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Despite use of 23-valent pneumococcal polysaccharide vaccine (PPV23) in England, disease burden among at-risk adults remains high. We evaluated the public health and budgetary impact of 20-valent pneumococcal conjugate vaccine (PCV20) compared to the current adult pneumococcal vaccination program.Five-year outcomes and costs of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP) among adults aged 65-99 years and adults aged 18-64 years with underlying conditions in England were projected using a deterministic cohort model. Hypothetical vaccination with PCV20 versus PPV23 was compared from the National Health Service (NHS) perspective.Replacing PPV23 with PCV20 would prevent 785 IPD hospitalizations, 11,751 CAP hospitalizations, and 1,414 deaths over 5 years, and would reduce medical care costs by £48.5 M. With vaccination costs higher by £107.2 M, projected net budgetary impact is £58.7 M. The budgetary impact would be greatest in year 1 (£26.3 M), and would decrease over time (to £1.6 M by year 5). The average budget increase (£11.7 M/year) represents0.01% of the Department of Health and Social Care total budget and3% of the vaccine budget.Use of PCV20 among adults currently eligible for PPV23 in England would substantially reduce the burden of pneumococcal disease, with modest budgetary impact.

The addition of pneumococcal conjugate vaccines (PCVs) to the United States (US) national immunization program led to significant reductions in incidence, mortality, and associated sequelae caused by pneumococcal disease (PD) in children and adults through direct and indirect protection. However, there remains clinical and economic burden due to PD caused by serotypes not included in the current 13-valent PCV (PCV13) formulation. To address this unmet need, 15-valent PCV (PCV15) and 20-valent PCV (PCV20), containing additional serotypes to PCV13, were recently approved in the US for adults and are anticipated for pediatrics in the near future. The study objective was to estimate the annual number of cases, deaths, and economic burden of PD due to serotypes included in PCV13, PCV15, and PCV20 for both US pediatric and adult populations. An Excel-based model was developed to calculate clinical and economic outcomes using published age-group specific serotype coverage; incidence of invasive PD, community-acquired pneumonia, and acute otitis media; case fatality rates; and disease-related costs. The results showed that across all age groups, the estimated annual PD cases and associated deaths covered by PCV13 serotypes were 914,199 and 4320, respectively. Compared with PCV13 serotypes, the additional 2 and 7 serotypes covered by PCV15 and PCV20 were attributed with 550,475 and 991,220 annual PD cases, as well as 1425 and 3226 annual deaths, respectively. This clinical burden translates into considerable economic costs ranging from $903 to $1,928 million USD that could be potentially addressed by PCV15 and PCV20. The additional serotypes included in PCV20 contribute substantially to the clinical and economic PD burden in the US pediatric and adult populations. Despite the success of the PCV13 pediatric national immunization program and increased adult uptake of PCV13 and 23-valent polysaccharide vaccine, broader PCV serotype coverage is needed across all ages to further reduce pneumococcal disease burden.

Despite the current pneumococcal vaccination program in England for older adults and adults with underlying conditions, disease burden remains high. We evaluated cost-effectiveness of 20-valent pneumococcal conjugate vaccine (PCV20) compared to current pneumococcal recommendations for adults in England.Lifetime outcomes/costs of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP) among adults aged 65-99 years and adults aged 18-64 years with underlying conditions in England were projected using a deterministic cohort model. Vaccination with PCV20 was compared with 23-valent pneumococcal polysaccharide vaccine (PPV23) from the National Health Service perspective.PCV20 was cost saving compared with PPV23 in base case and most sensitivity analyses. In the base case, replacing PPV23 with PCV20 prevented 7,789 and 140,046 cases of IPD and hospitalized CAP, respectively, and 22,199 associated deaths, resulting in incremental gain of 91,375 quality-adjusted life-years (QALYs) and incremental savings of £160M. In probabilistic sensitivity analyses, PCV20 (vs. PPV23) was cost saving in 85% of simulations; incremental cost per QALY was below £30,000 in 99% of simulations.PCV20 vaccination in adults aged 65-99 years and those aged 18-64 years with underlying comorbidities in England is expected to prevent more hospitalizations, save more lives, and yield lower overall costs than current recommendations for PPV23.

