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Background The thrice weekly dosing regimen of DOTS has shown low rifampicin plasma concentrations as an independent risk factor for unfavourable tuberculosis (TB) outcome. With introduction of daily regimen using fixed dose combinations (FDC) under National Tuberculosis Elimination Programme (NTEP) the existence of suboptimal plasma levels of first-line antitubercular drugs and its clinical significance remain poorly understood. Method We included a prospective cohort of newly diagnosed pulmonary tuberculosis (PTB) patients receiving 4-FDC daily regimen under NTEP. Plasma concentration at 2 hours (C2h) of each drug was determined after two weeks of treatment using liquid chromatography (LCMS/MS) developed by us. TB card and laboratory reports were reviewed for baseline characteristics and clinical status at 2, 4 and 6 months after the initiation of treatment. At a 1 year follow-up, therapy failure was defined as death or a relapse of tuberculosis. Results Among 40 PTB patients, the C2h post dose plasma concentrations of H, R and E were suboptimal in 25%, 60% and 10% respectively. The C2h of H, R, Z and E were respectively 4.2 ± 2.0, 7.3 ± 2.8, 39.2 ± 8.8 and 3.5 ± 1.2 μg/ml; 60% of the patients had suboptimal plasma concentrations and commonly it was observed with H and R. C2h were lower than expected for at least two drugs i.e. H and R in 25% (10/40) of the patients. Plasma concentration of isoniazid and rifampicin has always been considered important for microbiological response and treatment outcome and low concentrations has been associated with poor treatment response. These patients may require a two year follow up and critical evaluation for prevention of MDR-TB. However, all the TB patients were cured and none of them had recurrence within one year follow up. Conclusions All the pulmonary TB patients administering 4-FDC daily regimen under programmatic settings were cured despite the suboptimal levels of isoniaizd and rifampicin. All the patients achieved pyrazinamide plasma levels and probably this could be the reason behind favourable outcome. Further study is required on large sample size with various subset of population to understand the need of therapeutic drug monitoring.

Objectives This study assessed the efficacy and safety of novel β-lactam/β-lactamase inhibitor combinations in adult patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). Methods PubMed, Web of Science, the Cochrane Library, Ovid MEDLINE, Embase and EBSCO databases were searched for randomized controlled trials (RCTs) published before September 13, 2020. Only RCTs comparing the treatment efficacy of novel β-lactam/β-lactamase inhibitor combinations with other antibiotics for HAP/VAP in adult patients were included in this integrated analysis. Results Three RCTs were included, and no significant difference in clinical cure rate of the test of cure (TOC) was observed between the novel β-lactam/β-lactamase inhibitor combination and comparators (odds ratio [OR], 1.01; 95% CI, 0.81-1.27; I2 = 35%). The 28-day all-cause mortality was 16.2% and 17.6% for patients receiving the novel β-lactam/β-lactamase inhibitor combination and those receiving comparators, respectively, and no significant difference was noted (OR, 0.90; 95% CI, 0.69-1.16; I2 = 11%). Compared with the comparators, the novel β-lactam/β-lactamase inhibitor combination was associated with a similar microbiological response (OR, 1.06; 95% CI, 0.73-1.54; I2 = 64%) and a similar risk of AEs (treatment-emergent AEs [TEAEs]: OR, 1.04; 95% CI, 0.83-1.30; I2 = 0%; serious AEs: OR, 1.14; 95% CI, 0.79-1.63; I2 = 68%; treatment discontinuation for TEAE: OR, 0.90; 95% CI, 0.62-1.31; I2 = 11%). Conclusions The clinical and microbiological responses of novel β-lactam/β-lactamase inhibitor combinations in the treatment of HAP/VAP were similar to those of other available antibiotics. These combinations also shared a similar safety profile to that of comparators.

The potential usefulness of lopinavir-ritonavir on Covid 19 infection during the first wave of contamination in France had boosted Kaletra® syrup prescription to the point of causing its national shortage. In the intensive care units of Parisian hospitals in charge of patients with life-threatening viral contamination, caregivers had to resort to lopinavir-ritonavir-based tablets, crushing them and then dispersing the powder in milk to facilitate administration by nasogastric tube. The difficulties and poor control of this degraded mode, which does not always ensure control of the amount of the drug in the prepared dose and may induce insufficient antiviral exposure, led us to develop in a very short time, while ensuring quality control proportional to the risk, a liquid form as an alternative to Kaletra® oral solution shortage. For this purpose, we describe this compounding formulation and its preparation process, while justifying the quality control strategy adapted to the risk as well as its chemical and physical stability. Based on the chemical and physical studies, the preparation was showed to be stable during at least 2 months between +2°C and +8°C and 1 week at room temperature. This has resulted in the design of kits that include multi-dose packaging and a measuring device and contain the appropriate quantities of drugs to ensure at least one week's treatment for each patient, during which time the kit in use can be stored at room temperature. The intensive care team used this treatment under conditions that they considered well adapted until the imported specialty became available.

BACKGROUND Sacubitril/valsartan (LCZ696) has progressed to be one of the most promising medication since its approval for chronic heart failure with reduced ejection fraction. Recent data have suggested a superior blood pressure control with LCZ696. STUDY QUESTION What is the antihypertensive efficacy and safety profile of sacubitril/valsartan? DATA SOURCES Randomized controlled trials (RCTs) comparing the efficacy and safety of LCZ696 against a placebo or angiotensin receptor blocker (ARB). RCTs were identified from a comprehensive search in PubMed, Embase, Cochrane library, and clinicaltrials.gov. STUDY DESIGN We used a change in systolic and diastolic blood pressures, both sitting as well as ambulatory, to calculate relevant effect sizes with their standard errors from the available change in mean and SD data. In addition, we also collected categorical data for the reported adverse effects from these trials. We performed a series of pairwise meta-analyses between LCZ696 versus an active comparator or a placebo. RESULTS Eleven RCTs with a total of 6028 participants had the relevant data available. Our meta-analysis showed that LCZ696 is an effective and a safe treatment for hypertension. It outperformed ARBs in every category, and the results are consistent across the different dosages of LCZ696. Compared with ARBs, 200 mg of LCZ696 reduced systolic blood pressure and diastolic blood pressure (DBP) by 4.62 mm Hg (95% confidence interval, 3.33-5.90, P < 0.001) and 2.13 mm Hg (95% confidence interval, 1.69-2.57, P < 0.001), respectively. Similarly, 400 mg of LCZ696 reduced systolic blood pressure and diastolic blood pressure by 5.50 mm Hg (2.94-8.07, P < 0.001) and 2.51 mm Hg (1.80-3.21, P < 0.001), respectively, in comparison with ARBs. The adverse effects with LCZ696 were not significantly higher compared with ARBs or placebo. CONCLUSIONS Sacubitril/valsartan is more effective for the management of hypertensive patients, compared with an ARB. Long-term prospective studies are required to identify whether this result translates into morbidity and mortality benefits.

