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Current antiretroviral (ARV) therapy for the treatment of human immunodeficiency virus (HIV-1)-infected patients provides long-term control of viral load (VL). Darunavir (DRV) is a nonpeptidomimetic protease inhibitor approved for use with a ritonavir booster (DRV/r). This study evaluated the effectiveness of DRV/r in combination with other ARV agents in routine clinical practice in Italy. In this descriptive observational study, data on utilization of DRV/r, under the conditions described in the marketing authorization, were collected from June 2009 to December 2012. Effectiveness (VL <50 copies/mL), tolerability, and durability in four patient groups (two DRV/r-experienced, one ARV-experienced DRV/r-naïve, and one ARV-naïve) were analyzed. Secondary objectives included immunological response, safety, and persistence/discontinuation rates. In total, 875 of 883 enrolled patients were included in the analysis: of these, 662 (75.7%) completed the follow-up until the end of 2012 and 213 (24.3%) withdrew from the study earlier. Initial DRV dose was 600 mg twice daily (67.1%) or 800 mg once daily (32.9%). Only 16 patients (1.8%) withdrew from the study due to virological failure. Virological response proportions were higher in patients virologically suppressed at study entry versus patients with baseline VL ≥50 copies/mL in each ARV-experienced group, while there was no consistent difference across study groups and baseline VL strata according to baseline CD4(+) cell count. CD4(+) cell count increased from study entry to last study visit in all the four groups. DRV/r was well tolerated, with few discontinuations due to study-emergent nonfatal adverse events (3.0% overall, including 2.1% drug-related) or deaths (3.0% overall, all non-drug-related); 35.3% of patients reported ≥1 adverse events. These observational data show that DRV/r was effective and well tolerated in the whole patient population described here. The DRV/r-containing regimen provided viral suppression in a high percentage of patients in all groups, with low rates of discontinuation due to virological failure.

•Prompt initiation of diuretic therapy was not correlated with faster decongestion in acute heart failure.•The timing of decongestion but not diuretics was associated with better biomarker trajectories.•Residual congestion rather than the timing of decongestion or diuretics predicted prognosis. Prompt treatment may mitigate the adverse effects of congestion in the early phase of heart failure (HF) hospitalization, which may lead to improved outcomes. We analyzed 814 acute HF patients for the relationships between time to first intravenous loop diuretics, changes in biomarkers of congestion and multiorgan dysfunction, and 1-year composite end point of death or HF hospitalization. B-type natriuretic peptide (BNP), high sensitivity cardiac troponin I (hscTnI), urine and serum neutrophil gelatinase–associated lipocalin, and galectin 3 were measured at hospital admission, hospital day 1, 2, 3 and discharge. Time to diuretics was not correlated with the timing of decongestion defined as BNP decrease ≥ 30% compared with admission. Earlier BNP decreases but not time to diuretics were associated with earlier and greater decreases in hscTnI and urine neutrophil gelatinase–associated lipocalin, and lower incidence of the composite end point. After adjustment for confounders, only no BNP decrease at discharge was significantly associated with mortality but not the composite end point (p = 0.006 and p = 0.062, respectively). In conclusion, earlier time to decongestion but not the time to diuretics was associated with better biomarker trajectories. Residual congestion at discharge rather than the timing of decongestion predicted a worse prognosis.

