Healthcare resource utilization and costs among patients with alpha-1 antitrypsin deficiency with liver and/or lung disease: a longitudinal retrospective study in the USA.

Aim: To evaluate all-cause and liver-associated healthcare resource utilization (HCRU) and costs among patients with alpha-1 antitrypsin deficiency (AATD) with liver disease (LD) and/or lung disease (LgD). Materials & methods: This was a retrospective analysis of linked administrative claims data from the IQVIA PharMetrics® Plus and the IQVIA Ambulatory Electronic Medical Records (AEMR) databases from 1 July 2021 to 31 January 2022. Patients with AATD in the IQVIA PharMetrics Plus database were included with ≥1 inpatient or ≥2 outpatient medical claims ≥90 days apart with a diagnosis of AATD, or with records indicating a protease inhibitor (Pi)*ZZ/Pi*MZ genotype in the IQVIA AEMR database with linkage to IQVIA PharMetrics Plus. For a patient's identified continuous enrollment period, patient time was assigned to health states based on the initial encounter with an LD/LgD diagnosis. A unique index date was defined for each health state, and HCRU and costs were calculated per person-year (PPY). Results: Overall, 5136 adult and pediatric patients from the IQVIA PharMetrics Plus and IQVIA AEMR databases were analyzed. All-cause and liver-associated HCRU and costs were substantially higher following onset of LD/LgD. All-cause cost PPY ranged from US $11,877 in the absence of either LD/LgD to US $74,015 in the presence of both LD and LgD. Among liver transplant recipients in the AATD with LD health state, liver-associated total costs PPY were US $87,329 1-year pre-transplantation and US $461,752 1-year post-transplantation. In the AATD with LgD and AATD with LD and LgD health states, patients who received augmentation therapy were associated with higher all-cause total costs PPY and lower liver-associated total costs PPY than their counterparts who did not receive augmentation therapy. Conclusion: Patients with AATD had increased HCRU and healthcare costs in the presence of LD and/or LgD. HCRU and healthcare costs were highest in the AATD with LD and LgD health state.

Clinical and Cost Benefits of Anti-Obesity Medication for US Veterans Participating in the MOVE! Weight Management Program.

Abstract This study investigated the clinical and economic impact of anti-obesity medications (AOMs; orlistat, liraglutide, phentermine/topiramate extended-release [ER], naltrexone ER/bupropion ER) among United States Veterans with obesity participating in Motivating Overweight/Obese Veterans Everywhere! (MOVE!), a government-initiated weight management program. The study population was identified from electronic medical records of the Veterans Health Administration (2010-2020). Clinical indices of obesity and health care resource utilization and costs were evaluated at 6, 12, and 24 months after the initial dispensing of an AOM in the AOM+MOVE! cohort (N = 3732, mean age 57 years, 79% male) or on the corresponding date of an inpatient or outpatient encounter in the MOVE! cohort (N = 7883, mean age 58 years, 81% male). At 6 months postindex, the AOM+MOVE! cohort had better cardiometabolic indices (eg, systolic blood pressure, diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, hemoglobin A1c) than the MOVE! cohort, with the trends persisting at 12 and 24 months. The AOM+MOVE! cohort was significantly more likely than the MOVE! cohort to have weight decreases of 5%-10%, 10%-15%, and >15% and lower body mass index at 6, 12, and 24 months. The AOM+MOVE! cohort also had fewer inpatient and emergency department visits than the MOVE! cohort, which was associated with lower mean total medical costs including inpatient costs. These results suggest that combining AOM treatment with the MOVE! program could yield long-term cost savings for the Veterans Affairs network and meaningful clinical improvements for Veterans with obesity.

Characteristics, Treatment Patterns, and Clinical Outcomes of Chronic Hepatitis B Across 3 Continents: Retrospective Database Study.