Objective To evaluate the long-term safety and efficacy of indacaterol/glycopyrronium (IND/GLY) in patients with COPD in a real-world setting in Japan. Methods This 52-week, multicentre, post-marketing surveillance conducted in Japan between December 2013 and August 2019 included patients using IND/GLY for the first time to relieve airway obstructive disorder-related symptoms. Safety outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), and serious ADRs during the 52-week period. The incidence of priority variables, including cardiovascular/cerebrovascular (CCV) AEs, β-adrenergic-related or anticholinergic AEs and cough, was also assessed. Safety outcomes were also evaluated in elderly patients. Efficacy outcomes included a physician's global assessment, COPD assessment test (CAT) and lung function test. Results Of the 1,167 patients registered, 1,108 were included in the safety and efficacy analysis. In the safety analysis population, the incidence of AEs was 13.54%, that of SAEs was 4.69%, that of ADR was 3.61%, and that of serious ADRs was 0.36% over 52 weeks. CCV AEs, β-adrenergic-related and anticholinergic AEs and cough were reported as 2.62%, 1.99% and 0.63%, respectively. The physician's global assessment showed that the overall response rate at the last assessment was 74.19%. The mean (95% confidence interval) CAT scores decreased from the start of treatment to Week 52 with IND/GLY (-6.9 [-7.8 to -6.1]). The lung function (FEV1 and FVC) improved over time from the start of IND/GLY to Week 52. Conclusion IND/GLY demonstrated a good long-term safety profile in a real-world setting in Japanese patients with COPD, with beneficial effects in terms of the lung function and symptoms in clinical use.

Most patients with psoriasis present with localized mild-to-moderate disease. In this case, the application of topical treatments in the first-line setting is recommended in most cases. Among different topical options, the fixed-dose combination of betamethasone dipropionate (BD) and vitamin D analogue (Cal) aerosol foam (Enstilar®, Leo Pharma) is approved as first-line topical therapy for the treatment of psoriasis in USA and the EU, due to its high efficacy and its favorable administration scheme. The PSO-LONG was the first trial to report on the long-term efficacy and safety of the Cal/DB foam treatment for the proactive management of psoriasis and now, the indications of Cal/BD foam included its use in the psoriasis maintenance treatment. However, the precise role of this treatment and the potential therapeutic schemes in the long-term management of psoriasis need further clarification. This Position Paper, authored by a group of Italian Expert Dermatologists, critically discusses the long-term management of psoriasis with Cal/BD foam in clinical practice. In particular, the biological rationale in the proactive treatment with Cal/BD foam and current evidence regarding this therapeutic approach are presented, along with its application also in patients with moderate-to-severe disease, difficult-to-treat lesions, or within combination regimens. In addition, strategies to improve adherence to long-term treatment of psoriasis are discussed,.

OBJECTIVE This work aims to analyze the impact of Spain's National Center for Cardiovascular Research (CNIC-Ferrer)'s cardiovascular (CV)-polypill on blood pressure (BP) and low-density lipoprotein cholesterol (cLDL) levels in patients in our healthcare area who previously took equipotent doses of statins and antihypertensives. MATERIAL AND METHODS All patients in our healthcare area (Santiago de Compostela, Spain) who, as of December 31, 2019, had an active prescription for the CV-polypill (CNIC-Ferrer) since January 16, 2015 were registered. The index date was the start date of the CV-polypill prescription. The drugs the patient had previously received for dyslipidemia and hypertension were analyzed, classifying them by their equivalent potency to atorvastatin and ramipril. Changes in cLDL and BP were analyzed by means of Student's t-test for paired samples. RESULTS We analyzed 547 patients with a mean age of 71.5 ± 11.5 years. The majority were men (60.6%). We observed a decrease in cLDL (-10.6 [95% CI: -7.0, -14.3], p

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA, Trikafta) is the newest Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator drug approved by the Food and Drug Administration. Post-marketing reports with earlier CFTR modulators suggest these medications can impact mood, and in clinical trials an adverse effect of headache was reported with all currently approved CFTR modulators. However, there are no other documented reports of mental status changes during clinical trials or in post-marketing reports with elexacaftor/tezacaftor/ivacaftor. In this case series, we describe 6 patients who reported "mental fogginess" or other mental status changes shortly after initiation of this drug. The mechanism of this patient-reported side effect is still unclear. All patients noticed a change within the first 3 months of therapy. The management differed in each case, with all four cystic fibrosis (CF) care teams utilizing a patient-centered decision-making approach to address this concern.

Introduction Monoclonal antibody therapy has been reported to be highly effective for preventing hospitalisation and severe cases in patients with Coronavirus Disease 2019 (COVID-19). However, since the drug is not readily available, it is important to rapidly and appropriately identify high-risk patients who can benefit most from therapy. Therefore, we designed a risk scoring system to identify at-risk COVID-19 patients in our region during the largest surge of COVID-19, from July to September 2021. Methods According to the risk scores, confirmed COVID-19 patients were introduced to receive REGN-CoV-2 to our hospital by regional health centre from 18th August (Term 3). The primary outcome was the comparison of the number of hospitalisation and severe condition with other periods, the 4th wave (Term 1) and the early part of the 5th wave (Term 2) in Japan. Results During Term 3, 115 patients were stratified with the scoring system and administered REGN-COV-2. The number of hospitalisation vs severe cases were 60 (5.2%) vs 14 (1.2%), 8 (1.5%) vs 3 (0.6%) and 21 (1.2%) vs 2 (0.1%), in term 1, 2 and 3, respectively. Among those aged

Purpose Gastric cancer with para-aortic node (PAN) metastasis has a chance to be cured with multidisciplinary treatment of D2 and PAN dissection (PAND) following neoadjuvant chemotherapy (NAC), but its prognosis remains unsatisfactory. To establish a better multidisciplinary treatment, a better surrogate endpoint is needed. The present study focused on a pathological complete response at the PANs alone as a new surrogate endpoint and evaluated its prognostic value. Methods The study examined patients who received radical gastrectomy with D2 and PAND after NAC for gastric cancer with PAN metastasis from 2004 to 2015. The study compared five methods of evaluating the response to NAC: RECIST, clinical disappearance of PANs (cPAN), histological response of the primary tumor defined by Japanese Classification of Gastric Carcinoma (JCGC histological criteria) and Becker's criteria, and pathological disappearance of PANs (pPAN). The efficacy of these methods was compared using the hazard ratio (HR) for death between responders and non-responders. Results Thirty-two patients were analyzed. The respective HR and 5-year overall survival rates of responders and non-responders were 1.316 and 49.1% vs. 60.0% by RECIST, 1.106 and 52.9% vs. 52.5% by cPAN, 0.246 and 71.3% vs. 28.6% by JCGC histological criteria, 0.239 and 76.2% vs. 36.8% by Becker's criteria, and 0.074 and 81.0% vs. 0.0% by pPAN. Conclusions A pathological complete response at the PANs had the lowest HR and clearly differentiated the survival, suggesting it might be a good surrogate endpoint for identifying future candidates for NAC in multidisciplinary treatment for gastric cancer with PAN metastasis.

