Search

Traumatic dental injuries result in damage to many dental and periradicular structures. They can be conservatively managed depending on the extent of the injury. Maxillary central incisors are most commonly involved in traumatic dental injuries mainly because of their anterior and protrusive positioning. The treatment of immature permanent teeth with severe internal resorption poses a lot of challenges to the clinician. The objective of the present article is to report successful management of traumatised maxillary central incisor with incomplete root formation and severe internal resorption in a 10-year-old boy using triple antibiotic paste, mineral trioxide aggregate and fibre-reinforced composite.

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.

BACKGROUND The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults. METHODS The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole. RESULTS As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation. CONCLUSIONS These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.

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.

This study aimed to evaluate the pulpal responses of monkey's pulp after direct pulp capping (DPC) with the novel mineral trioxide aggregate containing phosphorylated pullulan-based material (MTAPPL). Seventy-two teeth were randomly divided into four groups: MTAPPL; Nex-Cem MTA (NX); TheraCal LC (TH); and Dycal (DY). Histopathological changes in the pulps were observed at days 3, 7 and 70. On day 3, mild inflammatory responses were observed in the MTAPPL, no to moderate inflammatory responses in the TH, whereas moderate inflammatory responses in the NX and DY. No mineralized tissue formation (MTF) was observed in all groups. On day 7, no or mild inflammatory responses were observed in all groups. Initial MTF was observed except for DY. No inflammation with complete MTF including presence of odontoblast-like cells was observed in the MTAPPL, NX and TH groups at day 70. These findings indicate that MTAPPL could be an efficient DPC material.

Several therapeutic regimens for COVID-19 have been studied, such as combination antiviral therapies. We aimed to compare outcome of two types of combination therapies atazanavir/ritonavir (ATV/r) or lopinavir/ritonavir (LPV/r) plus hydroxychloroquine among COVID-19 patients. 108 patients with moderate and severe forms of COVID-19 were divided into two groups (each group 54 patients). One group received ATV/r plus hydroxychloroquine, and the other group received hydroxychloroquine plus LPV/r. Then, both groups were evaluated and compared for clinical symptoms, recovery rates, and complications of treatment regimens. Our findings showed a significant increase in bilirubin in ATV/r-receiving group compared to LPV/r receivers. There was also a significant increase in arrhythmias in the LPV/r group compared to the ATV/r group during treatment. Other findings including length of hospital stay, outcome, and treatment complications were not statistically significant. There is no significant difference between protease inhibitor drugs including ATV/r and LPV/r in the treatment of COVID-19 regarding clinical outcomes. However, some side effects such as hyperbilirubinemia and arrhythmia were significantly different by application of atazanavir or lopinavir.

Portland cement (PC) is used in challenging endodontic situations in which preserving the health and functionality of pulp tissue is of considerable importance. PC forms the main component of mineral trioxide aggregate (MTA) and demonstrates similar desirable properties as an orthograde or retrograde filling material. PC is able to protect pulp against bacterial infiltration, induce reparative dentinogenesis, and form dentin bridge during the pulp healing process. The biocompatibility, bioactivity, and physical properties of PC have been investigated in vitro and in animal models, as well as in some limited clinical trials. This paper reviews Portland cement’s structure and its characteristics and reaction in various environments and eventually accentuates the present concerns with this material. This bioactive endodontic cement has shown promising success rates compared to MTA; however, considerable modifications are required in order to improve its characteristics and expand its application scope as a root repair material. Hence, the extensive chemical modifications incorporated into PC composition to facilitate preparation and handling procedures are discussed. It is still important to further address the applicability, reliability, and cost-effectiveness of PC before transferring into day-to-day clinical practice.

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.

PURPOSE We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone. PATIENTS AND METHODS Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, –10% for the difference in the overall CR rate). RESULTS Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, –2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% ( P < .001) and 0.3% versus 3.6% ( P < .001), respectively. CONCLUSION FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.

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.