Abstract Background Nonsteroidal anti-inflammatory drugs (NSAIDs) do not always provide sufficient pain relief in dogs with osteoarthritis (OA). Hypothesis The use of amantadine in addition to NSAID therapy will provide improved pain relief when compared with the use of nonsteroidal analgesics alone in naturally occurring OA in dogs. Animals Thirty-one client-owned dogs with pelvic limb lameness despite the administration of an NSAID. Methods The study was randomized, blinded, and placebo controlled with parallel groups (days 21–42). On day 0, analgesic medications were discontinued. On day 7, all dogs received meloxicam for 5 weeks. On day 21, all dogs received amantadine (3–5 mg/kg once daily per os) or placebo for 21 days, in addition to receiving meloxicam. Assessments were performed before the study and on days 7, 21, and 42. Primary outcome measures were blinded owner assessments of activity using client-specific outcome measures (CSOM) on days 0, 7, 21, and 42. Data were analyzed by a mixed model approach. Results For CSOM activity, there was a significant time by treatment effect (P=.009). On the basis of the planned post hoc t-tests of postrandomization means, there was a significant difference between treatment groups on day 42 (P=.030), with the amantadine group being more active. Conclusions and Clinical Importance In dogs with osteoarthritic pain refractory to an NSAID, physical activity is improved by the addition of amantadine. Amantadine might be a useful adjunct therapy for the clinical management of canine osteoarthritic pain.

Two experiments were conducted to evaluate the effect of supplemental Gln on growth performance, development of the gastrointestinal tract, and humoral immune response of broilers. Immediately after hatch 6 replicate pens of 6 chicks were randomly assigned to 1 of 7 (experiment 1) or 5 (experiment 2) dietary treatments for 21 d. On d 4, 7, 14, and 21, twelve chicks per treatment (2 chicks/pen) were killed for thymus, spleen, bursa, duodenum, jejunum, ileum, bile, and blood sample collections and weights. In experiment 1, the effect of 1 or 4% Gln addition to the feed, water, or both was compared with a corn-soybean meal (SBM) control diet. All diets were formulated to be isocaloric and isonitrogenous. Weight gain improved significantly (P < 0.05) when chicks were fed diets with 1% Gln as compared with chicks fed the control diet (11% average improvement). The addition of 4% Gln to the diet or water depressed (P < 0.05) growth performance. Based on the results from experiment 1, 1% Gln supplementation to the diet was determined to be ample and most practical. Thus in experiment 2, diets supplemented with 1% Gln were fed for 4, 7, 14, or 21 d after which time chicks were fed the corn-SBM control diet until the experiment was terminated at 21 d. Weight gain improved significantly (P < 0.05) when chicks were fed diets supplemented with 1% Gln throughout the 21-d study. In both experiments, chicks fed diets supplemented with 1% Gln for 21 d had higher concentrations of bile, intestinal, and sera IgA and sera IgG (P < 0.05). Chicks fed diets with 1% Gln had heavier intestinal relative weights and longer intestinal villi (P < 0.05) as compared with the chicks fed the corn-SBM diet. Our results indicate that the addition of 1% Gln to the diet of broiler chicks improves growth performance and may stimulate development of the gastrointestinal tract and humoral immune response.

LDH may represent an indirect marker of neo-angiogenesis and worse prognosis in many tumour types. We assessed the correlation between LDH and clinical outcome for biliary tract cancer (BTC) patients treated with first-line chemotherapy. Overall, 114 advanced BTC patients treated with first-line gemcitabine and cisplatin were included. Patients were divided into two groups (low vs. high LDH), according to pre-treatment LDH values. Patients were also classified according to pre- and post-treatment variation in LDH serum levels (increased vs. decreased). Median progression free survival (PFS) was 5.0 and 2.6 months respectively in patients with low and high pre-treatment LDH levels (p = 0.0042, HR = 0.56, 95% CI: 0.37–0.87). Median overall survival (OS) was 7.7 and 5.6 months (low vs. high LDH) (p = 0.324, HR = 0.81, 95% CI: 0.54–1.24). DCR was 71% vs. 43% (low vs. high LDH) (p = 0.002). In 38 patients with decreased LDH values after treatment, PFS and OS were respectively 6.2 and 12.1 months, whereas in 76 patients with post-treatment increased LDH levels, PFS and OS were respectively 3.0 and 5.1 months (PFS: p = 0.0009; HR = 0.49; 95% IC: 0.33–0.74; OS: p < 0.0001; HR = 0.42; 95% IC: 0.27–0.63). Our data seem to suggest that LDH serum level may predict clinical outcome in BTC patients receiving first-line chemotherapy.