Background Brexanolone (Zulresso) is the first Federal Drug Administration–approved drug for the treatment of postpartum depression. Brexanolone is a positive allosteric modulator of the GABAA receptor and is given over 60 hours by infusion in a medical setting. This drug has been shown to be effective at significantly reducing Hamilton Rating Scale for Depression scores at 60 hours and 30 days after infusion; however, data beyond 30 days have not yet been available. There have been limited clinical programs able to offer brexanolone owing to the complexity of setting up this treatment in a medical setting. Purpose This study sought to obtain follow-up data from 16 patients who received a brexanolone infusion at UNC Hospitals in Chapel Hill, NC, between October 2019 and December 2020 and were beyond the 30-day postinfusion time point. We describe the methods used to successfully implement this treatment program in an academic medical center and discuss associated challenges and lessons learned with patient selection and process improvements. Methods Hamilton Rating Scale for Depression scores were collected before and after infusion from 16 patients who received a brexanolone infusion at UNC. Patients were subsequently contacted for a follow-up interview to obtain Hamilton Rating Scale for Depression scores and complete a semistructured interview at least 30 days past treatment end (between 3 and 16 months after infusion). Results All 16 patients had a significant reduction in Hamilton Rating Scale for Depression scores at 60 hours, scores dropping on average from 23.9 (standard deviation = 2.6) to 7.6 (standard deviation = 2.9). Eleven of 16 patients consented to provide follow-up data. Follow-up Hamilton Rating Scale for Depression scores remained lower than postinfusion at an average of 6.7 points (standard deviation = 5.1). Conclusion With a strategic cross-disciplinary approach, a Clinical Brexanolone Treatment Program was established at UNC Hospitals in 2019. Sixteen patients have been treated in the program, and 11 participated in a follow-up interview. All 11 patients gave very positive feedback about their treatment. Our program has found brexanolone to be a useful clinical tool in treating women with significant symptoms of postpartum depression.

Aims The coronavirus disease‐2019 (COVID‐19) pandemic has changed the landscape of medical care delivery worldwide. We aimed to assess the influence of COVID‐19 pandemic on hospital admissions and in‐hospital mortality rate in patients with acute heart failure (AHF) in a retrospective, multicentre study. Methods and results From 1 January 2019 to 31 December 2020, a total of 101 433 patients were hospitalized in 24 Cardiology Departments in Poland. The number of patients admitted due to AHF decreased by 23.4% from 9853 in 2019 to 7546 in 2020 (P

Despite being an important patient group, adult cystic fibrosis patients with an FEV1 below 40%predicted have been excluded from clinical trials with elexacaftor/tezacaftor/ivacaftor. We conducted a real-life 3 months follow-up study in 14 adult CF patients (median FEV1 34%predicted) demonstrating significant treatment effects in terms of FEV1 (an increase of 12%predicted at 4 weeks, remaining stable thereafter). Corresponding decreases in lung clearance index LCI (by 31%predicted, down from baseline 247%predicted) and ventilation heterogeneity in the acinar compartment (Sacin) (by 411%predicted, down from baseline 798%predicted) suggest a distinct peripheral lung effect. One patient had intermittent treatment interruptions because of drug-induced liver injury. Our real-life data confirm that treatment with elexacaftor/tezacaftor/ivacaftor is effective in severely obstructive patients, and this is the first study to show time evolution of ventilation distribution improvement, pointing to the peripheral lung as the main site of treatment effect.

BACKGROUND Scabies is a contagious skin disease resulting from Sarcoptes scabiei infestation. There are no approved over-the-counter treatments, and approved prescription products have disadvantages, including potential resistance. Spinosad, an insecticide derived from fermentation of a soil actinobacterium, shows promise as a potential treatment agent. OBJECTIVE Combined results from 2 controlled clinical studies were used to evaluate the efficacy of 0.9% spinosad topical suspension in the eradication of scabies. METHODS Each study included index subjects (the youngest household members with active scabies) and up to 5 other members in each household. Subjects applied 0.9% spinosad or vehicle once. Primary efficacy was the percentage of index subjects with complete cure on day 28. Additional efficacy included clinical cure, microscopic cure, and lesion counts. RESULTS Spinosad at 0.9% is not equivalent to vehicle in the percentage of index subjects achieving complete cure on day 28 (78.1% vs 39.6%, respectively; P

ObjectivesLong-acting reversible contraceptives are effective contraceptives for women with HIV, but there are limited data on etonogestrel implant and antiretroviral therapy pharmacokinetic drug-drug interactions. We evaluated etonogestrel/antiretroviral therapy drug-drug interactions, and the effects of etonogestrel on ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, and efavirenz pharmacokinetics.Study designWe enrolled postpartum women using etonogestrel implants and receiving ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, or efavirenz-based regimens between 2012 and 2015. Etonogestrel implants were inserted 2 to 12 weeks postpartum. We performed pharmacokinetic sampling pre-etonogestrel insertion and 6 to 7 weeks postinsertion. We measured antiretroviral concentrations pre and postetonogestrel insertion, and compared etonogestrelconcentrations between antiretroviral regimens. We considered a minimum serum etonogestrelconcentration of90 pg/mLadequate for ovulation suppression.ResultsWe collected pharmacokinetic data for 74 postpartum women, 22 on ritonavir-boosted-atazanavir, 26 on ritonavir-boosted-lopinavir, and 26 on efavirenz. The median serum concentrations of etonogestrel when co-administered were highest with etonogestrel/ritonavir-boosted-atazanavir (604 pg/mL) and etonogestrel/ritonavir-boosted-lopinavir (428 pg/mL), and lowest with etonogestrel/efavirenz (125 pg/mL); p < 0.001. Minimum concentration (Cmin) of ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were lower after etonogestrel implant insertion, but overall exposure, predose concentrations, clearance, and half-lives were unchanged. We found no significant change in efavirenz exposure after etonogestrel insertion.ConclusionsUnlike efavirenz, ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were not associated with significant decreases in etonogestrel concentrations. Efavirenz was associated with a significant decrease in etonogestrel concentrations.ImplicationsThe findings demonstrate no interactions between etonogestrel and ritonavir-boosted-lopinavir or ritonavir-boosted-atazanavir, but confirm the decreased efficacy of etonogestrel with efavirenz-based antiretrovirals. This information should be used to counsel women with HIV who desire long-acting reversible contraceptives.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR-activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21_L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed.

Purpose To define the burden of morbidity and mortality arising from COVID-19 in individuals with primary (PID) and secondary immunodeficiency (SID) in the United Kingdom. Methods In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. Anonymised demographic data, pre-SARS-CoV-2 infection lymphocyte counts, co-morbidities, targeted treatments and outcomes were collected. Three groups were analysed in further detail: individuals with common variable immunodeficiency (CVID), individuals with any PID, including CVID, receiving immunoglobulin replacement therapy (IgRT) and individuals with secondary immunodeficiency. Results A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID, had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Conclusion Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Introduction Fixed-dose long-acting beta2-agonist (LABA)/inhaled corticosteroid (ICS) combinations and add-on therapies as needed are the mainstay for maintenance therapy in asthma. However, more than 40% of patients have an inadequately controlled disease. The development of triple fixed-dose combinations consisting of long-acting muscarinic antagonist (LAMA)/LABA/ICS has paved the way for a new approach to reach therapeutic goals of an optimal control of symptoms and an effective prevention of future exacerbations. Areas covered A search was conducted on PubMed (MEDLINE), using the MeSH terms [asthma] + [indacaterol] + [glycopyrronium] +[mometasone furoate] + [treatment], until October 2021. Original data from clinical trials, prospective and retrospective studies and reviews were selected. Clinical studies with IND/MF/GLY (Enerzair Breezhaler) are summarized, and its place in current asthma therapy is examined. Expert opinion Triple therapy has been shown to be an effective and safe therapeutic option for asthma patients who remain uncontrolled despite ICS/LABA combination. The recently approved single-inhaler indacaterol/glycopyrronium/mometasone fixed dose combination has demonstrated to significantly reduce exacerbations, improve FEV1, symptoms and quality of life compared to ICS/LABA, including, salmeterol/fluticasone combination. Moreover, once-daily dosing may improve adherence.