Background While much is known about the cost of community-acquired pneumonia (CAP) during the acute phase of illness, little is known about the potential attributable cost of CAP thereafter. Objective The aim of this study was to assess long-term attributable costs associated with CAP among adults in US clinical practice. Methods A retrospective matched cohort design and data from a US private healthcare claims repository were employed. In each month during the study period (2011–2016), adults who were hospitalized for CAP in that month (‘CAP patients’) were matched (1:1, without replacement) on demographic, clinical, and healthcare profiles to adults who did not develop CAP in that month (‘comparison patients’). All-cause healthcare expenditures were tallied for the qualifying CAP hospitalization and during the 30-day period post-discharge (collectively, ‘acute phase’), as well as from the end of the acute phase to the end of the 3-year follow-up period (‘long-term phase’). Results The study population included 43,975 matched pairs of CAP patients and comparison patients. Expenditures averaged $33,380 (95% confidence interval [CI] $32,665–$34,161) for the CAP hospitalization and $4568 (95% CI $4385–$4749) during the 30-day period thereafter (vs. $2075 [95% CI $1989–$2167] in total for the comparison patients). During the long-term phase, all-cause expenditures averaged $83,463 (95% CI $81,318–$85,784) for CAP patients versus $51,017 (95% CI $49,553–$52,491) for comparison patients, and thus attributable expenditures during this phase totaled $32,446 (95% CI $29,847–$35,075). The majority of attributable CAP expenditures (53% of $68,319) occurred during the acute phase, while 21%, 14%, and 12% occurred during the first, second, and third years, respectively, after the acute phase. Conclusions Our findings provide additional evidence that the cost of CAP requiring hospitalization is high, and that the impact of CAP extends well beyond the expected time for resolution of acute inflammatory signs. Electronic supplementary material The online version of this article (10.1007/s41669-020-00240-9) contains supplementary material, which is available to authorized users.

Background Many studies have used the Wechsler Intelligence Scale (WISC) to examine the characteristics of autism spectrum disorder (ASD). However, most studies have been based on profile analysis, not on content analysis. Objective The objective of the present study was to apply the WISC-IV to clinical assessment of ASD and clarify how the characteristics of the disorder were reflected in specific items. Methods The study participants were 20 patients aged 5-16 years diagnosed with ASD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We recruited 20 patients with attention-deficit/hyperactivity disorder (ADHD) and 20 patients with other disorders (neurotic disorders) as controls. We then compared the scores of the ninth item of the WISC-IV ("Comprehension") among the three groups. Results The differences observed between the ASD vs. the other disorders group were not significant by the standard scoring method. Thus, a two-level scoring method of 0 and ≥1 point was adopted. As a result, significantly more participants in the ASD group scored 0 points compared with the ADHD and other disorders groups. Discussion The results of the present study revealed that a characteristic of ASD appeared in the ninth item of "Comprehension" on the WISC-IV.

Productivity benefits of health technologies are ignored in typical economic evaluations from a health payer’s perspective, risking undervaluation. We conduct a productivity-based cost-benefit analysis from a societal perspective and estimate indirect costs of adult pneumococcal disease, vaccination benefits from the adult 13-valent pneumococcal conjugate vaccine (PCV13 Adult), and rates of return to PCV13 Adult for a range of hypothetical vaccination costs. Our context is Turkey’s funding PCV13 for the elderly and for non-elderly adults with select comorbidities within the Ministry of Health’s National Immunization Program. We use a Markov model with one-year cycles. Indirect costs from death or disability equal the expected present discounted value of lifetime losses in the infected individual’s paid and unpaid work and in caregivers’ paid work. Vaccination benefits comprise averted indirect costs. Rates of return equal vaccination benefits divided by vaccination costs, minus one. Input parameters are from public data sources. We model comorbidities’ effects by scalar multiplication of the parameters of the general population. Indirect costs per treatment episode of inpatient community-acquired pneumonia (CAP), bacteremia, and meningitis – but not for outpatient CAP – approach or exceed Turkish per capita gross domestic product. Vaccination benefits equal $207.02 per vaccination in 2017 US dollars. The rate of return is positive for all hypothetical costs below this. Results are sensitive to herd effects from pediatric vaccination and vaccine efficacy rates. For a wide range of hypothetical vaccination costs, the rate of return compares favorably with those of other global development interventions with well-established strong investment cases.

