUSIONS: HAMN and LAMN share high rates of KRAS and GNAS co-mutations supporting a common histogenesis and distinguishing them from MACA. Acquisition of TP53 or ATM mutations by HAMN may drive its progression to a more advanced phenotype.

Colorectal carcinomas with mucinous differentiation are associated with high frequent mutation of KRAS or BRAF mutations, irrespective of quantity of mucinous component.

BACKGROUND: Mucinous adenocarcinoma (MAC) is a distinct type of colorectal cancer (CRC) associated with poor response to treatment and poorer prognosis. MAC is diagnosed by WHO definition when the extracellular mucin is more than 50% of the lesion. We aimed at assessing the gene expression profiles of the CRCs with any mucinous features (> 5%) in a retrospective study. METHODS: The data of a 50-gene next generation sequencing (NGS) panel of 166 CRCs was analyzed and the gene mutational profile with morphologic features was correlated. RESULTS: We identified the different genetic mutation profiles between CRCs with and without mucinous component, but noticed a similar genetic profile between MACs and CRCs with mucinous component, irrespective of the percentage (if mucinous component more than 5%). The different genetic mutation profile related to MSI status was also identified between two groups of tumors. The most frequent mutations in CRCs with mucinous component are KRAS (28/49, 57.1%) and BRAF (19/49, 38.7%), PIK3CA (16/49, 32.6%), followed by APC (12/49, 24.5%) and TP53 (11/49, 22.5%). The combined mutation frequency of the two key factors in the EGFR signaling pathway, KRAS and BRAF, in the CRCs with and without mucinous component is 95.9 and 52.1%, respectively. CONCLUSIONS: The dysregulation of EGFR pathway plays a critical role in the development of CRCs with mucinous component, irrespective of the percentage. The result suggested that the current cut off of 50% mucin component to define mucinous adenocarcinoma might be challengeable.

Patient Age Is Inversely Associated with Injury Counts Caused by Motor Vehicle Crashes.

Associations between age and fracture incidence, total number of fractures, and total number of injuries per occupant occurring in motor vehicle crashes were evaluated. An observational study of the Crash Injury Research and Engineering Network was conducted. Multivariable logistic regression and negative binomial models were used to relate age (2064, 65+ years) to fracture incidence, total number of fractures per occupant, and total number of injuries, adjusting for sex and change in vehicle velocity (deltav). Over 90% of occupants had at least one fracture for a total of 5,846 fracture injuries. The older age group experienced a 15% increase in the incidence of total injuries sustained compared to the younger group (Incident Rate Ratio = 1.15, 95% Confidence Interval = 1.081.23, p 0.0001). Older patients should be considered for polytrauma evaluation even with a lower energy motor vehicle crash. (Journal of Surgical Orthopaedic Advances 29(1):3639, 2020).

Epidural Abscess in the Lumbar Spine: A Single Institution's Experience With Nonsurgical and Surgical Management.

The purpose of this study was to compare patient factors and outcomes in conservatively and surgically treated patients with spinal epidural abscess (SEA). This was a single-center retrospective review of adult patients treated for SEA of the lumbar spine. Primary treatment outcome was readmission for recurrent abscess. Sixty-one patients met inclusion criteria: 59% male, mean age 56.9 years, and body mass index 30.8 kg/m2. Initially 47.5% of patients were treated with conservative measures and 52.5% were treated with surgery. In the conservative group, 31.0% failed treatment and underwent delayed surgery; 26.2% of the overall cohort was readmitted for SEA. Readmitted patients had a greater incidence of history of methicillin-resistant Staphylococcus aureus (p = .048), recurrent infections (p = .008), and recent sepsis and bacteremia (p = .005). Nearly one-third of patients failed initial conservative treatment and needed delayed surgery; however, no significant differences were found between the two treatment groups. Patients with a past history of infections may require more aggressive treatment and closer follow-up, because they are at higher risk for recurrence and readmission. (Journal of Surgical Orthopaedic Advances 28(3):224-231, 2019).

Developing precision medicine for people of East Asian descent.