Objectives To systematically evaluate the efficacy and safety of Arbidol and lopinavir/ritonavir (LPV/r) in the treatment of coronavirus disease 2019(COVID-19) using a meta-analysis method. Methods The China Knowledge Network, VIP database, WanFang database PubMed database, Embase database, and Cochrane Library were searched for a collection of comparative studies on Arbidol and lopinavir/ritonavir in the treatment of coronavirus disease 2019. Meta-analysis was used to evaluate the efficacy and safety of Arbidol and lopinavir/ritonavir in the treatment of COVID-19. Results The results of the systematic review indicated that Arbidol had a higher positive-to-negative conversion rate of SARS-CoV-2 nucleic acid on Day 7 [P=0.03], a higher positive-to-negative conversion rate of SARS-CoV-2 nucleic acid on Day 14 [P=0.006], a higher improvement rate of chest CT on Day 14 [P=0.02], a lower incidence of adverse reactions [P=0.002] and lower rate of mortality[P=0.007]. There was no difference in the rate of cough disappearance on Day 14 [P=0.24] or the rate of severe/critical illness [P=0.07] between the two groups. Conclusions Arbidol may be superior tolopinavir/ritonavir in the treatment of COVID-19. However, due to the small number of included studies and the number of patients, high-quality multi-centre large-sample randomized double-blind controlled trials are still needed for verification. This article is protected by copyright. All rights reserved.

Objective The concept of minimally invasive endodontics recommends less-invasive vital pulp therapy (VPT) modalities over more aggressive traditional endodontic approaches in mature permanent teeth with carious pulp exposure, including irreversible pulpitis (IP) cases. Consequently, VPT needs to be compared with root canal therapy (RCT) in terms of treatment outcomes. This randomized clinical trial compares the results of full pulpotomy using two calcium-silicate cements, i.e., mineral trioxide aggregate (MTA) and calcium-enriched mixture (CEM) cement, with RCT in mature permanent teeth. Materials and methods A total of 157 carious pulp exposure cases in two academic centers with/without established IP were selected/included/randomly appointed to three study arms; (i) RCT (n = 51) as the reference treatment, (ii) pulpotomy with ProRoot MTA (PMTA; n = 55), and (iii) pulpotomy with CEM cement (PCEM; n = 51) as two alternative VPT treatments. Two-year clinical/radiographic results were the outcomes of interest. Data were statistically analyzed through the analysis of variance, chi-square, Fisher exact test, and Kruskal–Wallis. Results At 2-year recall, 147 teeth were examined (6.4% dropout). All molars, except for one, were clinically functional/symptom-free, and there was no statistical difference between the three study arms (p = 0.653). The radiographic success rates in RCT, PMTA, and PCEM arms were 98%, 100%, and 97.9%, respectively, without statistically significant differences (p = 0.544). Conclusion In the management of mature permanent teeth with/without established IP, all experimental groups exhibited equivalent/comparable results. Clinical relevance Simple VPT using MTA/CEM can be suggested/recommended as a viable advantageous alternative to RCT for the management of carious pulp exposures with/without sign/symptoms of IP.

The authors sought to investigate associations between sacubitril/valsartan adherence and clinical outcomes after hospitalization for heart failure with reduced ejection fraction (HFrEF).Sacubitril/valsartan improves outcomes in HFrEF, though the extent to which medication adherence is associated with outcomes in routine care is less well characterized.The authors analyzed patients aged ≥65 years hospitalized for HFrEF within the Get With the Guidelines-Heart Failure registry linked with Medicare claims between October 2015 and September 2018 who were discharged with sacubitril/valsartan. Sacubitril/valsartan adherence was assessed using medication fills to calculate proportion of days covered (PDC) through 90 days postdischarge. Associations between postdischarge adherence (PDC or ≥80%) and risk of readmission and death within 1 year were examined by comparing cumulative incidences and adjusted event rates.Among 897 patients prescribed sacubitril/valsartan at discharge, 295 (32.9%) had PDC ≥80% and 602 (67.1%) had PDC 80%. Baseline characteristics were balanced between groups. Compared with patients with PDC 80%, patients with PDC ≥80% had a significantly lower adjusted hazard of all-cause rehospitalization (HR: 0.66 [95% CI: 0.48-0.89]) and death (HR: 0.42 [95% CI: 0.22-0.79]) at 90 days and at 1 year (HR: 0.69 [95% CI: 0.56-0.86] and HR: 0.53 [95% CI: 0.38-0.74], respectively). For every 5 percentage point increase in PDC, patients experienced a significant reduction in rehospitalization (HR: 0.98 [95% CI: 0.97-0.99]) and death (HR: 0.96 [95% CI: 0.94-0.97]) at 1 year.In patients hospitalized for HFrEF and discharged on sacubitril/valsartan, high adherence to sacubitril/valsartan within 90 days after discharge was associated with substantially lower rates of readmission and death. Additional efforts to improve adherence with sacubitril/valsartan and other guideline-directed medical therapies in HFrEF are warranted.

Background Heart failure and sleep-disordered breathing have been increasingly recognized as co-occurring conditions. Their bidirectional relationship warrants investigation into whether heart failure therapy improves sleep and sleep-disordered breathing. We sought to explore the effect of treatment with sacubitril/valsartan on sleep-related endpoints from the AWAKE-HF study. Methods and Results AWAKE-HF was a randomized, double-blind study conducted in 23 centers in the United States. Study participants with heart failure with reduced rejection fraction and New York Heart Association class II or III symptoms were randomly assigned to receive treatment with either sacubitril/valsartan or enalapril. All endpoints were assessed at baseline and after 8 weeks of treatment. Portable sleep-monitoring equipment was used to measure the apnea-hypopnea index, including obstructive and central events. Total sleep time, wake after sleep onset and sleep efficiency were exploratory measures assessed using wrist actigraphy. The results were as follows 140 patients received treatment in the double-blind phase (sacubitril/valsartan, n = 70; enalapril, n = 70). At baseline, 39% and 40% of patients randomly assigned to receive sacubitril/valsartan or enalapril, respectively, presented with undiagnosed, untreated, moderate-to-severe sleep-disordered breathing (≥ 15 events/h), and nearly all had obstructive sleep apnea. After 8 weeks of treatment, the mean 4% apnea-hypopnea index changed minimally from 16.3/h to 15.2/h in the sacubitril/valsartan group and from 16.8/h to 17.6/h in the enalapril group. Mean total sleep time was long at baseline and decreased only slightly in both treatment groups at week 8 (–14 and –11 minutes for sacubitril/valsartan and enalapril, respectively), with small changes in wake after sleep onset and sleep efficiency in both groups. Conclusions In a cohort of patients with heart failure with reduced rejection fraction who met prescribing guidelines for sacubitril/valsartan, one-third had undiagnosed moderate-to-severe obstructive sleep apnea. The addition of sacubitril/valsartan therapy did not significantly improve sleep-disordered breathing or sleep duration or efficiency. Patients who meet indications for treatment with sacubitril/valsartan should be evaluated for sleep-disordered breathing.