Background: Recent studies of community-acquired pneumonia (CAP) have recognized acute cardiac complications-such as myocardial infarction, arrhythmia, or congestive heart failure (CHF)-as frequent complications during the acute process. As well, a prolonged vulnerability to exacerbations of underlying comorbidities-such as CHF and COPD-has been observed following CAP. We hypothesized that young adults with underlying asthma could also be adversely impacted over a prolonged time period following CAP.Methods: Using a retrospective matched-cohort design and data from a US private healthcare claims repository (>15 M persons annually), we selected all adults 18-49 years of age with evidence of asthma as their only comorbidity for inclusion in the source population. Then, from the source population, we matched one comparison patient to each CAP patient based on index date, age, sex, and selected markers for health status (eg, history of asthma-related healthcare encounters), and evaluated subsequent outpatient and inpatient encounters for asthma exacerbations.Results: Asthma exacerbations were identified twice as often in the 12 months subsequent to acute CAP. Cumulative incidence proportions for asthma exacerbations requiring hospitalization or emergency department care after 12 months of follow-up were 19.9% for those previously hospitalized with CAP versus 9.0% for matched comparison patients (difference, 10.9%; p

Pathophysiological changes after acute hospitalizations may influence physical functioning in older adults, which can lead to disability and loss of independence. This study evaluated the association between pneumonia, fracture, heart attack, stroke, and other hospitalizations with major mobility disability (MMD) and gait speed. This was a secondary analysis of the Lifestyle Interventions and Independence for Elders (LIFE) Study, which was conducted across eight sites during 2010–2013 with longitudinal follow-up for 1635 individuals over an average of 2.6 years. Participants included adults ≥70 years old with pre-existing mobility limitations randomized to a physical activity intervention or a health education control arm. Hospitalizations were recorded via self-report and adjudicated by medical reviewers. MMD was measured by the inability to complete a 400 m walk test, or other proxies, as a binary outcome. Gait speed was recorded during the walk test in meters per second (m/s) and measured on a linear scale. Mixed-effects repeated measures regression adjusted for baseline demographics, comorbid conditions, and frailty. Among the 1635 participants, there were 1458 hospitalizations, which included 80 (5.5% of all hospitalizations) cases of pneumonia, 92 (6.3%) hospitalized fractures, 87 (6.0%) heart attacks, and 61 (4.2%) strokes. In the short-term measurement period immediately following hospitalization (1 day to 6 months), stroke (OR = 3.98 (3.41–4.54)) had the strongest association with MMD followed by fracture (OR = 3.03 (2.54–3.52)), pneumonia (OR = 2.76 (2.23–3.30)), and heart attack (OR = 2.03 (1.52–2.53)). Associations with long-term (6–12 months after) MMD were decreased or not significant for all causes. Pneumonia, fracture, stroke, and other hospitalizations were associated with short-term relative gait speed changes between −4.8% up to −19.5%, and only fracture was associated with long-term changes. Hospitalizations for pneumonia, heart attack, stroke, and fractures were associated with short-term decreases in mobility in older adults. Older adults may be at risk for decreased mobility and disability following acute hospitalizations, with the magnitude determined by the cause of the precipitating event.

