Search

Objective: Persistent (≥2 months) major salivary gland enlargement in primary SS (pSS) patients is a well-known sign of possible involvement by B cell lymphoma. The study aimed to evaluate the diagnostic accuracy and safety of US-guided core needle biopsy (CNB) of major salivary glands compared with open surgical biopsy., Methods: Prospective pSS patients (cases) with clinically persistent salivary gland enlargement underwent US-guided CNB and were compared with retrospective pSS patients (controls) submitted to open surgical biopsy. The features analysed were pre-biopsy clinical and laboratory findings, adequacy of the material for histology and diagnostic-rendered and biopsy-related complications (reported by the patient with a questionnaire and clinically verified)., Results: Thirteen cases underwent US-guided CNB: in nine, biopsy was performed on the parotid gland and in four it was performed on the submandibular gland. Sufficient material was obtained for pathological diagnosis in all samples. The final diagnoses were 5 (38.5%) B cell lymphoma, 1 (7.7%) lymphoepithelial sialadenitis, 4 (30.7%) other sialadenitis (granulomatous consistent with sarcoidosis, IgG4-related disease, chronic sclerosing, diffuse chronic) and 3/13 (23.1%) miscellaneous lesions. Thirteen controls underwent open surgical biopsy of the parotid. In one, inadequate material was obtained, while in 12 (92.3%) the pathologic diagnoses were 4 (33.3%) B cell lymphoma, 2 (16.7%) lymphoepithelial sialadenitis, 4 (33.3%) uncertain lymphoproliferative lesions and 2 (16.7%) miscellaneous lesions. Six cases (46.1%) reported six transient complications and 12/13 (92.3%) controls had 2 persistent and 14 transient complications., Conclusion: US-guided CNB represents a novel, clinically relevant and safe approach for the management of pSS patients with parotid or submandibular persistent enlargement., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In resource-limited settings, genotype testing at virologic failure on first-line antiretroviral therapy (ART) may identify patients with wild-type (WT) virus. After adherence counseling, these patients may safely and effectively continue first-line ART, thereby delaying more expensive second-line ART., Methods: We used the Cost-Effectiveness of Preventing AIDS Complications International model of human immunodeficiency virus (HIV) disease to simulate a South African cohort of HIV-infected adults at first-line ART failure. Two strategies were examined: no genotype vs genotype, assuming availability of protease inhibitor-based second-line ART. Model inputs at first-line ART failure were mean age 38 years, mean CD4 173/µL, and WT virus prevalence 20%; genotype cost was $300 per test and delay to results, 3 months. Outcomes included life expectancy, per-person costs (2010 US dollars), and incremental cost-effectiveness ratios (dollars per years of life saved [YLS])., Results: No genotype had a projected life expectancy of 106.1 months, which with genotype increased to 108.3 months. Per-person discounted lifetime costs were $16 360 and $16 540, respectively. Compared to no genotype, genotype was very cost-effective, by international guidance, at $900/YLS. The cost-effectiveness of genotype was sensitive to prevalence of WT virus (very cost-effective when prevalence ≥ 12%), CD4 at first-line ART failure, and ART efficacy. Genotype-associated delays in care ≥ 5 months decreased survival and made no genotype the preferred strategy. When the test cost was <$100, genotype became cost-saving., Conclusions: Genotype resistance testing at first-line ART failure is very cost-effective in South Africa. The cost-effectiveness of this strategy will depend on prevalence of WT virus and timely response to genotype results.

Background: Recent trials report the short-term efficacy of tenofovir-based pre-exposure prophylaxis (PrEP) for prevention of human immunodeficiency virus (HIV) infection. PrEP's long-term impact on patient outcomes, population-level transmission, and cost-effectiveness remains unknown., Methods: We linked data from recent trials to a computer model of HIV acquisition, screening, and care to project lifetime HIV risk, life expectancy (LE), costs, and cost-effectiveness, using 2 PrEP-related strategies among heterosexual South African women: (1) women receiving no PrEP and (2) women not receiving PrEP (a tenofovir-based vaginal microbicide). We used a South African clinical cohort and published data to estimate population demographic characteristics, age-adjusted incidence of HIV infection, and HIV natural history and treatment parameters. Baseline PrEP efficacy (percentage reduction in HIV transmission) was 39% at a monthly cost of $5 per woman. Alternative parameter values were examined in sensitivity analyses., Results: Among South African women, PrEP reduced mean lifetime HIV risk from 40% to 27% and increased population discounted (undiscounted) LE from 22.51 (41.66) to 23.48 (44.48) years. Lifetime costs of care increased from $7280 to $9890 per woman, resulting in an incremental cost-effectiveness ratio of $2700/year of life saved, and may, under optimistic assumptions, achieve cost savings. Under baseline HIV infection incidence assumptions, PrEP was not cost saving, even assuming an efficacy >60% and a cost <$1. At an HIV infection incidence of 9.1%/year, PrEP achieved cost savings at efficacies ≥50%., Conclusions: PrEP in South African women is very cost-effective by South African standards, conferring excellent value under virtually all plausible data scenarios. Although optimistic assumptions would be required to achieve cost savings, these represent important benchmarks for future PrEP study design.