Objectives The objective of this study was to evaluate the efficacy of different dosing regimens of ceftazidime/avibactam (CZA) in patients with Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) pulmonary infections. Methods A total of 70 KPC-Kp strains were isolated from sputum and bronchoalveolar lavage samples of patients with pulmonary infections in three hospitals in northern China from April 2015 to October 2015. Monte Carlo simulation (MCS) was performed using population pharmacokinetic parameters of CZA combined with the minimum inhibitory concentration (MIC) distributions gained from antimicrobial susceptibility testing to predict the efficacy of different dosing regimens. Various CZA dosing regimens were modelled using MCS. Results The in vitro study showed potent activity of CZA against KPC-Kp strains with MIC50/90 values of 1/2 mg/L, with a susceptibility rate of 95.7%. The values of cumulative fraction of response (CFR) for bactericidal (50%fT>5 × MIC) target were as follows: for patients with creatinine clearance (CLCr) >51 mL/min, the CFR was 96.01% for 2.5 g CZA every 12 h (q12h) and 97.14% for 2.5 g CZA every 8 h (q8h); and for patients with moderate renal impairment (CLCr >30 to ≤50 mL/min), the CFR was 95.75% for 1.25 g CZA q12h and 97.09% for 1.25 g CZA q8h. Conclusion This study indicated that the recommended dose of CZA can provide adequate pharmacodynamic exposure for treating KPC-Kp pneumonia.

Background The prognosis of patients with borderline resectable pancreatic cancer with arterial contact (BRPC-A) is extremely poor, and effective preoperative treatment is indispensable. We evaluated the clinical efficacy and safety of neoadjuvant chemotherapy, including gemcitabine, nab-paclitaxel and S-1 (GAS), for patients with BRPC-A. Material and methods A multicentre, single-arm, phase II study was performed. Patients were administered 1000 mg/m2 gemcitabine on day 1, 125 mg/m2 nab-paclitaxel on day 1 and 60–100 mg/day S-1 on days 1–7 during a 14-day cycle. Patients were then assessed for resectability and response to treatment after six cycles. The primary end-points were 2-year overall survival (OS) rate and median OS time (trial registration: jRCTs061180045, UMIN000016630). Results Forty-seven patients with BRPC-A were eligible for the present study. Six courses of neoadjuvant GAS regimen were completed in all eligible patients. The rate of grade III/IV toxicities occurred in 14 (30%) patients during the neoadjuvant GAS regimen. The response and disease control rates were 43% and 96%, respectively. Forty-five (96%) patients received potentially curative pancreatectomy, whereas two did not owing to disease progression. R0 resection was performed in 40 (86%) of 47 eligible patients. Eleven (24%) patients experienced postoperative major complications (>grade III), including one mortality. The 2-year OS rate and median OS time among 47 eligible patients were 70.1% and 41.0 months, respectively. Conclusions The neoadjuvant GAS chemotherapy regimen for BRPC-A showed good efficacy with mild toxicity, resulting in a high R0 resection rate and prolonged survival in patients with BRPC-A.

Background Plasmodium falciparum gametocytaemia has been associated with anaemia. The aim of this review was to synthesize available evidence on the comparative effect of dihydroartemisinin-piperaquine (DHA-PQ) and artemether-lumefantrine (AL) on gametocyte clearance and haemoglobin recovery in children with uncomplicated P. falciparum malaria in Africa. Methods A systematic literature search was undertaken to identify relevant articles from online databases. The search was performed from August 2020 to 30 April 2021. Extracted data from eligible studies were pooled as risk ratios with 95% confidence intervals (CI). Results Gametocyte carriage was reduced in both treatment groups, with no significant difference found between the groups. However, on days 28 and 42, a significant increase in serum haemoglobin level from baseline was observed in the DHA-PQ group (standardized mean difference 0.15, 95% CI 0.05–0.26; participants=2715; studies=4; I2=32%, high quality of evidence) compared with the AL group (mean difference 0.35, 95% CI 0.12–0.59; participants=1434; studies=3; I2=35%, high quality of evidence). Conclusion DHA-PQ had a greater impact on haemoglobin recovery than AL on days 28 and 42; this difference was significant.

Radiation therapy is a major treatment modality used in > 60% of cancer patients as definitive local treatment for inoperable locoregionally confined tumors and as palliative therapy. Although cytotoxic chemotherapy enhances the effectiveness of treatment, the benefit over radiation therapy alone is modest. There is a need to enhance the effectiveness of local tumor control over what sequentially or concurrently administered cytotoxic chemotherapy provides. Although many biological pathways are known to enhance the effectiveness of radiation therapy, there is currently a paucity of drugs approved for use in combination. Several clinical trials have tested the effectiveness of combining targeted agents or immunotherapies with radiation therapy, but the results of these trials have been negative, likely stemming from the relative lack of preclinical evidence using appropriate experimental standardization or model systems. Accelerating the identification of agents tested in an appropriate clinical context and experimental systems or models would greatly enhance the potential to bring forward early testing of drugs that would not only be safe but also more effective. This article provides an overview of the opportunities and challenges of developing therapeutics to combine with radiation therapy, and some guidance toward preclinical and early clinical testing to improve the chance that advanced phase testing of drug-radiation combinations would be successful in the long term.

Excessive sympathetic outflow following trauma can lead to cardiac dysfunction, inflammation, coagulopathy, and poor outcomes. We previously reported that buprenorphine analgesia decreased survival after hemorrhagic trauma. Our aim is to examine the underlying mechanisms of mortality in a non-compressible hemorrhage rat model resuscitated with saline or adenosine, lidocaine, magnesium (ALM). Anesthetized adult male Sprague-Dawley rats were randomly assigned to Saline control group or ALM therapy group (both n = 10). Hemorrhage was induced by 50% liver resection. After 15 min, 0.7 mL/kg 3% NaCl ± ALM intravenous bolus was administered, and after 60 min, 0.9% NaCl ± ALM was infused for 4 h (0.5 mL/kg/h) with 72 h monitoring. Animals received 6-12-hourly buprenorphine for analgesia. Hemodynamics, heart rate variability, echocardiography, and adiponectin were measured. Cardiac tissue was analyzed for adrenergic/cholinergic receptor expression, inflammation, and histopathology. Four ALM animals and one Saline control survived to 72 h. Mortality was associated with up to 97% decreases in adrenergic (β-1, α-1A) and cholinergic (M2) receptor expression, cardiac inflammation, myocyte Ca2+ loading, and histopathology, indicating heart ischemia/failure. ALM survivors had higher cardiac output and stroke volume, a 30-fold increase in parasympathetic/sympathetic receptor expression ratio, and higher circulating adiponectin compared to Saline controls. Paradoxically, Saline cardiac adiponectin hormone levels were higher than ALM, with no change in receptor expression, indicating intra-cardiac synthesis. Mortality appears to be a "systems failure" associated with CNS dysregulation of cardiac function. Survival involves an increased parasympathetic dominance to support cardiac pump function with reduced myocardial inflammation. Increased cardiac α-1A adrenergic receptor in ALM survivors may be significant, as this receptor is highly protective during heart dysfunction/failure.