Pathophysiological changes caused by pneumonia may influence physical functioning in older adults. This study was a secondary analysis of the Lifestyle Interventions and Independence for Elders (LIFE) Study. The LIFE Study included 1635 individuals over an average follow-up of 2.6 years at eight clinical sites during 2010–2013. Adults ≥70 years-old with mobility limitations (Short Physical Performance Battery score ≤9) were randomized to a physical activity (exercise) intervention or health education control arm. This analysis evaluated the association between pneumonia events and major mobility disability (MMD), gait speed, and physical activity levels. Pneumonia events, classified as inpatient or outpatient, were assessed by self-report during longitudinal follow-up. MMD was measured by the inability to complete a 400-m walk test, or other proxies, as a binary outcome and separately analyzed as “short-term” and “long-term” MMD. Short-term MMD was defined as MMD occurring in the assessment period immediately following (between 1-day to 6-months after) a pneumonia event and long-term was in the following assessment period (6 to 12 months after the event). Short- and long-term gait speed was similarly recorded during the walk test in meters per second (m/s) and measured on a linear scale. Physical activity levels were captured via accelerometry and shown visually. Mixed-effects repeated measures regression adjusted for intervention assignment, baseline demographics, comorbid conditions, and frailty. Among the 1635 participants, n = 174 (10.7%) had a pneumonia event of which 80 (46% of events) were hospitalized. Those with pneumonia during follow-up had higher baseline medication use, prior hospitalizations, and higher prevalence of lung disorders but similar baseline functioning. Pneumonia hospitalization was associated with a 4-fold increase [OR = 4.1 (3.2–5.0)] and outpatient events were associated with a 2-fold increase [OR = 2.6 (2.1–3.1)] in the odds of short-term MMD. Pneumonia hospitalizations, but not outpatient events, were associated with a nearly 10% decrement in short-term gait speed. Pneumonia events were not associated with either long-term MMD or gait speed outcomes. Physical activity levels decreased from baseline immediately following the pneumonia episode (10–30% reductions) and returned to baseline after 6 months. These results emphasize the importance of managing pneumonia risk factors to prevent disease in order to maintain physical independence and activity in older adults.

Alkenes and aromatics significantly contribute to the photochemical reactions in the Kanto Region, where the level of ozone frequently exceeds the level for photochemical smog warnings in summer. The major aromatic sources have been cataloged in the Pollutant Release and Transfer Register (PRTR) database in Japan; however, the major alkene sources are not included. We investigated the hourly variations in the volatile organic compound (VOC) concentrations at four sampling sites in the Tokyo Bay coastal area, which has a variety of VOC sources, including the petrochemical industry, chemical facilities, iron–steel plants, and refineries. The 116-component VOC data were used to conduct a positive matrix factorization (PMF) analysis to apportion the VOC sources; then, the source regions were estimated by combining the concentration ratios of the factors with the wind direction data. We used the hourly VOC data for the PMF analysis because alkenes are short-lived. Six factors were estimated using the PMF method and identified as liquefied petroleum gas + industry, aged air mass, fuel evaporation, petrochemical industry, aromatics, and solvent usage. The mean contribution ratios of these six factors were 8.9%, 19.9%, 9.3%, 10.4%, 9.9%, and 14.0%, respectively, whereas the mean contribution ratio of the residual was 27.7%. By combining the alkene concentration and factor contribution ratios with the wind direction, the petrochemical industry in the Kawasaki coastal area was demonstrated to be the main alkene source. In addition, the petrochemical industry makes the largest contribution to ozone production according to the OH radical loss rates of the six factors.

Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)–mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.