Erythrokeratoderma variabilis (EKV) is characterized by fixed hyperkeratotic plaques and transient erythema. Mutations in the genes GJB3 and GJB4, which encode connexin (Cx)31 and Cx30.3, are associated with EKV. We report one novel mutation in Cx31 and one recurrent mutation in Cx30.3 in two different families. One novel rare sequence variant of unknown clinical significance was also identified. This finding extends the spectrum of known EKV-associated mutations.

Background: The United States and international agencies have signaled their commitment to containing the human immunodeficiency virus (HIV) epidemic via early case identification and linkage to antiretroviral therapy (ART) immediately at diagnosis. We forecast outcomes of this approach if implemented in Washington DC., Methods: Using a mathematical model of HIV case detection and treatment, we evaluated combinations of HIV screening and ART initiation strategies. We define current practice as no regular screening program and ART at CD4 counts < or = 350 cells/microL, and we define test and treat as annual screening and administration of ART at diagnosis. Outcomes include life expectancy of HIV-infected persons and changes in the population time with transmissible HIV RNA levels. Data, largely from Washington DC, include undiagnosed HIV prevalence of 0.6%, annual incidence of 0.13%, 31% rate of test offer, 60% rate of acceptance, and 50% linkage to care. Input parameters, including optimized ART efficacy, are varied in sensitivity analyses., Results: Projected life expectancies, from an initial mean age of 41 years, are 23.9, 25.0, and 25.6 years for current practice, test and treat, and test and treat with optimized ART, respectively. Compared with current practice, test and treat leads to a 14.7% reduction in time spent with transmissible HIV RNA level in the next 5 years; test and treat with optimized ART results in a 27.3% reduction., Conclusions: An expanded HIV test and treat program in Washington DC will increase life expectancy of HIV-infected patients but will have a modest impact on HIV transmission over the next 5 years and is unlikely to halt the HIV epidemic.

Background: World Health Organization guidelines for antiretroviral treatment (ART) in resource-limited settings recommend either stavudine or tenofovir as part of initial therapy. We evaluated the clinical outcomes and cost-effectiveness of first-line ART using tenofovir in India, compared with current practice using stavudine or zidovudine., Methods: We used a state-transition model of human immunodeficiency virus (HIV) disease to examine strategies using different nucleoside reverse-transcriptase inhibitors, combined with lamivudine and nevirapine, compared with no ART: (1) stavudine, (2) stavudine with substitution by zidovudine after 6 months, (3) zidovudine, and (4) tenofovir. Data were from the Y. R. Gaitonde Centre for AIDS Research and Education in Chennai, India, and published studies. Results. Discounted mean per person survival was 36.9 months (40.2 months undiscounted) with no ART, 115.5 months (145.3) with stavudine-containing ART, 115.7 months (145.6) with stavudine and 6-month zidovudine substitution, 115.8 months (145.6) with zidovudine-containing ART, and 125.8 months (162.0) with initial tenofovir. Discounted lifetime medical costs were $610 with no ART and ranged from $5580 with stavudine-containing ART to $5720 with zidovudine-containing ART. Initial tenofovir had an incremental cost-effectiveness ratio of $670 per year of life saved, compared with no ART, and was more economically efficient than the other regimens., Results: were most sensitive to variations in the costs of first-line tenofovir, access to additional ART after treatment failure, and quality of life adjustment., Conclusions: Using tenofovir as part of first-line ART in India will improve survival, is cost-effective by international standards, and should be considered for initial therapy for HIV-infected patients in India.