Introduction The combination of angiotensin-converting enzyme inhibitors and beta-blockers is recommended in a wide range of patients with hypertension, including those with stable coronary artery disease and/or elevated heart rate. This post hoc analysis of three observational studies provides effectiveness and safety data on treatment with perindopril on top of bisoprolol-based therapy, in routine clinical practice. Methods Data were analyzed from three open-label, prospective, multicenter, observational studies of Canadian patients with mild-to-moderate hypertension, which shared the same inclusion and exclusion criteria, treatment duration, and primary outcome. This post hoc analysis focused on the subpopulation of patients treated with perindopril on top of bisoprolol-based therapy. All patients were followed for 16 weeks and underwent baseline, week 4, and week 16 visits. Primary outcomes were mean changes in blood pressure (BP) and proportion of patients achieving BP control (

Plaque psoriasis is a common, chronic and relapsing inflammatory skin disease clinically characterized by erythema and scaling desquamation. As over 90% of psoriasis patients benefit from topical therapies, local treatments continue to play an eminent role in management strategies. One such topical treatment is the fixed dose combination of calcipotriol (CAL) and betamethasone dipropionate (BDP).Pooled analysis of two different phase 3 clinical trails to compare superiority regarding efficacy, safety and quality of life (QoL) between CAL/BDP PAD-cream and CAL/BDP TS.The data from two phase 3, multicentre, randomized, investigator-blind, active and vehicle-controlled trials enrolling patients with psoriasis were pooled and analysed. Investigational products included a CAL/BDP cream based on PAD™ Technology (PAD-cream) designed for high skin penetration and increased patient preference, an active control (marketed CAL/BDP topical suspension/gel, in the following abbreviated as CAL/BDP TS) and cream vehicle, which were applied once daily for 8 weeks.Efficacy and safety of the novel CAL/BDP PAD-cream formulation for the topical treatment of psoriasis demonstrated superiority for all efficacy end points after 8 weeks of treatment. PGA treatment success for CAL/BDP PAD-cream (43.2%) was greater than CAL/BDP TS (31.9%; P 0.0001), the mean per cent reduction in mPASI for CAL/BDP PAD-cream was 64.6% compared to 56.4% for CAL/BDP TS (P 0.0001) and DLQI 0/1 was obtained by 43.8% in the CAL/BDP PAD-cream group versus 34.2% in the CAL/BDP TS group (P = 0.0005). There was no adverse drug reaction reported with a frequency of1%, associated with the CAL/BDP PAD-cream.The novel fixed dose combination CAL/BDP PAD-cream offers greater efficacy, superior patient QoL and equivalent favourable safety for the topical treatment of psoriasis, in comparison to the currently available topical suspension/gel.

Objective Evaluate bioequivalence, based on norelgestromin (NGMN) and ethinyl estradiol (EE) plasma concentrations, and adhesion of a transdermal contraceptive patch containing a newly sourced adhesive component (test) at end of shelf life (EOSL) vs. the marketed EVRA patch (reference) at beginning of shelf life (BOSL). Materials and methods In this randomized, double-blind, two-way crossover study, healthy women received a single, 7-day application of test and reference patches in 4 sequences: two 11-day treatment periods separated by a 21-day washout. Assessments included NGMN and EE pharmacokinetics (PK), adhesion (per European Medicines Agency (EMA) 5-point scale), irritation potential and application-site reactions, and tolerability. Patches were bioequivalent if 90% CIs of geometric mean ratios (GMRs) of test/reference for Cmax, AUC168h, AUC0-tlast, and AUC∞ were 80 - 125%. Patch adhesion was comparable if ratios of geometric mean cumulative adhesion percentages were ≥ 90%. Results 68 women were randomized, and 62 completed both treatments. 55 and 59 participants in the reference and test group, respectively, had patch adhesion ≥ 80% (EMA score 0 - 1) at end of treatment. Bioequivalence was demonstrated: GMRs for pharmacokinetic (PK) parameters ranged from 102.76 - 105.57% for NGMN and 93.78 - 94.80% for EE, and associated 90% CIs were fully within the bioequivalence acceptance range (80 - 125%) for both. The patches had comparable adhesion properties (GMR, 101.4% (90% CI: 99.2 - 103.6)) and incidences of treatment-emergent adverse events. Conclusion NGMN-EE transdermal test patch at EOSL was bioequivalent to the marketed patch at BOSL, supporting widening the product's shelf-life specification. Adhesive properties and safety profiles were comparable between patches.

Aims The angiotensin receptor–neprilysin inhibitor (ARNI), sacubitril/valsartan, confers additional protective effects compared with angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs) in terms of reversed left ventricular (LV) remodelling and improves the prognosis of patients with heart failure (HF). However, few studies have examined the effects of ARNI on the left atrium. Accordingly, this study compared the effects of ARNI and ACEI/ARB on left atrial (LA) remodelling in heart failure with reduced ejection fraction (HFrEF). Methods and results This was a single‐centre retrospective study of patients with HFrEF hospitalized at the First Affiliated Hospital of Dalian Medical University between 26 February 2016 and 8 July 2020. Patients were classified into ARNI and ACEI/ARB groups and further subgroups based on the left atrial volume index (LAVI): mildly abnormal (29 mL/m2 ≤ LAVI

The purpose of this survey is to explore changes in the management of COVID-19 during the first versus the second wave, with particular emphasis on therapies, antibiotic prescriptions, and elderly care. An internet-based questionnaire survey was distributed to European Society of Clinical Microbiology and Infectious Diseases (ESCMID) members. Therapeutic approach to patients with mild-to-moderate (PiO2/FiO2 200–350) and severe (PiO2/FiO2

Background The global COVID-19 pandemic is currently underway. A massive worldwide vaccination campaign is still underway, representing the most promising weapon available to stop the pandemic. Methods and Results However, research continues to investigate the most effective drug treatments to reduce and avoid the most serious complications caused by COVID-19 infection. Recently, new evidence of good therapeutic efficacy against COVID-19 has emerged for the antiviral Remdesivir and the immunomodulatory Baricitinib, also in combination. The first one showed SARS-CoV-2 antireplicative activity, the second one useful to reduce the hyperinflammatory state caused by cytokine storm in the most severe phases of the infection. Conclusions In this short communication we describe the molecular pharmacological mechanisms and the latest evidence for the use of these therapeutic agents in the treatment of COVID-19 infection.

Background The efficacy of modified FOLFIRINOX (mFOLFIRINOX) as a second-line chemotherapy treatment for metastatic pancreatic adenocarcinoma (mPAC), remains unclear. This multi-center randomised phase III trial aimed to elucidate the efficacy of mFOLFIRINOX as a second-line chemotherapy treatment for mPAC patients with good performance status. Patients and methods Eighty mPAC patients (age, 19–75 years) refractory to first-line gemcitabine-based chemotherapy were randomly selected to receive mFOLFIRINOX or S-1. mFOLFIRINOX comprised oxaliplatin (65 mg/m2), irinotecan (135 mg/m2), and leucovorin (400 mg/m2) on day 1 and continuous 5-FU infusion (1000 mg/m2) over 24 h on days 1–2 every 2 weeks. S-1 comprised body surface area-dependent oral S-1, divided into two doses per day on days 1–28 every 6 weeks. Results Overall survival was the primary endpoint. The objective response and disease control rates were higher in the mFOLFIRINOX than in the S-1 group (15% versus 2%; p = .04 and 67% versus 37%; p = .007). The median progression-free survival rates were 5.2 and 2.2 months in the mFOLFIRINOX and S-1 groups, respectively (adjusted hazard ratio [HR]: .4; 95% confidence interval [CI]: .2-.6; p Conclusion Administration of mFOLFIRINOX as a second-line chemotherapy treatment for mPAC patients refractory to gemcitabine-based chemotherapy resulted in increased survival rates than S-1 treatment alone.

Spirometry is a crucial test used in the diagnosis and monitoring of patients with chronic obstructive pulmonary disease (COPD). Severe acute respiratory syndrome coronavirus 2 pandemic has posed numerous challenges in performing spirometry. Dynamic-ventilatory digital radiography (DR) provides sequential chest radiography images during respiration with lower doses of radiation than conventional X-ray fluoroscopy and computed tomography. Recent studies revealed that parameters obtained from dynamic DR are promising for evaluating pulmonary function of COPD patients. We report two cases of COPD evaluated by dynamic-ventilatory DR for pulmonary function and treatment efficacy and discuss the potential of dynamic DR for evaluating COPD therapy.