INTRODUCTION: The prevalence of chronic hepatitis B virus (HBV) infection is high in many countries; however, robust, real-world epidemiological data are lacking. This study describes the prevalence, characteristics, treatment patterns, and long-term clinical outcomes of patients with chronic HBV infection in the US, Germany, and Taiwan. METHODS: This was a retrospective cohort analysis of three healthcare/insurance claims databases. Individuals were identified as patients with chronic HBV infection if their records contained HBV diagnostic codes from 1 January 2010 to 31 December 2012 (Germany and Taiwan) or 1 January 2013 (USA). Included patients were indexed on 1 January 2013. Patients' demographics, clinical characteristics, and healthcare utilisation were described. Treatment patterns and long-term clinical outcomes over follow-up (to 31 December 2016 or loss to follow-up) were estimated. RESULTS: The prevalence of chronic HBV infection was 0.10%, 0.17%, and 2.39% in the US, Germany, and Taiwan respectively. Prevalence was very low in children, increased rapidly in adulthood, and peaked in 50- < 65 year olds before declining in the elderly. More US (16.6%) and German (15.4%) patients were HIV ± HCV coinfected than in Taiwan (4.1%). Baseline clinical characteristics and healthcare utilisation were broadly similar between countries. In total, 19.2%, 11.1%, and 5.9% of non-coinfected adult patients received treatment at index in the US, Germany, and Taiwan, respectively; most frequently with nucleos(t)ide analogue monotherapy (94.4%, 97.2%, 99.8% of treated patients, respectively) and rarely with interferons (0.27%, 1.63%, and 0.06%, respectively). Untreated Taiwanese patients were more likely to remain untreated than elsewhere, and treated Taiwanese patients were less likely to persist with therapy. Generally, the cumulative incidence of long-term clinical outcomes was lowest in Germany. CONCLUSION: This study provides a contemporary, real-world, intercontinental snapshot of chronic HBV infection. Long-term sequelae occurred in all populations, and treatment levels were low, suggesting an unmet need for (or access to) effective treatments.

Chronic obstructive pulmonary disease is associated with an increased risk of herpes zoster: A retrospective United States claims database analysis.

Chronic obstructive pulmonary disease (COPD) has been reported as a potential risk factor for developing herpes zoster (HZ). We aimed at comparing incidence rates of HZ between people with versus without COPD in the US. This retrospective cohort study used data from Optum's de-identified Clinformatics Data Mart database from 1/1/2013 through 12/31/2018. We identified two cohorts of people ≥40 years without prior HZ, HZ vaccination, postherpetic neuralgia (PHN) or HZ ophthalmicus: those with (COPD+) and those without (COPD-) a COPD diagnosis. Adjusted incidence rate ratios (aIRRs) of HZ and PHN were calculated using generalized linear models, controlling for the propensity score of being diagnosed with COPD and relevant demographic and clinical characteristics. People in the COPD+ cohort (n = 161 970) were considerably older, had more comorbidities and were more likely to use corticosteroids than those in the COPD- cohort (n = 9 643 522). The incidence rate of HZ was 5.7-fold higher in the COPD+ versus COPD- cohorts (13.0 vs. 2.3 per 1000 person-years [PY]; aIRR, 2.77; 95% confidence interval [CI], 2.69 to 2.85; P < 0.001). The unadjusted incidence rate of PHN was 1.7-fold higher in the COPD+/HZ+ versus COPD-/HZ+ cohort (64.8 vs. 37.1 per 1000 PY), but not after adjustment (aIRR, 1.07; 95% CI, 0.79 to 1.45). HZ and PHN incidence rates increased with age. After adjustment, COPD+ adults had a 2.8-fold increased risk of developing HZ. These results may help to increase awareness about potential risk factors for HZ and highlight the need for vaccination among those at increased risk.

The acute effects of azithromycin use on cardiovascular mortality as compared with amoxicillin-clavulanate in US Veterans.