Background Following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in the United States, epidemiology of pneumococcal disease shifted such that disease incidence in the elderly exceeded that in children. We evaluated the impact of replacing PCV7 with PCV13 on disease burden in adults and identified age/risk-specific subgroups with the highest remaining disease burden. Methods A retrospective design and data from two US healthcare claims repositories were used. Study population included adults aged ≥18 years and was stratified by age (18–49, 50–64, 65–74, ≥75) and risk profile (healthy, at-risk, high-risk). Rate ratios comparing invasive pneumococcal disease (IPD), all-cause hospitalized pneumonia (ACHP), and pneumococcal pneumonia requiring hospitalization among at-risk and high-risk adults vs healthy counterparts were estimated for 2007–2010 (pre-PCV13), 2011–2012 (peri-PCV13), and 2013–2015 (post-PCV13). Results Across study periods, IPD and ACHP rates increased with age (2–27 times higher in persons ≥75 vs 18–49) and comorbidity (4–20 times higher in high-risk vs healthy). From pre- to post-PCV13 period, IPD rates declined 5%–48% and ACHP rates declined 4%–19% across age and risk groups (ACHP did not decline in persons ≥75). Decline in IPD and ACHP was attenuated among older adults and those with comorbidities. Accordingly, rate ratios among at-risk and high-risk persons (vs healthy counterparts) increased during the peri- and post-PCV13 periods compared with the pre-PCV13 period. Conclusions The switch to PCV13 was associated with large declines in pneumococcal disease among US adults. However, the decline was attenuated with increasing age (and, for ACHP, was absent in persons ≥75) and in those with comorbidities., Declining incidence of invasive pneumococcal disease and all-cause pneumonia following introduction of 13-valent pneumococcal conjugate vaccine for children was observed in adults aged ≥18 years. However, decline varied by age and comorbidity profile, with smaller reductions in older individuals and those with comorbidity.

During new drug development, clinical drug interaction studies are carried out in accordance with the mechanism of potential drug interactions evaluated by in vitro studies. The obtained information should be provided efficiently to medical experts through package inserts and various information materials after the drug's launch. A recently updated Japanese guideline presents general procedures that are considered scientifically valid at the present moment. In this review, we aim to highlight the viewpoints of the Japanese guideline and enumerate drugs that were involved or are anticipated to be involved in evident pharmacokinetic drug interactions and classify them by their clearance pathway and potential intensity based on systematic reviews of the literature. The classification would be informative for designing clinical studies during the development stage, and the appropriate management of drug interactions in clinical practice.

Background Increasing evidence suggests the impact of pneumonia persists beyond hospital discharge and the acute phase of respiratory symptoms. We characterized short-term and long-term risks of mortality and hospital readmission across the adult age span and spectrum of comorbidities. Methods Retrospective cohort design and Optum's de-identified Integrated Claims-Clinical dataset (2012–2018) were employed. Study population comprised adults who had ≥1 pneumonia hospitalization; each hospitalization ≥365 days apart was considered. Cumulative risks of all-cause mortality (from pneumonia hospitalization through 360-day post-discharge period) and all-cause hospital readmission (during 360-day post-discharge period) were summarized on an overall basis as well as by age and comorbidity profile (i.e., healthy, at-risk, high-risk). Results Study population totaled 37,006 patients who contributed 38,809 pneumonia hospitalizations; mean age was 71 years, 51% were female, and 88% had at-risk (33%) or high-risk (55%) conditions. Mortality was 3.5% in hospital, 8.2% from admission to 30 days post-discharge, and 17.7% from admission to 360 days post-discharge. Hospital readmission was 12.5% during the 30-day post-discharge period, and 42.3% during the 360-day post-discharge period. Mortality risk increased with age and severity of comorbidity profile; readmission risk was highest for persons aged 65–74 years and persons with high-risk conditions. Conclusions All-cause mortality up to 1 year following pneumonia hospitalization was substantial, and was associated with increasing age and worsening comorbidity profile. Both readmission and mortality were greater at all ages in at-risk and high-risk subgroups (vs. healthy counterparts). Strategies that prevent pneumonia and/or associated pathophysiologic changes, especially among individuals with comorbidities, have the potential to reduce morbidity and mortality.