Outcome expectations of direct pulp capping in carious teeth are obscured by a clinically unknown infiltration and breakdown of the dental pulp tissue. Histologic studies showed that this soft tissue breakdown is related to the innate immune system. We hypothesized 1) that a neutrophil biomarker could predict the outcome of direct pulp capping and 2) that using sodium hypochlorite (NaOCl) as a lavage solution to remove necrotized infected pulp tissue could improve it. In this randomized trial in mature posterior teeth causing no or mild discomfort with carious pulpal exposures, pulpal fluid was collected to assess neutrophil gelatinase (matrix metalloproteinase 9 [MMP-9]) per total protein (TP) levels as a predictive local biomarker. Subsequently, the dentin-pulp wound was randomly washed with a 2.5% NaOCl or a physiologic saline solution (1:1 allocation), capped with mineral trioxide aggregate, and the tooth was immediately restored with a resin-based composite restoration. Ninety-six patients were included, and 84 individuals could be followed up to treatment failure or clinically confirmed pulp survival after a minimum of 1 y. The entire data were fitted to a Cox proportional hazards model to assess the influence of the observational variables MMP-9/TP and discomfort with the randomized lavage treatment on pulp survival. The Kaplan-Meier pulp survival rates after 1 y were 55% for saline and 89% for NaOCl lavage. The inflammatory state of the pulp tissue as reflected by MMP-9/TP levels and NaOCl lavage had a highly significant ( P

Introduction Hyperphosphatemia is a common complication as chronic kidney disease (CKD) progresses and most patients undergoing dialysis are prescribed oral phosphate binder therapy to control serum phosphate concentrations. Sucroferric oxyhydroxide is an iron-based phosphate binder approved for the treatment of hyperphosphatemia in CKD patients on dialysis. Areas covered This article reviews key safety and effectiveness data for sucroferric oxyhydroxide from both prospective clinical trials and real-world observational studies. Expert opinion Sucroferric oxyhydroxide potently binds dietary phosphate in the gastrointestinal (GI) tract, resulting in effective reduction of serum phosphate concentrations with a relatively low daily pill burden. Data from clinical trials and real-world observational studies show sucroferric oxyhydroxide has a favorable safety and tolerability profile. The most frequent side effects observed with sucroferric oxyhydroxide are GI-related, mainly discolored (black) stools and mild or moderate transient diarrhea, both of which are manageable. There is minimal systemic iron absorption from sucroferric oxyhydroxide, and therefore the drug is associated with a low risk of iron accumulation. Sucroferric oxyhydroxide also displays low potential for drug-drug interactions with other commonly prescribed oral medications. Overall, sucroferric oxyhydroxide offers an effective and well-tolerated treatment option for the management of hyperphosphatemia.

OBJECTIVE To investigate the efficacy and safety of additional S-1 chemotherapy to S-1 plus oxaliplatin (SOX) regimen chemotherapy for Stage III gastric carcinoma (GC) after radical resection. PATIENTS AND METHODS A total of 161 patients who were pathologically diagnosed as Stage III GC after D2 gastrectomy and received SOX regimen adjuvant chemotherapy between January 2012 and April 2016 were included in this retrospective study. SOX regimen postoperative chemotherapy was composed of Oxaliplatin and S-1, administrated every 3 weeks for 8 scheduled courses. After SOX chemotherapy, 76 patients preferred additional chemotherapy with S-1 (the ACT group), while additional S-1 chemotherapy was not given to the other 85 patients (control group). The ACT with S-1 was administrated every 3 weeks for 8 scheduled courses. Treatment was terminated in case of life-threatening adverse events or tumor progression, or patients' demand for termination. Progression-free survival (PFS), overall survival (OS), and adverse events were analyzed. RESULTS ACT group obtained markedly improved 3-year PFS [p = 0.04; hazard ratio (HR) for disease progression, 0.58; 95% confidence interval (CI), 0.34-0.98] and OS than the control group (p = 0.0469; HR for death, 0.56; 95% CI, 0.32-0.99). No chemotherapy-related mortality occurred. Patients of the ACT group suffered more common and severer hand-foot syndrome (HFS) (p = 0.02). CONCLUSIONS Additional S-1 chemotherapy may be helpful for improving the disease progression and survival for patients with Stage III GC after radical resection with an acceptable safety profile.

Background A three-pronged approach to acne treatment—combining an antibiotic, antibacterial, and retinoid—could provide greater efficacy and tolerability than single or dyad treatments, while potentially improving patient compliance and reducing antibiotic resistance. Objectives We aimed to evaluate the efficacy and safety of triple-combination, fixed-dose topical clindamycin phosphate 1.2%/benzoyl peroxide (BPO) 3.1%/adapalene 0.15% (IDP-126) gel for the treatment of acne. Methods In a phase II, double-blind, multicenter, randomized, 12-week study, eligible participants aged ≥ 9 years with moderate-to-severe acne were equally randomized to once-daily IDP-126, vehicle, or one of three component dyad gels: BPO/adapalene; clindamycin phosphate/BPO; or clindamycin phosphate/adapalene. Coprimary endpoints were treatment success at week 12 (participants achieving a ≥ 2-grade reduction from baseline in Evaluator’s Global Severity Score and clear/almost clear skin) and least-squares mean absolute changes from baseline in inflammatory and noninflammatory lesion counts to week 12. Treatment-emergent adverse events and cutaneous safety/tolerability were also assessed. Results A total of 741 participants were enrolled. At week 12, 52.5% of participants achieved treatment success with IDP-126 vs vehicle (8.1%) and dyads (range 27.8–30.5%; P ≤ 0.001, all). IDP-126 also provided significantly greater absolute reductions in inflammatory (29.9) and noninflammatory (35.5) lesions compared with vehicle or dyads (range inflammatory, 19.6–26.8; noninflammatory, 21.8–30.0; P < 0.05, all), corresponding to > 70% reductions with IDP-126. IDP-126 was well tolerated, with most treatment-emergent adverse events of mild-to-moderate severity. Conclusions Once-daily treatment with the novel fixed-dose triple-combination clindamycin phosphate 1.2%/BPO 3.1%/adapalene 0.15% gel demonstrated superior efficacy to vehicle and all three dyad component gels, and was well tolerated over 12 weeks in pediatric, adolescent, and adult participants with moderate-to-severe acne. Clinical Trial Registration ClinicalTrials.gov identifier NCT03170388 (registered 31 May, 2017). Supplementary Information The online version contains supplementary material available at 10.1007/s40257-021-00650-3.

Background: Recent research suggests that a significant number of those who receive advanced treatments for Parkinson’s disease (PD) do not report improvements for some symptoms, which may relate to their pre-treatment expectations. It is important that expectations of treatment are measured and discussed prior to advanced treatment. Objective: The primary aim of this study was to develop a measure of treatment expectations of two advanced-stage treatments in PD, deep brain stimulation (DBS), and Levodopa/Carbidopa Intestinal Gel (LCIG). A secondary aim was to explore potential predictors of treatment expectations. Methods: The questionnaire-based measure was developed by researchers in conjunction with a highly experienced clinician, and evaluated treatment expectations in 189 people aged 46–91 years (M = 71.35, SD = 8.73; 61% male) with idiopathic PD. Results: The overall measure demonstrated excellent internal consistency (α= 0.96). Exploratory factor analysis suggested the scale was unidimensional for both DBS and LCIG. Participant expectations of the two treatments differed significantly, with expectations being higher for DBS. Perceived symptom severity was the strongest predictor of treatment expectations. Conclusion: This scale has potential to inform clinicians about client expectations prior to advanced stage therapy for PD, with a view to the management of these expectations. Further evaluation of the scale is required across different treatment contexts.