PURPOSE: Azithromycin is a common first-line antibiotic for respiratory infection; however, there is conflicting evidence regarding risk of cardiovascular death. We assessed cardiovascular and noncardiovascular mortality associated with azithromycin versus amoxicillin-clavulanate among US Veterans treated for nonear-nose-throat respiratory infection ("respiratory") or ear-nose-throat infection indication. METHODS: Electronic health record data from the US Veterans Health Administration database were used to identify Veterans (30-74 years) with outpatient dispensings of oral azithromycin versus amoxicillin-clavulanate for respiratory or ear-nose-throat infection (January 01, 2000-December 31, 2014). Outcomes assessed were risk of cardiovascular death and noncardiovascular death within 1-5 and 6-10 days postdispensing. Inverse probability of treatment-weighted proportional hazards models and binomial regression models were used to estimate hazard ratios (HRs) and compute risk differences (RD) per million courses of therapy. Cardiac death (subset of cardiovascular death) was assessed in sensitivity analyses. RESULTS: There were 629 345 azithromycin and 168 429 amoxicillin-clavulanate dispensings for respiratory indications, 143 783 azithromycin, and 203 142 amoxicillin-clavulanate dispensings for ear-nose-throat indications. For respiratory indications, azithromycin was not associated with a significantly different risk of cardiovascular death versus amoxicillin-clavulanate within 1-5 days postdispensing (HR [95% confidence interval (CI)]: 1.12 [0.63, 2.00]; RD [95% CI]: 11 [-43, 64] deaths/million courses of therapy). No elevated risk for azithromycin was found for ear-nose-throat indications. Pooled results for both indications via meta-analysis showed no association between antibiotics and cardiovascular mortality. There was no significant difference in risk of noncardiovascular or cardiac death between antibiotics postdispensing. CONCLUSION: Azithromycin was not associated with elevated risk of cardiovascular or noncardiovascular death versus amoxicillin-clavulanate among US Veterans.

Free combination of dutasteride plus tamsulosin for the treatment of benign prostatic hyperplasia in South Korea: analysis of drug utilization and adverse events using the National Health Insurance Review and Assessment Service database.

OBJECTIVE: To assess the use and safety of free combination therapy (dutasteride and tamsulosin), dutasteride monotherapy, or tamsulosin monotherapy in patients with benign prostatic hyperplasia (BPH). METHODS: This non-interventional retrospective cohort study used claims data from the Korea Health Insurance Review and Assessment-National Patient Sample database. Patients with BPH ≥ 40 years of age receiving combination therapy (dutasteride 0.5 mg and tamsulosin 0.4 mg daily) or dutasteride 0.5 mg, or tamsulosin 0.4 mg daily dose between 2012 and 2017 were included. The frequency, duration of treatment and risk of any adverse event (AE) or serious AE (SAE) was compared for combination therapy versus each monotherapy using non-inferiority testing. RESULTS: Of 14,755 eligible patients, 1529 (10.4%) received combination therapy, 6660 (45.1%) dutasteride monotherapy, and 6566 (44.5%) tamsulosin monotherapy. The proportion of patients treated with combination therapy exceeded the pre-specified 3% threshold for 'frequent' use. Safety results indicated a similar risk of any AE and SAE irrespective of treatment group. The adjusted relative risk for any AE over the treatment observation period comparing combination therapy with dutasteride monotherapy was 1.07 (95% confidence interval [CI] 1.03, 1.12), and with tamsulosin monotherapy was 0.98 (95% CI 0.95, 1.02) demonstrating non-inferiority. The adjusted relative risk for any SAE was 1.07 (95% CI 0.66, 1.74) and 0.90 (95% CI 0.56, 1.45), compared with dutasteride and tamsulosin monotherapy, respectively. Although the SAE results did not statistically demonstrate non-inferiority of combination therapy based on pre-specified margins, the 95% CI for the risk ratio estimates included the null with a lower limit below the non-inferiority margins, indicating no meaningful differences in SAE risk between groups. Absolute SAE risks were low. CONCLUSION: Combination therapy with dutasteride and tamsulosin is frequently used in real-world practice in South Korea for treatment of BPH and demonstrates a safety profile similar to either monotherapy.

Fear of falling and related factors during everyday activities in patients with chronic stroke.

The aim of this study was to examine the impact of physical function, anxiety, and depression on the fear of falling associated with everyday activities in patients with stroke. This was a cross-sectional descriptive survey. Convenience sampling was used to select 127 patients with stroke who were undergoing rehabilitative therapy at a single rehabilitation hospital in South Korea. Fear of falling, anxiety, and depression were assessed using structured questionnaires. Physical parameters, including lower extremity function, functional mobility, balance ability, and lower extremity muscle strength, were measured using objective methods. A multiple regression analysis was used to identify the predictors of fear of falling. Female patients had a higher fear of falling associated with walking outdoors compared to male patients. Lower extremity strength was the only significant predictor of fear of falling when adjusting for age, sex, Mini Mental State Examination scores, and fall experience. Lower extremity strength was identified as the most important factor affecting the fear of falling associated with everyday activities in patients with stroke. Preventing muscle weakness in the lower extremities and providing education and support to improve patients' self-efficacy in outdoor activities are strategies that can be used to reduce the fear of falling in patients with stroke.