The goal of precision medicine is to separate patient populations into groups to ultimately provide customized care tailored to patients. In terms of precision medicine, ~540 million people in the world have a genetic variant of the aldehyde dehydrogenase 2 (ALDH2) enzyme causing a flushing response and tachycardia after alcohol consumption. The genetic variant is identified as ALDH2*2 and originates from East Asian descendants of the Han Chinese. The variant is particularly important to consider when discussing lifestyle choices with patients in terms of risk for developing specific diseases, preventative screening, and selection of medications for treatment. Here we provide examples why patients with an ALDH2*2 variant need more individualized medical management which is becoming a more standard practice in the precision medicine era.

Synthesis of cis-[Cr(diimine)2(1-methylimidazole)2](3+) Complexes and an Investigation of Their Interaction with Mononucleotides and Polynucleotides.

A protocol is presented for the synthesis of chromium(III) complexes of the type cis-[Cr(diimine)2(1-methylimidazole)2](3+). These compounds exhibit large excited-state oxidizing powers and strong luminescence in solution. Emission is quenched by added guanine, yielding rate constants that track the driving force for guanine oxidation. The cis-[Cr(TMP)(DPPZ)(1-MeImid)2](3+) species binds strongly to duplex DNA with a preference for AT base sites in the minor groove and may serve as a precursor for photoactivated DNA covalent adduct formation.

Ovary preservation in the treatment of childhood Meigs syndrome.

Meigs syndrome, the combination of benign ovarian tumor, ascites, and pleural effusion, is present in a small percentage of ovarian fibromas and is infrequently reported in children. When associated with elevated CA-125 suspicion is raised for malignancy, often prompting aggressive surgical intervention. We present a case of childhood Meigs syndrome and review the relevant literature with emphasis on ovary preservation. Out of nine identified pediatric cases, one involved ovary sparing treatment and none recurred or progressed to malignancy. Our report highlights the importance of presurgical identification of Meigs syndrome in order to curtail salpingo-oophorectomy when feasible.

Colorectal Signet Ring Cell Carcinoma Presenting as Ulcerating Rectosigmoid Stricture.

Colorectal signet ring cell carcinoma is a rare type of colon cancer. Early diagnosis remains challenging because of nonspecific colonoscopy findings, such as diffuse circumferential thickening, stricture, and ulcerations, and the potential absence of typical pathological features in the initial biopsy sample. In this article, we report a 41-year-old man with ulcerating rectosigmoid stricture in the rectosigmoid colon with inconclusive histology. Subsequently, the patient developed small bowel obstruction and was diagnosed with stage 4 colorectal signet ring cell carcinoma with peritoneal carcinomatosis.

Histologic Predictors of Clinical Outcomes and Healthcare Utilization in Patients With Ileal Pouch-Anal Anastomosis.

BACKGROUND: The prognostic significance of histology in ileal pouch-anal anastomosis (IPAA) remains unclear. The aim of this study was to evaluate if histologic variables are predictive of IPAA clinical outcomes and healthcare utilization. METHODS: This was a retrospective cohort study of patients with IPAA undergoing surveillance pouchoscopy at a tertiary care institution. Pouch body biopsies were reviewed by gastrointestinal pathologists, who were blinded to clinical outcomes, for histologic features of acute or chronic inflammation. Charts were reviewed for clinical outcomes including development of acute pouchitis, chronic pouchitis, biologic or small molecule initiation, hospitalizations, and surgery. Predictors of outcomes were analyzed using univariable and multivariable logistic and Cox regression. RESULTS: A total of 167 patients undergoing surveillance pouchoscopy were included. Polymorphonuclear leukocytes (odds ratio [OR], 1.67), ulceration and erosion (OR, 2.44), chronic inflammation (OR, 1.97), and crypt distortion (OR, 1.89) were associated with future biologic or small molecule initiation for chronic pouchitis. Loss of goblet cells was associated with development of chronic pouchitis (OR, 4.65). Pyloric gland metaplasia was associated with hospitalizations (OR, 5.24). No histologic variables were predictive of development of acute pouchitis or surgery. In an exploratory subgroup analysis of new IPAA (<1 year), loss of goblet cells was associated with acute pouchitis (OR, 14.86) and chronic pouchitis (OR, 12.56). Pyloric gland metaplasia was again associated with hospitalizations (OR, 13.99). CONCLUSIONS: Histologic findings may be predictive of IPAA outcomes. Pathologists should incorporate key histologic variables into pouchoscopy pathology reports. Clinicians may need to more closely monitor IPAA patients with significant histologic findings.

