Miracle-dz/UniFAR-FTUs huggingface dataset:
Universal Testing, Expanded Treatment, and Incidence of HIV Infection in Botswana.

BACKGROUND The feasibility of reducing the population-level incidence of human immunodeficiency virus (HIV) infection by increasing community coverage of antiretroviral therapy (ART) and male circumcision is unknown. METHODS We conducted a pair-matched, community-randomized trial in 30 rural or periurban communities in Botswana from 2013 to 2018. Participants in 15 villages in the intervention group received HIV testing and counseling, linkage to care, ART (started at a higher CD4 count than in standard care), and increased access to male circumcision services. The standard-care group also consisted of 15 villages. Universal ART became available in both groups in mid-2016. We enrolled a random sample of participants from approximately 20% of households in each community and measured the incidence of HIV infection through testing performed approximately once per year. The prespecified primary analysis was a permutation test of HIV incidence ratios. Pair-stratified Cox models were used to calculate 95% confidence intervals. RESULTS Of 12,610 enrollees (81% of eligible household members), 29% were HIV-positive. Of the 8974 HIV-negative persons (4487 per group), 95% were retested for HIV infection over a median of 29 months. A total of 57 participants in the intervention group and 90 participants in the standard-care group acquired HIV infection (annualized HIV incidence, 0.59% and 0.92%, respectively). The unadjusted HIV incidence ratio in the intervention group as compared with the standard-care group was 0.69 (P = 0.09) by permutation test (95% confidence interval [CI], 0.46 to 0.90 by pair-stratified Cox model). An end-of-trial survey in six communities (three per group) showed a significantly greater increase in the percentage of HIV-positive participants with an HIV-1 RNA level of 400 copies per milliliter or less in the intervention group (18 percentage points, from 70% to 88%) than in the standard-care group (8 percentage points, from 75% to 83%) (relative risk, 1.12; 95% CI, 1.09 to 1.16). The percentage of men who underwent circumcision increased by 10 percentage points in the intervention group and 2 percentage points in the standard-care group (relative risk, 1.26; 95% CI, 1.17 to 1.35). CONCLUSIONS Expanded HIV testing, linkage to care, and ART coverage were associated with increased population viral suppression. (Funded by the President's Emergency Plan for AIDS Relief and others; Ya Tsie ClinicalTrials.gov number, NCT01965470.).
Cellular prion protein is present in dopaminergic neurons and modulates the dopaminergic system

Cellular prion protein (PrPC) is widely expressed in the brain. Although the precise role of PrPC remains uncertain, it has been proposed to be a pivotal modulator of neuroplasticity events by regulating the glutamatergic and serotonergic systems. Here we report the existence of neurochemical and functional interactions between PrPC and the dopaminergic system. PrPC was found to co‐localize with dopaminergic neurons and in dopaminergic synapses in the striatum. Furthermore, the genetic deletion of PrPC down‐regulated dopamine D1 receptors and DARPP‐32 density in the striatum and decreased dopamine levels in the prefrontal cortex of mice. This indicates that PrPC affects the homeostasis of the dopaminergic system by interfering differently in different brain areas with dopamine synthesis, content, receptor density and signaling pathways. This interaction between PrPC and the dopaminergic system prompts the hypotheses that the dopaminergic system may be implicated in some pathological features of prion‐related diseases and, conversely, that PrPC may play a role in dopamine‐associated brain disorders.
Sampling-based approach to determining outcomes of patients lost to follow-up in antiretroviral therapy scale-up programs in Africa.

Evaluating outcomes among the millions of HIV-infected patients starting antiretroviral therapy (ART) in settings with limited resources is key to understanding the effect of current treatment programs and guiding future strategies. Accurately assessing survival outcomes has been precluded by substantial numbers of patients not returning for care. One year after starting ART 15% to 30% of patients are lost to follow-up. Only by determining the outcomes of those lost can true survival and program impact be understood. We present a sampling-based strategy to address this. (excerpt)
Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal‐Cell Carcinoma

BACKGROUND The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal‐cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear. METHODS In an open‐label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear‐cell renal‐cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6‐week cycle (429 patients). The primary end points were overall survival and progression‐free survival in the intention‐to‐treat population. The key secondary end point was the objective response rate. All reported results are from the protocol‐specified first interim analysis. RESULTS After a median follow‐up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab–axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression‐free survival was 15.1 months in the pembrolizumab–axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab–axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab–axitinib group and in 70.6% in the sunitinib group. CONCLUSIONS Among patients with previously untreated advanced renal‐cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression‐free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE‐426 ClinicalTrials.gov number, NCT02853331.)
Anti‐BCMA CAR T‐Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma

BACKGROUND Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T‐cell therapy that targets B‐cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma. METHODS In this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×106, 150×106, 450×106, or 800×106 CAR‐positive (CAR+) T cells in the dose‐escalation phase and 150×106 to 450×106 CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety. RESULTS Results for the first 33 consecutive patients who received a bb2121 infusion are reported. The data‐cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression‐free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD‐negative status (≤10‐4 nucleated cells). CAR T‐cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion. CONCLUSIONS We report the initial toxicity profile of a BCMA‐directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB‐401 ClinicalTrials.gov number, NCT02658929.)
Dor: quinto sinal vital, um desafio para o cuidar em enfermagem

A dor e considerada uma experiencia subjetiva, que deve ser avaliada e descrita como o quinto sinal vital. No entanto, se observa que esta pratica e pouco frequente nos ambientes hospitalares. Este estudo busca identificar o conhecimento da equipe de enfermagem em relacao a avaliacao da dor, sensibilizando-a para institui-la como quinto sinal vital, no cotidiano profissional. Caracteriza-se como uma pesquisa quanti-qualitativa, realizada no Centro de Terapia Intensiva, num hospital do Rio Grande do Sul. Os participantes foram quatorze membros da equipe de enfermagem. Os resultados apontaram que esta equipe tem nocao de apenas uma escala para avaliacao da dor e reconhecem alguns sinais de dor, mas nao tem como pratica sistematica entende-la como quinto sinal vital. Assim, ao avaliar os outros sinais, nao investiga a dor. Acredita-se que a educacao possibilita o cuidado qualificado, em que as reais necessidades do cliente sao atendidas.
Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder.

BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse. METHODS In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death). RESULTS The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was -0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference, -0.29; 95% CI, -0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group. CONCLUSIONS Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).
Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.

BACKGROUND Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors. METHODS We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. RESULTS A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. CONCLUSIONS First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).
LRRK2(I2020T) functional genetic interactors that modify eye degeneration and dopaminergic cell loss in Drosophila

Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta is the primary cause for motor symptoms observed in Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most commonly linked contributor to familial PD. LRRK2 is suggested to be involved in a wide variety of cellular processes, but deciphering its role in the pathogenesis of PD has been difficult. Modelling PD in rodents has been a persistent challenge for the field. However, the fruit fly has been exploited to recapitulate PD gene related dopaminergic cell loss. Using the GAL4-UAS system and established models of hLRRK2 induced eye degeneration in Drosophila, we conducted an unbiased suppressor/enhancer screen to uncover genetic modifiers of LRRK2. We have identified 36 candidate interactors that modify LRRK2 induced toxicity in the Drosophila eye. Importantly, we determined that a subset of these interactors also modified hLRRK2(I2020T) induced dopaminergic neuronal loss in the fly brain and uncovered 16 candidates that modify dopaminergic cell loss. Our results suggest LRRK2 may be involved in a wide variety of cellular processes and the results from this screen provide an important genetic resource for further evaluation of LRRK2 function.
Ankle arthroscopy: Short-term outcome in ten consecutive patients

Fifteen ankle arthroscopies performed between 2005 and 2012 were analyzed to evaluate the risks and benefits of the procedure. All arthroscopies were performed by one surgeon using the same nonskeletal traction technique. Ten of the fifteen patients were succeed to reach to the follow up. Average follow-up was 22.65 months (range: 6-88). There were 8 males and 2 females patients. Average age was 45 (range: 34-66) years. The duration of preoperative symptoms averaged 40 (range: 5-120) months. Preoperative clinical and radiographic examination was performed. At the closing follow-up, clinical examination, visual analog scores and X rays were repeated. The diagnosis was osteochondral lesions of the talus in five patients, anterior bony impingement in 3, and soft tissue impingement or synovitis in 2. Overall, in seven patients (70%) the operative results were good; eight patients (80%) were satisfied by the procedure. Those patients who had been diagnosed with diffuse synovitis or posttraumatic chondromalacia had poor results, whereas patients with a localized osteochondral lesion of the talus, or localized bony or soft tissue impingement experienced the best results. There were no complications from ankle arthroscopy in this series. Ankle arthroscopy appears to be a relatively low-risk procedure with substantial benefits, particularly in localized disease of the ankle joint. J. Exp. Clin. Med., 2013; 30:15-17
Alteration of secretory IgA in human breast milk and stool samples after the intake of a probiotic — report of 2 cases

Only a few studies reveal immunological changes in breast milk after the intake of probiotic and none focus on secretory IgA (sIgA). The aim our report was to investigate the levels of sIgA in human breast milk and stools before and after 4 weeks of probiotic intake in a patient with ulcerative colitis (UC) and a control. The study included 2 lactating women: 1 with UC and 1 control. Both received daily 3.75 billion viable Lactobacillus bulgaricus for 28 days. SIgA was measured in breast milk and stools before and after the probiotic intake. The concentration of sIgA in breast milk before the probiotic intake in UC was 408.5 vs 137.4 µg/ml in contol. Fecal sIgA in UC was 420 vs 274 µg/ml in control. After 28 days of probiotic intake there was a decrease in breast milk sIgA in UC but an increase in control — 266.7 vs 914 µg/ml respectively. There was an increase in fecal sIgA both in UC and control — 674.4 vs 1033 µg/ml. It is tempting to speculate that the different sIgA secretion towards the probiotic may be a result of an altered mucosal immune response in UC.
China and HIV - a window of opportunity.