Transition Metal-Free, Methoxide-Catalyzed Synthesis of Pyridoindolones.

A simple transition metal-free strategy for the synthesis of pyrido[1,2-a]indolone derivatives has been devised through sodium methoxide-catalyzed intramolecular cyclization of 2-alkenylated N-pyrimidyl indoles. The reactions involved a Smiles rearrangement/cyclization cascade, which resulted in a new series of N-fused indoles, potentially applicable skeletons in medicinal chemistry. This reaction presents simple eco-friendly reaction conditions, a high atom- and cost-economy, a short reaction time, and a broad range of substrate scope with high reaction efficiency.

Retrospective analysis of adherence to HIV treatment and healthcare utilization in a commercially insured population.

AIMS: Single-tablet regimens (STRs) can improve antiretroviral therapy (ART) adherence; however, the relationship between long-term adherence and patient healthcare resource utilization (HRU) is unclear. The objective of this study was to assess long-term ART adherence among people living with HIV (PLHIV) using STRs and multi-tablet regimens (MTRs) and compare HRU over time by adherence. MATERIALS AND METHODS: This retrospective study analyzed medical and pharmacy claims (Optum Clinformatics Data Mart Database). Included PLHIV were aged ≥18 years, had ≥1 medical claim with an HIV diagnosis, and had pharmacy claims for a complete STR or MTR. Adherence was analyzed as the proportion of days covered (PDC), stratified as ≥95%, very high; 90-95%, high; 80-90%, moderate; <80%, low. Cumulative all-cause and HIV-related HRU were calculated across 4 years. Among PLHIV with ≥4-year follow-up, HRU was assessed by adherence. RESULTS: Among 15,153 PLHIV included, 63% achieved PDC ≥90% during Year 1. Among the subgroup of PLHIV with ≥4-year follow-up (N = 3,818), the proportion maintaining PDC ≥90% fell from 67% in Year 1 to 54% by Year 4. The difference from Years 1 to 4 in the proportion of PLHIV with PDC ≥90% was 13% and 17% in the STR and MTR groups, respectively. Cumulative HRU across the 4-year follow-up was higher in PLHIV with low vs high adherence (27% with low adherence had ≥1 emergency room visit vs 17% for very high, p < .0001; 15% with low adherence had ≥1 inpatient stay vs 7% for very high, p < .0001). CONCLUSIONS: ART adherence showed room for improvement, particularly over the long term. PLHIV receiving STRs exhibited higher adherence vs those receiving MTRs; this difference increased over time. The proportion of PLHIV with higher HRU was significantly higher among those with lower adherence and became greater over time. Interventions and alternative therapies to improve adherence among PLHIV should be explored.

Increased Health Care Resource Utilization and Costs Associated with Herpes Zoster Among Patients Aged ≥50 Years with Chronic Obstructive Pulmonary Disease in the United States.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are potentially at increased risk of herpes zoster (HZ). Little is known about the impact of an HZ episode on health care resource utilization (HRU) and costs among patients with COPD. METHODS: This retrospective cohort study of individuals aged ≥50 years in the United States (US) used administrative claims data from Optum's de-identified Clinformatics Data Mart Database for commercially insured and Medicare Advantage members (2013-2018). Two cohorts of patients with COPD, with HZ (COPD+/HZ+) and without HZ (COPD+/HZ-), were identified. All-cause and COPD-related HRU rates and costs (2018 US dollars) were compared between cohorts for up to 12 months of follow-up. Comparisons were controlled for baseline differences through propensity score adjustment. RESULTS: A total of 3415 COPD+/HZ+ and 35,360 COPD+/HZ- patients (mean ages 73.2 ± 9.0 and 72.4 ± 9.4 years, respectively) were identified. Patients in the COPD+/HZ+ versus COPD+/HZ- cohort had increased use of all-cause (adjusted incidence rate ratio [aIRR] 1.17; 95% confidence interval [CI] 1.14, 1.21) and COPD-related (aIRR 1.27; 95% CI 1.21, 1.34) medical services (both P<0.001) and higher mean total all-cause ($4140 versus $3749 per person per month [PPPM]; adjusted cost difference +$313 PPPM) and COPD-related ($1541 versus $1231 PPPM; +$152 PPPM) costs (both P<0.004) in the year after HZ. CONCLUSIONS: HRU and cost burden is higher in patients with COPD with vs without HZ. These results could help to estimate the potential cost benefits of HZ vaccination among patients with COPD.