A diversidade metabólica e a adaptabilidade genética dos fungos endofíticos torna-os uma fonte inesgotável de produtos bioativos. Diversas são as vantagens da interação endofítico-hospedeiro e os benefícios obtidos pela planta hospedeira resultante das interações com os fungos endofíticos, tem motivado diversos estudos, especialmente sobre a produção de metabólitos secundários com diversas atividades farmacológicas, como anticancerígena, antioxidante, antimicrobiana e antiviral. Os flavonóides são metabólitos secundários pertencentes a um grupo de substâncias naturais com estrutura fenólica variável e que desempenham um papel fundamental contra agentes oxidantes atuando também como agente terapêutico em patologias, como o câncer, inflamação, processos alérgicos e outras. A capacidade antioxidante destes compostos seria decorrente às suas propriedades sequestrante de radicais livres e quelante de íons metálicos. O presente trabalho teve como objetivo avaliar o potencial de 2 fungos endofíticos isolados da cana-de-açúcar para a produção de flavonóides. Os fungos foram caracterizados morfologicamente através de microcultivo e, através de triagem química nos sobrenadantes de cultura, foi detectada a presença de compostos com estrutura fenólica, sugestivo de flavonóides. Estes resultados indicam que os metabólitos secundários de micro-organismos endofíticos podem apresentar um amplo valor de aplicação biotecnológica.

The magnetostriction of Co-Ga alloys: Co-14Ga, Co-24Ga and Co-33Ga (atomic), is studied at room temperature for the first time. All three alloys are ferromagnetic. Co-14Ga microstructure is biphasic, a mixture of e (hcp) and α (fcc) phases. Co-24Ga presents three phases e, α and β (ordered bcc) and Co-33Ga is single β phase alloy. It was found that all three alloys present negative saturation magnetostriction λ s . The most interesting material for applications would be the alloy Co-33Ga since the magnetostriction saturates for a small field.

Summary: Recent successes in tumor immunotherapies have highlighted the importance of tumor immunity. However, most of the work conducted to date has been on T cell immunity, while the role of B cell immunity in cancer remains more elusive. In this study, immunogenetic repertoire profiling for tumor-infiltrating B and T cells in gastric cancers was carried out to help reveal the architecture of B cell immunity in cancer. Humoral immunity in cancer was shown to involve oligoclonal expansions of tumor-specific and private B cell repertoires. We find that B cell repertoires in cancer are shaped by somatic hypermutation (SHM) either with or without positive selection biases, the latter of which tended to be auto-reactive. Importantly, we identified sulfated glycosaminoglycans (GAGs) as major functional B cell antigens among gastric tumors. Furthermore, natural anti-sulfated GAG antibodies discovered in gastric cancer tissues showed robust growth-suppressive functions against a wide variety of human malignancies of various organs. : Katoh et al. profile immunoglobulin repertoires of tumor-infiltrating B cells, identifying sulfated glycosaminoglycan as a major functional B cell antigen in tumors. Repertoire profiling for tumor-infiltrating B cells may pave the way to the development of therapeutic antibodies. Keywords: repertoire sequence, immunogenetics, tumor immunity, tumor-infiltrating B cell, sulfated glycosaminoglycan, therapeutic antibody, gastric cancer

Two vaccines, 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13), are widely available for the prevention of pneumococcal disease in adults. However, it is unclear how cost-effective these pneumococcal vaccine choices are in the Hong Kong healthcare environment. We aimed to assess the cost-effectiveness of a sequential administration of PCV13 followed by PPSV23 compared to a single dose of PPSV23 vaccination for pneumococcal disease control in Hong Kong adults aged ≥65 years and individuals aged 20-64 years with immunocompromising and chronic conditions. A previously developed deterministic cohort sequential model was applied to compare the outcomes of two vaccination strategies from a societal perspective. Population-specific model input, including incidence, mortality, case-fatality, risk group distribution, vaccination costs, disease management, and productivity loss, was estimated from a Hong Kong-wide electronic medical database. Costs were valued in US$ in 2017. Vaccination strategies with an incremental cost-effectiveness ratio (ICER, defined as incremental cost per QALY saved) less than one local GDP per capita ($46,193 in 2017) were defined as highly cost-effective. Deterministic sensitivity analyses (SA) were conducted. Compared with single-dose PPSV23, sequential vaccination of PCV13 followed by PPSV23 was cost-saving for adults aged ≥20 years. In the deterministic SA, the base-case results were robust for tested parameter uncertainties. Future vaccination policies should consider the cost-effectiveness of a sequential vaccination strategy as a measure to reduce the vaccine-preventable pneumococcal disease burden in Hong Kong.