BACKGROUND The aim of study was to understand anti-glaucoma fixed dose drug combination use in real-world settings, focussing on drug selection, repeated prescription of the same active ingredient, and administration of fixed dose combinations, thus providing a reference for doctors during prescription and pharmacists during prescription review, ultimately educating patients on medication. METHODS A retrospective, observational, single-centre study was conducted. Outpatient prescriptions for anti-glaucoma eye drops from 01 January to 31 March 2021 were extracted. The prescriptions containing anti-glaucoma fixed dose combinations were analysed, and the rationale for each prescription was reviewed. RESULTS There were 10,947 ophthalmic patients with anti-glaucoma eye drop prescriptions in the study period. Of these, 4002 (36.5%) were prescribed anti-glaucoma fixed dose drug combinations. Approximately 80% of the patients were prescribed brinzolamide/timolol, while about 10% received prostaglandin analogues/timolol eye drops. Less than 40% of prescriptions were for monotherapy with fixed dose combinations. The most commonly duplicated drug class was β-receptor antagonists. An increase in prescribing drugs containing the same ingredient was observed for regimens containing various medicines. CONCLUSION More than 60% of the combinations were used together with other anti-glaucoma drugs. The advantages of these fixed dose combinations in improving patient compliance need to be reassessed in real-word settings. Prescriptions containing duplicated ingredients were common. However, they were not necessarily considered unreasonable because the dosage forms were administered at different times. For prescriptions containing repetitive ingredients, pharmacists should judge the rationale by evaluating the dosing frequency and drug indications and explain the appropriate administration to patients.

Background & Aims Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs. Methods Longitudinal samples from 177 patients enrolled in a phase IIIb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off. Results Of 177 patients, 169 (95.5%) were PI-naive. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs. Conclusion Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates. Lay summary Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations. Clinical trial number NCT03092375 .

Casirivimab/imdevimab (Ronapreve™; REGEN-COV™) is a co-packaged combination of two neutralizing immunoglobulin gamma 1 (IgG1) human monoclonal antibodies (casirivimab and imdevimab) against the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Casirivimab/imdevimab received its first emergency use authorization for the treatment of COVID-19 in November 2020 in the USA, with similar authorizations subsequently granted in various other countries, including India, Canada, and Switzerland. In February 2021, casirivimab/imdevimab was granted a positive scientific opinion in the EU for the treatment of COVID-19. In July 2021, casirivimab/imdevimab received its first approval in Japan for the treatment of mild or moderate COVID-19, followed in August 2021 by its conditional approval for the prophylaxis and treatment of acute COVID-19 infection in the UK. The combination was also granted provisional determination in Australia in August 2021, indicating its eligibility to be considered for provisional registration for COVID-19 treatment and prevention. This article summarizes the milestones in the development of casirivimab/imdevimab leading to these first approvals for COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01620-z.

According to the World Health Organisation, pneumonia and other lower respiratory tract infections are one of the leading causes of death all over the world. Simultaneous treatment of pneumonia with antibacterial drugs and concomitant medicines may result in adverse drug reactions (ADRs). The aim of the study was to analyse ADRs resulting from drug-drug interactions in different empiric antibiotic treatment regimens used for mild community-acquired pneumonia (CAP), taking into account the concomitant symptomatic non-antibacterial treatment and chronic disease treatment. Materials and methods: the authors analysed spontaneous reports in the VigiBase global database (starting from the date the database was created and until 15 February 2021) on ADRs resulting from interactions of medicinal products included in the Russian clinical guidelines for CAP. Results: the authors compiled a list of antibacterial drugs (amoxicillin+clavulanic acid, amoxicillin, ampicillin, azithromycin, clarithromycin, levofloxacin, moxifloxacin, cefotaxime, ceftriaxone, linezolid), as well as lists of medicinal products for symptomatic and concomitant treatment, based on the approved guidelines for management of CAP and frequent comorbid chronic diseases. They searched VigiBase for ADRs that may have resulted from drug-drug interactions involving these medicinal products. Conclusions: the analysis of adverse reactions used for mild CAP treatment demonstrated that the largest number of ADRs were associated with drug-drug interactions involving azithromycin, while the smallest number of ADRs were associated with cefotaxime and ceftriaxone. Further study of drug-drug interactions will help to prevent potential ADRs, identify rational drug combinations, and improve the existing patient management strategies.

BACKGROUND Levodopa-carbidopa intestinal gel (LCIG) is an advanced therapy for patients with Parkinson Disease (PD). Weight loss has been pointed out as an adverse event of LCIG infusion. AIMS OF THE STUDY To compare weight changes between three groups of PD patients: patients treated with LCIG, patients within the first year of subthalamic deep brain stimulation (STN-DBS) and patients treated exclusively with oral treatment during 1 year of follow up. METHODS Patients treated with LCIG were retrospectively matched by age, gender, disease duration and Hoehn and Yahr to patients undergoing STN-DBS and to patients both receiving the standard of care treatment and unwilling advanced therapies (SOC). Clinical features and weight were collected at baseline, and 12 months after introducing the treatment (LCIG and STN-DBS groups) or for one year of treatment (SOC). RESULTS Eighteen patients were included in each group. They had no differences in clinical and demographic features, except for cognitive impairment. There was a mean weight (-5.8kg ±6.8) and BMI (-2.1kg/m2±2.6) reduction in the LCIG group after 12 months, while there was a slight weight loss in the SOC (-1.4kg ±3.1) and a weight increase in the STN-DBS group (5.4kg ±4.7). Differences of weight were statistically different between, LCIG and STN-DBS (P

Background:. Central nervous system (CNS) symptoms after efavirenz (EFV) treatment in people living with human immunodeficiency virus (HIV) could persist and impact their quality of life. We assessed the impact of EFV-based regimen replacement with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF), which is considered an alternative option for subjects who do not tolerate EFV. Most specifically, we assessed the safety and the efficacy of E/C/F/TAF and its effects on the participants’ neuropsychiatric toxicity symptoms in a real-life setting. Methods:. A prospective cohort study was conducted among virologic suppressed HIV-positive participants receiving EFV-based regimens with ongoing CNS toxicity ≥ grade 2. The participants were switched to single-pill combination regimens E/C/F/TAF and followed up for 48 weeks. The neuropsychiatric toxicity symptoms were measured using a CNS side effects questionnaire, as well as the Hospital Anxiety and Depression Scale and the Pittsburgh Sleep Quality Index. The primary outcome measure was the proportion of participants experiencing grade 2 or higher CNS toxicity after EFV switch off at weeks 12, 24, and 48. Secondary endpoints included virologic and immunological responses and the effect on fasting lipids at week 48 after switch. Results:. One hundred ninety-six participants (96.9% men, median age: 37.5 years, median: 3.7 years on prior EFV-containing regimens) were included in the study. Significant improvements in anxiety and sleep disturbance symptoms were observed at 12, 24, and 48 weeks after switching to E/C/F/TAF (P

Objectives: To evaluate the efficacy in reduction of depressive symptoms, and safety and tolerability of second-generation antipsychotics (SGAs) to manage pediatric bipolar depression (PBD). Method...