CoIII-Catalyzed C-H Alkenylation and Allylation with Cyclopropenes via Sequential C-H/C-C Bond Activation.

An atom-economical strategy for the C-H alkenylation and C-H allylation of arenes by employing cyclopropenes as versatile alkenylating and allylating reagents is reported, catalyzed by cobalt. The Co-catalyzed C-H alkenylation process involves sequential C-H and C-C bond cleavage. Under the optimized conditions, broad-ranging alkenylated (hetero)arenes were synthesized with complete (E)-stereoselectivity (up to 91%). The consecutive C-H allylation proved viable under basic conditions via double-bond migration of the initially generated alkenyl (hetero)arenes, thus leading to allylated (hetero)arenes with high stereoselectivity of olefin (E/Z ratio = 91:9 to 100:0).

The Relationships Between Oncology Nurses' Attitudes Toward a Dignified Death, Compassion Competence, Resilience, and Occupational Stress in South Korea.

OBJECTIVES: In recent years, South Korea has become more concerned about a dignified death and the 'well-dying' law has been enacted. Oncology nurses' perceptions of death are crucial in maintaining dying patients' sense of dignity; fostering their physical, mental, and spiritual quality of life; and ensuring that they die a comfortable death. This study accordingly examined the relationships between attitudes towards a dignified death, compassion competence, resilience, and occupational stress to provide basic data to promote better attitudes towards death among oncology nurses in South Korea. DATA SOURCES: This study, conducted between 2 to 31 January 2018, adopted a descriptive cross-sectional design. Oncology nurses (N = 329) participated, and the differences in their attitudes towards a dignified death correlating to their demographic and work-related characteristics were analysed using t-tests and analyses of variance. Pearson's correlations were used to examine the relationships between nurses' attitudes towards a dignified death, compassion competence, resilience, and occupational stress. CONCLUSION: Participants' attitudes towards a dignified death were weaker than those of the general population but stronger than those of non-oncology nurses. Attitudes towards a dignified death were significantly correlated with compassion competence and resilience-traits that appear to enable nurses' efficient response to various stressful situations. IMPLICATIONS FOR NURSING PRACTICE: Educational programmes should promote nurses' compassion competence and resilience. Nurses should receive death-related education to reduce the stress that arises from providing end-of-life care and enhance their attitudes towards a dignified death.

Veterans Affairs Prostate Cancer Treatment Sequencing (VAPCaTS): A Real-World Evidence Study of Men with Metastatic Prostate Cancer.

INTRODUCTION: Limited real-world data are available on treatment sequences for patients with metastatic hormone-sensitive prostate cancer treated with androgen deprivation therapy plus docetaxel or abiraterone who progress to castrate resistance. METHODS: Veterans Health Affairs electronic medical records were used to analyze 240 men treated for metastatic hormone-sensitive prostate cancer with androgen deprivation therapy plus either docetaxel ("docetaxel cohort," 208 patients, selected to be overrepresented, July 2014 to August 2018) or abiraterone ("abiraterone cohort," 32 patients, December 2016 to September 2018) who received at least 1 treatment after progressing to castrate resistance. RESULTS: For docetaxel and abiraterone cohorts, respectively, mean age at androgen deprivation therapy initiation was 65 and 72 years, and median followup was 2.2 and 1.4 years. Overall, the maximum number of metastatic castrate resistant prostate cancer treatment lines was 6; 106 patients (44%) had 1, 71 (30%) had 2, and 63 (26%) had 3 or more lines. Most patients received an androgen receptor targeted agent for initial metastatic castrate resistant prostate cancer treatment (94% vs 78% in docetaxel vs abiraterone cohort). Androgen receptor targeted agents were given consecutively to 62% of the docetaxel cohort receiving second line therapy, and to 78% of the abiraterone cohort. Across all metastatic castrate resistant prostate cancer treatment lines 72 (30%) received a taxane (47 docetaxel and 41 cabazitaxel). CONCLUSIONS: Most patients received androgen receptor targeted agents as first metastatic castrate resistant prostate cancer treatment regardless of initial metastatic hormone-sensitive treatment. Moreover, a large proportion were treated with consecutive androgen receptor targeted agents. Given recent evidence suggesting poorer outcomes with this treatment in some patients, longer followup is needed to assess the association between treatment sequence and optimal outcomes.