Chinese and international health officials express optimism about controlling the HIV–AIDS epidemic but emphasize the need to move quickly. Bates Gill and Dr. Susan Okie explain that, given China's enormous population, even a small increase in prevalence could be devastating. Bates Gill discusses the largely rural HIV epidemic in China, the turnaround in the central government's approach to HIV–AIDS, and the remaining obstacles to controlling the epidemic. Gill is a China scholar at the Center for Strategic and International Studies, Washington, D.C.
Differential regulation of AChR clustering in the polar and equatorial region of murine muscle spindles

Intrafusal fibers of muscle spindles are innervated in the central region by afferent sensory axons and at both polar regions by efferent γ‐motoneurons. We previously demonstrated that both neuron–muscle contact sites contain cholinergic synapse‐like specialisation, including aggregates of the nicotinic acetylcholine receptor (AChR). In this study we tested the hypothesis that agrin and its receptor complex (consisting of LRP4 and the tyrosine kinase MuSK) are involved in the aggregation of AChRs in muscle spindles, similar to their role at the neuromuscular junction. We show that agrin, MuSK and LRP4 are concentrated at the contact site between the intrafusal fibers and the sensory‐ and γ‐motoneuron, respectively, and that they are expressed in the cell bodies of proprioceptive neurons in dorsal root ganglia. Moreover, agrin and LRP4, but not MuSK, are expressed in γ‐motoneuron cell bodies in the ventral horn of the spinal cord. In agrin‐ and in MuSK‐deficient mice, AChR aggregates are absent from the polar regions. In contrast, the subcellular concentration of AChRs in the central region where the sensory neuron contacts the intrafusal muscle fiber is apparently unaffected. Skeletal muscle‐specific expression of miniagrin in agrin−/− mice in vivo is sufficient to restore the formation of γ‐motoneuron endplates. These results show that agrin and MuSK are major determinants during the formation of γ‐motoneuron endplates but appear dispensable for the aggregation of AChRs at the central region. Our results therefore suggest different molecular mechanisms for AChR clustering within two domains of intrafusal fibers.
Two-Incision Anterior Cruciate Ligament Reconstruction with Tensioned Femoral Post Fixation

Anterior cruciate ligament reconstruction is a commonly performed orthopaedic sports medicine procedure. The technique is currently performed with miniarthrotomy or one- or two-incision endoscopic techniques. Graft choices include autograft patellar tendon, hamstring, or quadriceps tendon or allograft patellar tendon or Achilles tendon. The two-incision technique offers the advantage of placement of the femoral tunnel independently of the tibial tunnel. This allows for a more anatomic posterior position of the tunnel with a more anatomic graft angle. Use of angled post fixation on one side of the graft allows for postfixation adjustment of graft tension.
Cijfers uit de registratie van huisartsen: peiling 2007.

Peiling 1 januari 2013 Praktijken • De praktijkdefinitie is sinds de peiling van 2012 bijgesteld. Niet het praktijkadres, maar de praktijk waar de huisarts zich toe rekent, wordt als uitgangspunt genomen. • Er zijn 5.088 praktijken op 3.979 praktijklocaties. • De praktijkvorm wordt nog steeds bepaald a.d.h.v. het aantal zelfstandigen en hidha’s werkzaam in de praktijk. • Kijken we naar praktijkvormen, dan is: – 50% een solopraktijk; – 35% een duopraktijk; – 16% een groepspraktijk. Zelfstandig gevestigden, HIDHA’s en waarnemers • Er zijn: – 7.894 zelfstandig gevestigde huisartsen; – 971 hidha’s; – 2.210 waarnemers (geschat aantal). • Van de zelfstandig gevestigde huisartsen en hidha’s is 20% jonger dan 40 jaar en 44% vrouw. • Van de zelfstandig gevestigden en hidha’s werkt: – 28% in een solopraktijk; 17% op een sololocatie; – 38% in een duopraktijk; 28% op een duolocatie; – 33% in een groepspraktijk; 55% op groepslocatie. • Van de huisartsen (zelfstandig gevestigden en hidha’s tezamen) werkt 59% parttime. • De gemiddelde huisartsendichtheid is 4,1 fte huisarts per 10.000 inwoners. Pas afgestudeerde huisartsen • Er zijn naar schatting 624 praktijkzoekende huisartsen. • Van de praktijkzoekende huisartsen die gerespondeerd hebben is 77% op zoek naar een eigen praktijk en hiervan wil 81% een parttime baan. • Van de praktijkzoekende huisartsen, die gerespondeerd hebben, is: – 72% waarnemer; – 19% hidha; – 10% niet werkzaam als huisarts.