The frequency of COPD exacerbations during treatment with a triple inhaler — delivering a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled glucocorticoid — was compared with that with a LABA–LAMA or LABA–inhaled glucocorticoid.

Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum–etoposide) in treatment-naive patients with ES-SCLC. This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum–etoposide; durvalumab plus tremelimumab plus platinum–etoposide; or platinum–etoposide alone. All drugs were administered intravenously. Platinum–etoposide consisted of etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL per min or cisplatin 75–80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum–etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum–etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum–etoposide group versus the platinum–etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum–etoposide group and 269 to the platinum–etoposide group. Durvalumab plus platinum–etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59–0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5–14·8) in the durvalumab plus platinum–etoposide group versus 10·3 months (9·3–11·2) in the platinum–etoposide group, with 34% (26·9–41·0) versus 25% (18·4–31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum–etoposide group and 166 (62%) of 266 in the platinum–etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. First-line durvalumab plus platinum–etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. AstraZeneca.

Objective: Despite several decades of research, there is still uncertainty regarding the optimal lithium dosage regimen associated with a decreased risk of renal effects, such as polyuria, in patients with bipolar affective disorder. We present an updated review of the literature to provide an informed dosing regimen recommendation for prescribers. Method: Major databases MEDLINE and Embase were searched using terms, such as lithium, drug administration schedule, dose–response relationship, once daily, twice daily, and sustained release. In addition, the bibliographies of related publications were manually searched. Results: A total of 20 trials were included. Some trials showed a reduction in urine volume with single daily dosing (SDD), while others showed no change. The only trial evaluating patients newly started on lithium found a reduction in urinary frequency with SDD after 21 days. Trials examining renal biopsy results found that multiple daily doses were associated with more pathologic damage to the kidneys. SDD regimens were generally well tolerated, and no reduction in efficacy was noted in any of the trials. Conclusions: The available evidence is contradictory as to whether SDD of lithium reduces polyuria; however, no trial has demonstrated any downfall of SDD in terms of prophylactic efficacy or adverse effects. Given the added benefits of SDD, such as improved compliance, we recommend patients newly started on lithium should be converted to a SDD of lithium at bedtime once an appropriate daily dose is determined.

In this randomized, controlled trial involving women in South Africa and Uganda, twice-yearly subcutaneous lenacapavir was superior to daily oral emtricitabine–tenofovir disoproxil fumarate in preventing HIV infection.

Abstract Background Different chemotherapy regimes have been described for feline lymphoma with varying outcomes. Hypothesis In cats with lymphoma, a long-term, multiagent chemotherapy protocol will be effective and carry acceptable toxicity. Animals Twenty-three cats with histologically or cytologically confirmed diagnosis of lymphoma. Methods Prospective, single-arm clinical trial in which cats were treated with a chemotherapy protocol consisting of a cyclic combination of l-asparaginase, vincristine, cyclophosphamide, doxorubicin, methotrexate, and prednisolone with a planned total treatment time of 122 weeks. Results Complete remission (CR) rate was 74% (n = 17). Fourteen percent of cats attained partial remission (PR). Median duration of first CR was 264 days (range, 45–2,485 days). Six-month, 1-, and 2–5-year remission rates were 75, 50, and 34%, respectively. Duration of PR ranged between 23 and 63 days. Median survival in cats with CR was 296 days (range, 50–2,520 days). Six-month, 1-, 2-, and 3–5-year survival rates in cats with CR were 82, 47, 34, and 27%, respectively. Survival of cats achieving PR ranged between 38 and 120 days. Of the analyzed variables, only anatomical location had a significant influence on remission duration (P=.022). Actual median treatment time in cats with CR was 128 days (18 weeks). Hematologic and gastrointestinal toxicosis was infrequent and mostly low grade. Conclusions and Clinical Importance In this population of cats with lymphoma, chemotherapy was effective. With infrequent and mostly low-grade toxicosis, tolerability of the protocol may be considered good.