Potentiation of rifampin activity in a mouse model of tuberculosis by activation of host transcription factor EB.

Efforts at host-directed therapy of tuberculosis have produced little control of the disease in experimental animals to date. This is not surprising, given that few specific host targets have been validated, and reciprocally, many of the compounds tested potentially impact multiple targets with both beneficial and detrimental consequences. This puts a premium on identifying appropriate molecular targets and subjecting them to more selective modulation. We discovered an aminopyrimidine small molecule, 2062, that had no direct antimycobacterial activity, but synergized with rifampin to reduce bacterial burden in Mtb infected macrophages and mice and also dampened lung immunopathology. We used 2062 and its inactive congeners as tool compounds to identify host targets. By biochemical, pharmacologic, transcriptomic and genetic approaches, we found that 2062's beneficial effects on Mtb control and clearance in macrophages and in mice are associated with activation of transcription factor EB via an organellar stress response. 2062-dependent TFEB activation led to improved autophagy, lysosomal acidification and lysosomal degradation, promoting bacterial clearance in macrophages. Deletion of TFEB resulted in the loss of IFNγ-dependent control of Mtb replication in macrophages. 2062 also targeted multiple kinases, such as PIKfyve, VPS34, JAKs and Tyk2, whose inhibition likely limited 2062's efficacy in vivo. These findings support a search for selective activators of TFEB for HDT of TB.

Racial and Ethnic Disparities in Postcardiac Arrest Targeted Temperature Management Outcomes.

OBJECTIVES: To evaluate racial and ethnic disparities in postcardiac arrest outcomes in patients undergoing targeted temperature management. DESIGN: Retrospective study. SETTING: ICUs in a single tertiary care hospital. PATIENTS: Three-hundred sixty-seven patients undergoing postcardiac arrest targeted temperature management, including continuous electroencephalogram monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical variables examined in our clinical cohort included race/ethnicity, age, time to return of spontaneous circulation, cardiac rhythm at time of arrest, insurance status, Charlson Comorbidity Index, and time to withdrawal of life-sustaining therapy. CT at admission and continuous electroencephalogram monitoring during the first 24 hours were used as markers of early injury. Outcome was assessed as good (Cerebral Performance Category 1-2) versus poor (Cerebral Performance Category 3-5) at hospital discharge. White non-Hispanic ("White") patients were more likely to have good outcomes than white Hispanic/nonwhite ("Non-white") patients (34.4 vs 21.7%; p = 0.015). In a multivariate model that included age, time to return of spontaneous circulation, initial rhythm, combined electroencephalogram/CT findings, Charlson Comorbidity Index, and insurance status, race/ethnicity was still independently associated with poor outcome (odds ratio, 3.32; p = 0.003). Comorbidities were lower in white patients but did not fully explain outcomes differences. Nonwhite patients were more likely to exhibit signs of early severe anoxic changes on CT or electroencephalogram, higher creatinine levels and receive dialysis, but had longer duration to withdrawal of lifesustaining therapy. There was no significant difference in catheterizations or MRI scans. Subgroup analysis performed with patients without early electroencephalogram or CT changes still revealed better outcome in white patients. CONCLUSIONS: Racial/ethnic disparity in outcome persists despite a strictly protocoled targeted temperature management. Nonwhite patients are more likely to arrive with more severe anoxic brain injury, but this does not account for all the disparity.

Cp*Co(III)-Catalyzed γ-Selective C-H Allylation/Hydroamination Cascade for the Synthesis of Dihydroisoquinolines.

A Cp*Co(III)-catalyzed γ-selective C-H allylation/hydroamination cascade toward the synthesis of 3,4-dihydroisoquinolines (DHIQs) has been successfully developed, starting from NH ketimines and allyl carbonates. Notably, highly efficient and γ-selective C-H allylations were accomplished using γ-substituted allyl reagents, thus overcoming the issues of poor α/γ selectivity and low reactivity of previous transition metal-catalyzed C-H allylations. The stereochemistry of allyl carbonates was a crucial factor, and synthesis of the DHIQs was achieved using (Z)-allyl carbonates.

Clarithromycin use and the risk of mortality and cardiovascular events: A systematic review and meta-analysis.