Introduction: Polyarteritis nodosa (PAN) is a rare necrotizing vasculitis affecting small- and medium-sized arteries of multiple organs. Spreading to the genitourinary tract is very common, with invariable involvement of kidneys or testes, but its impact on erectile function remains undetermined., Aim: We describe a case of isolated PAN of the genitourinary tract diagnosed in a young man presenting with severe erectile dysfunction (ED), debate the critical issues of the differential diagnosis, and provide the long-term follow-up outcome., Methods: The case report profiled a 36-year-old man who presented with progressively worsening erectile function and was incidentally found to suffer from genitourinary PAN. Extensive clinical, laboratory, and instrumental investigations, including brachial artery dilation test, suggested an arteriogenic etiology for ED and excluded a systemic involvement by PAN. Management featured use of a long-term, on-demand phosphodiesterase type 5 (PDE5) inhibitor regimen for ED, and close surveillance with no immunosuppressive therapy for PAN., Main Outcome Measures: Clinical history data, brachial artery dilation test, response to PDE5 inhibitor therapy., Results: After 12 months of PDE5 inhibitor therapy, the patient recovered a normal erectile function, paralleled by restored endothelial function as assessed with brachial artery dilation test. At a 5-year clinical follow-up, he continued to have full erectile ability with only occasional use of PDE5 inhibitor, and no evidence of progressive PAN was documented., Conclusions: We propose PAN as a novel cause of arteriogenic ED, report the effective therapy with PDE5 inhibitor, and confirm the good long-term prognosis of isolated genitourinary PAN without immunosuppressive treatment.

Background: The combination of tenofovir and emtricitabine shows promise as HIV preexposure prophylaxis (PrEP). We sought to forecast clinical, epidemiologic, and economic outcomes of PrEP, taking into account uncertainties regarding efficacy, the risks of developing drug resistance and toxicity, behavioral disinhibition, and drug costs., Methods: We adapted a computer simulation of HIV acquisition, detection, and care to model PrEP among men who have sex with men and are at high risk of HIV infection (i.e., 1.6% mean annual incidence of HIV infection) in the United States. Base-case assumptions included 50% PrEP efficacy and monthly tenofovir-emtricitabine costs of $753. We used sensitivity analyses to examine the stability of results and to identify critical input parameters., Results: In a cohort with a mean age of 34 years, PrEP reduced lifetime HIV infection risk from 44% to 25% and increased mean life expectancy from 39.9 to 40.7 years (21.7 to 22.2 discounted quality-adjusted life-years). Discounted mean lifetime treatment costs increased from $81,100 to $232,700 per person, indicating an incremental cost-effectiveness ratio of $298,000 per quality-adjusted life-year gained. Markedly larger reductions in lifetime infection risk (from 44% to 6%) were observed with the assumption of greater (90%) PrEP efficacy. More-favorable incremental cost-effectiveness ratios were obtained by targeting younger populations with a higher incidence of infection and by improvements in the efficacy and cost of PrEP., Conclusions: PrEP could substantially reduce the incidence of HIV transmission in populations at high risk of HIV infection in the United States. Although it is unlikely to confer sufficient benefits to justify the current costs of tenofovir-emtricitabine, price reductions and/or increases in efficacy could make PrEP a cost-effective option in younger populations or populations at higher risk of infection. Given recent disappointments in HIV infection prevention and vaccine development, additional study of PrEP-based HIV prevention is warranted.

Background: In recent studies, subjects who had achieved suppression of the human immunodeficiency virus (HIV) RNA level while receiving an initial 3-drug antiretroviral regimen successfully maintained suppression while receiving treatment with a "boosted" protease inhibitor (PI) alone. We projected the long-term outcomes of this treatment simplification strategy to inform the design of a proposed multicenter, randomized clinical trial., Methods: We used published studies to estimate the efficacy, adverse effects, and cost of a sequence of HIV drug regimens for the simplification strategy, compared with those outcomes for the current standard-of-care (SOC) strategy. Using a published simulation model of HIV disease, we projected life expectancy, discounted quality-adjusted life expectancy (QALE), and discounted lifetime medical costs for each strategy., Results: Subjects who have not developed PI-resistant HIV infection at the time of failure of the simplification regimen have a greater life expectancy (27.9 vs. 27.1 years) and QALE (14.9 vs. 14.7 years), compared with SOC subjects, because they receive an additional line of therapy without negative consequences for future treatment options. The QALE for the simplification strategy remains higher than that for the SOC, unless a large proportion of patients experiencing virologic failure while receiving the simplification regimen develop PI resistance. Depending on the probability of simplification regimen failure, the advantage is maintained even if HIV develops PI resistance in 42%-70% of subjects. Projected lifetime costs are $26,500-$72,400 per person lower for the simplification strategy than for the SOC strategy., Conclusions: An HIV treatment simplification strategy involving use of a boosted PI alone may lead to longer survival overall at lower cost, compared with the SOC combination therapy, because the simplification strategy potentially adds an additional line of therapy. The risk of emergence of PI resistance during treatment with a simplified regimen is a critical determinant of the viability of this strategy.