In this retrospective cohort study, histologic variables of acute and chronic inflammation were associated with future development of chronic pouchitis, need for biologic or small molecule treatment for chronic pouchitis, and hospitalization.

Histologic Inflammation can Predict Future Clinical Relapse in Ulcerative Colitis Patients in Endoscopic Remission.

Background: In ulcerative colitis (UC), endoscopic improvement, defined as a Mayo Endoscopic Score (MES) of 0 or 1, is a target of treatment. The aim of our study was to evaluate the risk of clinical relapse between patients with an MES of 0 or 1 and determine if histologic activity using the Robarts Histopathologic Index (RHI) was predictive of clinical relapse. Methods: UC patients with an MES score of 0 or 1, no prior colectomy, and at least 1 year of outpatient follow-up after colonoscopy were included. Demographic, clinical characteristics, and clinical relapse were retrospectively collected. Biopsy specimens were read by a gastrointestinal pathologist. Primary outcome was defined as a composite of relapse requiring change in medical therapy, new steroid use, UC-related hospitalization, and/or colectomy. Results: Four hundred and forty-five UC patients were identified. Ninety-five percent of patients with MES 0 were in histologic remission by the RHI whereas only 35% of patients with MES 1 were in histologic remission. Twenty-six percent of patients experienced a clinical relapse; patients with MES 1 or RHI > 3 were significantly more likely to relapse (P < .01) compared to patients with MES 0 or RHI ≤ 3. When patients were stratified into 4 groups (MES 0, RHI ≤ 3; MES 0, RHI > 3; MES 1, RHI ≤ 3; MES 1, RHI > 3) and adjusted for age and sex, RHI > 3 was predictive of relapse (P = .008). Conclusions: UC patients with endoscopic improvement have a high rate of clinical relapse over time. Histologic activity is a predictor of clinical relapse.

Long-term morbidities following unintentional dural puncture in obstetric patients: A systematic review and meta-analysis.

STUDY OBJECTIVE: To investigate the association of unintentional dural puncture (UDP) and postdural puncture headache (PDPH) with the risk of chronic headache, backache, neckache and depression. We also investigated if epidural blood patch (EBP) is associated with reduced risk of these morbidities. DESIGN: Systematic review and meta-analysis. PATIENTS: Pregnant women who experienced UDP and/or PDPH versus those who had uneventful neuraxial procedures, and women who received EBP versus those who did not. INTERVENTIONS: None. MEASUREMENTS: Primary outcomes were headache, backache, and neckache lasting ≥12 months, and depression ≥1 month. Secondary outcomes included chronic headache, backache, and neckache persisting ≥1 and ≥ 6 months, and the effects of EBP on those outcomes at ≥1 and ≥ 12 months. Subgroup analyses of prospective studies and sensitivity analyses of primary outcomes excluding poor quality studies were performed. MAIN RESULTS: Twelve studies compared 6541 women with UDP and/or PDPH versus 1,004,510 with uncomplicated neuraxial procedures. Eight studies compared EBP (n = 3610) with no EBP (n = 3154). UDP and/or PDPH were associated with increased risk of headache (RR 3.95; 95%CI 2.13 to 7.34; I2 42%), backache (RR 2.72; 95%CI 2.04 to 3.62; I2 1%), and neckache (RR 8.09; 95%CI 1.03 to 63.35) persisting ≥12 months, and depression (RR 3.12; 95%CI 1.44 to 6.77; I2 90%) lasting ≥1 month. Results were consistent in analyses at ≥1 and ≥ 6 months, subgroup analyses of prospective studies, and after exclusion of one poor-quality study from our primary outcome. EBP was not associated with significant reduction in the risk of long-term morbidities. CONCLUSIONS: UDP and/or PDPH were associated with increased risk of chronic headache, backache, neckache, and depression. EBP was not associated with a significant reduction in those risks, but this conclusion is limited by the heterogeneity of current data and lack of information on the success of EBP in relieving acute PDPH symptoms.

Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses. Using mass cytometry (CyTOF) to analyze the immune cell composition in the lamina propria (LP) of patients with ulcerative colitis (UC) and Crohn's disease (CD), we observed an enrichment of CD4+ effector T cells producing IL-17A and TNF, CD8+ T cells producing IFNγ, T regulatory (Treg) cells, and innate lymphoid cells (ILC). The function of these immune cells is regulated by store-operated Ca2+ entry (SOCE), which results from the opening of Ca2+ release-activated Ca2+ (CRAC) channels formed by ORAI and STIM proteins. We observed that the pharmacologic inhibition of SOCE attenuated the production of proinflammatory cytokines including IL-2, IL-4, IL-6, IL-17A, TNF, and IFNγ by human colonic T cells and ILCs, reduced the production of IL-6 by B cells and the production of IFNγ by myeloid cells, but had no effect on the viability, differentiation, and function of intestinal epithelial cells. T cell-specific deletion of CRAC channel genes in mice showed that Orai1, Stim1, and Stim2-deficient T cells have quantitatively distinct defects in SOCE, which correlate with gradually more pronounced impairment of cytokine production by Th1 and Th17 cells and the severity of IBD. Moreover, the pharmacologic inhibition of SOCE with a selective CRAC channel inhibitor attenuated IBD severity and colitogenic T cell function in mice. Our data indicate that SOCE inhibition may be a suitable new approach for the treatment of IBD.

Primary hepatic signet ring cell neuroendocrine tumor: a case report with literature review.

Primary hepatic signet ring cell neuroendocrine tumor is extremely rare and is characterized by distinct intracytoplasmic hyaline vacuoles that are mucin negative and cytokeratin positive. The unique histological features may cause difficulty in diagnosis and delay patient care. Here the authors report a 49-year-old man with an incidental finding of a 2.7 cm liver mass in the absence of chronic liver disease. The resected tumor was grossly unencapsulated but well demarcated with friable tissue texture. Microscopically, the entire tumor consisted of sheets of monotonous cells separated by delicate microvasculature. The tumor cells had granular chromatin, inconspicuous nucleoli, and eosinophilic cytoplasm. Many of the tumor cells had eccentric, pale intracytoplasmic vacuoles resembling signet ring cells in adenocarcinoma. Immunohistochemical studies showed that the tumor cells were positive for neuroendocrine markers and that the intracytoplasmic vacuoles were negative for mucin but strongly positive for cytokeratins. Careful systemic search including OctreoScan scintigraphy (Mallinckrodt Medical, Inc., St. Louis, MO) and capsule endoscopy failed to reveal any other tumors. A diagnosis of primary hepatic signet ring cell neuroendocrine tumor was established. Ten months after surgery, the patient is well without any other detectable tumor on radiology. Serological neuroendocrine markers are also within normal limits.

Keratin 19 and mesenchymal markers for evaluation of epithelial-mesenchymal transition and stem cell niche components in primary biliary cholangitis by sequential elution-stripping multiplex immunohistochemistry.

Multiplexed immunohistochemical techniques give insight into contextual cellular relationships by offering the ability to collect cell-specific data with spatial information from formalin-fixed, paraffin-embedded tissue sections. We established an automated sequential elution-stripping multiplex immunohistochemical assay to address two controversial scientific questions in the field of hepatopathology: 1) whether epithelial-to-mesenchymal transition or mesenchymal-to-epithelial transition occurs during liver injury and repair of a chronic liver disease and 2) if there is a stromal:epithelial relationship along the canals of Hering that would support the concept of this biliary structure being a stem/progenitor cell niche. Our 4-plex assay includes both epithelial and mesenchymal clinical immunohistochemical markers and was performed on clinical human liver specimens in patients with primary biliary cholangitis. The assay demonstrated that in each specimen, co-expression of epithelial and mesenchymal markers was observed in extraportal cholangiocytes. In regard to possible mesenchymal components in a stem cell niche, 82.3% ± 5.5% of extraportal cholangiocytes were intimately associated with a vimentin-positive cell. Co-expression of epithelial and mesenchymal markers by extraportal cholangiocytes is evidence for epithelial to mesenchymal transition in primary biliary cholangitis. Vimentin-positive stromal cells are frequently juxtaposed to extraportal cholangiocytes, supporting an epithelial:mesenchymal relationship within the hepatobiliary stem cell niche. Our automated sequential elution-stripping multiplex immunohistochemical assay is a cost-effective multiplexing technique that can be readily applied to a small series of clinical pathology samples in order to answer scientific questions involving cell:cell relationships and cellular antibody expression.