BACKGROUND: Although studies reported increased cardiovascular (CV) risks in patients treated with macrolides, the risks remain controversial among clarithromycin (CLR) users. We aimed to summarize the association between CLR use and the risks of mortality and CV events. METHODS: We searched PubMed, EMBASE, Web of Science, and the Cochrane Library for randomized controlled trials (RCTs) and observational studies with population exposed to CLR published until December 31st, 2018. These studies reported either all-cause mortality (primary outcome) or CV adverse events (secondary outcomes) based on multivariate models. Effect measures were synthesized by study design and follow-up duration (long-term, ≥ 1 year; short-term, ≤ 3 months; and immediate, ≤ 2 weeks). This study has been registered on PROSPERO (ID: CRD42018089605). RESULTS: This meta-analysis included 13 studies (3 RCTs and 10 observational studies) and 8,351,815 subjects (1,124,672 cases and 7,227,143 controls). Overall, CLR use was not associated with increased long-term all-cause mortality (pooled rate ratio RR = 1.09, 95% CI = 0.91-1.32), either among patients with or without comorbidities of cardiovascular diseases. Comparing CLR users to placebo, there is no additional risks of cardiac mortality (pooled RR = 1.03, 95% CI = 0.53-2.01), acute myocardial infarction (pooled RR = 1.29, 95% CI = 0.98-1.68), and arrhythmia (pooled RR = 0.90, 95% CI = 0.62-1.32). CONCLUSIONS: Our findings suggested no significant association between CLR use and subsequent long-term all-cause mortality, regardless having comorbidity of cardiovascular diseases or not. Further RCTs investigating the short-term CV risks of CLR use compared to alternative antibiotics are warranted, particularly in high-risk populations.

Factors Influencing Exposure to Secondhand Smoke: Passive Inhalation in Student Nurses.

OBJECTIVES: To examine the factors affecting passive exposure to secondhand smoke (SHS) in non-smoking student nurses. METHODS: A cross-sectional study was performed in 196 college students who had not smoked cigarettes in the past 12 months. Urinary cotinine levels were examined to identify exposure to SHS, and social factors were identified that influenced exposure to SHS, including requests that smokers extinguish cigarettes. Logistic regression analysis was used to predict the factors influencing SHS. RESULTS: Urinary cotinine measurements showed that 32 students (16.3%) were exposed to SHS. Risk factors that increased exposure to SHS affected 80 students (40.8%) in the previous 7 days. Students who were exposed to SHS were 4.45-times more likely to have increased urinary cotinine levels than those who were not exposed. Students who asked others to extinguish their cigarettes were 0.34 times less likely to test positive than those who did not. CONCLUSION: Urinary cotinine was a useful biomarker for identifying exposure to SHS, with respect to the influence of demographic, health-related, and smoking-related factors. In non-smoking nursing students, avoiding exposure to SHS was attributed to self-assertive behavior by requesting smokers to extinguish cigarettes.

Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy.

OBJECTIVE: To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency. METHODS: Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1-3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without. RESULTS: AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05). CONCLUSION: AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.

Growing older with drug-resistant epilepsy: cognitive and psychosocial outcomes.

We aimed to investigate the cognitive and psychosocial outcomes of patients older than 50 with drug-resistant temporal lobe epilepsy as compared to a younger cohort. One hundred and thirty-one patients with temporal lobe epilepsy (47% age ≥ 50) who underwent comprehensive neuropsychological testing were retrospectively identified. A comparison of percentage of Z scores < - 1.5 between the older and younger cohort on Trail Making Tests A and B, Boston Naming Test, Rey Auditory Verbal Learning Test (RAVLT) delayed recall, and Rey-Osterrieth complex figure test delayed recall was performed as well as the presence of disability due to epilepsy and depression scores. Grading of white matter hyperintensities on MRI was also performed. Older patients with epilepsy were more likely to score Z < - 1.5 on the RAVLT (54.1 vs 32.8%) and were more likely to be on disability due to their seizures (23.0 vs 5.7%). A higher grade of white matter hyperintensities correlated with worse performance on Trail Making Test A, while a higher number of anti-epileptic drugs (AEDs) correlated with worse performance on Trail Making Test B regardless of age. The results of this study reveal that older patients with drug-resistant epilepsy are a vulnerable population with an impaired cognitive profile. In addition, limiting the number of AEDs and addressing markers of small vessel disease should also be prioritized by clinicians.