Objective: Rituximab, an anti-CD20 monoclonal antibody, has been used in lupus nephritis and membranous idiopathic nephropathy and has proved effective in non-renal manifestations of type II mixed cryoglobulinaemia (MC) syndrome. We investigated the possible efficacy and safety of rituximab in the treatment of cryoglobulinaemic nephritis., Methods: Five patients with active, biopsy-proven, glomerulonephritis in hepatitis C virus (HCV)-related type II MC syndrome were treated with four weekly infusions of rituximab (375 mg/m2) in monotherapy, without steroids whenever possible. Rituximab was the first-line therapy in three cases., Results: A rapid and sustained renal response was observed in all patients, in one of them without retreatment up to the last follow-up (month 21+). Renal biopsy was repeated after 6 months in one patient and histopathological improvement was documented. Three patients relapsed, at months +5, +7 and +12 of follow-up, respectively. Two of them were then retreated with rituximab and again presented a rapid improvement in renal function. Maintenance therapy with rituximab was performed in two patients: nephritis remission was maintained in both. Fc-gamma receptor 3a (FcgammaRIIIa) genotype characterization was consistent with the clinical response observed. Rituximab also proved effective against other active MC manifestations, when present. No major side-effects occurred and steroids were not required in the follow-up., Conclusions: Rituximab may provide effective and safe therapy in type II MC-related glomerulonephritis, possibly as first-line therapy, avoiding steroids and hazardous immunosuppressive treatment.

Recent studies indicate that GABA acts as a chemoattractant during rat cortical histogenesis. In vivo, GABA localizes in appropriate locations for a chemoattractant, along migratory routes and near target destinations for migrating cortical neurons. In vitro, GABA induces dissociated embryonic cortical neurons to migrate. Here, embryonic rat cortical slices were cultured in the presence or absence of GABA receptor (GABA-R) antagonists to assess GABA's effects on neuronal migration in situ. Gestational day 18 (E18) cortical slices were incubated overnight in bromodeoxyuridine (BrdU)-containing medium to label ventricular zone (vz) cells as they underwent terminal mitosis. The slices were then cultured in BrdU-free medium with or without GABA-R antagonists. In control slices, most BrdU(+) cells were observed in the cortical plate (cp) after 48 h. In contrast, cultures maintained in either saclofen (a GABA(B)-R antagonist) or picrotoxin (a GABA(A/C)-R antagonist) had few BrdU-labeled cp cells. However, the effects of the two antagonists were distinct. In the picrotoxin-treated slices, nearly half of all BrdU(+) cells remained in the vz and subventricular zone (svz), whereas saclofen treatment resulted in an accumulation of BrdU(+) cells in the intermediate zone (iz). Bicuculline, a GABA(A)-R antagonist, did not block, but rather enhanced migration of BrdU(+) cells into the cp. These results provide evidence that picrotoxin-sensitive receptors promote the migration of vz/svz cells into the iz, while saclofen-sensitive receptors signal cells to migrate into the cp. Thus, as cortical cells differentiate, changing receptor expression appears to modulate migratory responses to GABA.

Histologically detectable iron (HDI) and HFE mutations were searched for in liver biopsy specimens from 58 Italian patients with chronic hepatitis C, and morphologic features were compared to examine their reciprocal relation and their contribution to disease progression. HDI was evident in 48% of cases with features of nonhemochromatosis iron overload. Total, sinusoidal, and portal HDI increased with stage; grade was related to all iron scores because of the contribution of portal inflammation and interface hepatitis. HFE mutations were seen in 47% of patients with chronic hepatitis C and in 28% of control subjects; they were related to stage and the His63Asp mutation to portal HDI. On multivariate analysis, grade but not stage or HFE mutations was associated with HDI in all sites. Interface hepatitis with its sequelae (sinusoidal capillarization and microshunting) represents a major factor in iron deposition in chronic hepatitis C and justifies the features of HDI. HFE mutations are not responsible for HDI deposition but could favor the progression of virus-induced damage independently from interference with iron metabolism.

Avilamycin was extracted from feed with acetonitrile. Isolation of avilamycin factors from feed matrix interference was accomplished by normal-phase solid-phase extraction with silica as sorbent. Reversed-phase liquid chromatography was subsequently used to separate and quantitate the primary biologically active factors A and B for determination of chemical potency. This method combines specificity for avilamycins A and B in poultry feeds with simple sample preparation that removes matrix interferences. Recoveries of factor A ranged from 93.29 to 97.26%, with precision (relative standard deviation) ranging from 1.1 to 3.4%. Avilamycin factors in feed samples tested ranged from 4.45 to 17.82 micrograms/g for factor A and from 0.80 to 3.18 micrograms/g for factor B.