Drug interactions, in particular with concomitant drugs having a narrow therapeutic range, sometimes cause serious adverse drug reactions or attenuation of the therapeutic effect. Therefore, evaluation of the characteristics and severities of possible drug interactions in drug development is essential to understand such interactions to help prevent any potential risk for patients. In Japan, a regulatory document which was notified in 2001 to outline the basic principles of drug interaction studies during drug development was revised as a new guideline after 17 years to present general procedures that are currently considered scientifically valid. This article aims to present an overview of development process of the new Japanese guideline for investigating drug interactions and show the impact of implementating this guideline on drug interaction evaluations, thereby providing future perspectives of regulatory activities on drug interactions.

Community acquired pneumonia (CAP) carries high morbidity, mortality, and economic burden, which is even higher in adults diagnosed with chronic obstructive pulmonary disease (COPD). While several studies have assessed the clinical burden and mortality risk of CAP and COPD, very few studies focus on CAP burden from a COPD patient perspective. Individuals recently diagnosed with CAP and with pre-existing COPD were recruited through the COPD Foundation. The CAP Burden of Illness Questionnaire (CAP-BIQ), a content validated questionnaire assessing CAP symptomatology, duration of symptoms and CAP impact on work, activities and family, was administered at baseline and at 30-days follow-up. Of the 490 participants recruited, 481 had data sufficient for analysis. The prevalence of respiratory-related symptoms was very high (>90%) at the time of diagnosis with other generalized symptoms such as fatigue, trouble sleeping, headaches and confusion present in more than 60% of participants. Mean duration of symptoms varied from approximately 2 weeks for headaches and fever to more than a month for fatigue, wheezing, dyspnea, and cough. Employed participants missed an average of 21 days of work and those not employed missed 36 days of usual activities. Over 84% required help from family, friends or care givers. CAP is a serious and burdensome condition for people with COPD, a condition that can impair activities for weeks, frequently requires care from family or friends, and includes lingering symptoms. The patient-reported impact of CAP reported in this study underscores the need for prevention strategies in this population.

Tumor suppression by the extracts of Azadirachta indica (neem) works via anti-proliferation, cell cycle arrest, and apoptosis, demonstrated previously using cancer cell lines and live animal models. However, very little is known about the molecular targets and pathways that the neem extracts and the associated compounds act through. Here, we address this using a genome-wide functional pooled shRNA screen on head and neck squamous cell carcinoma cell line treated with crude neem leaf extracts, known for their anti-tumorigenic activity. By analyzing differences in global clonal sizes of the shRNA-infected cells cultured under no treatment and treatment with neem leaf extract conditions, assayed using next-generation sequencing, we found 225 genes affected the cancer cell growth in the shRNA-infected cells treated with neem extract. Pathway enrichment analyses of whole-genome gene expression data from cells temporally treated with neem extract revealed important roles played by the TGF-β pathway and HSF-1-related gene network. Our results indicate that neem extract simultaneously affects various important molecular signaling pathways in head and neck cancer cells, some of which may be therapeutic targets for this devastating tumor.

Background: Diazoxide is the first-line treatment for pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to elucidate the pharmacokinetics of diazoxide in children with HI. Methods: We obtained 81 blood samples from 22 children with HI. Measured serum diazoxide concentrations were used for population pharmacokinetic analysis. Patient factors influencing pharmacokinetics were estimated using nonlinear mixed-effects model analysis. Relationships between drug exposure and adverse drug reactions were also investigated. Results: Diazoxide disposition in the body was described by a 1-compartment model. Oral clearance (CL/F) and the volume of distribution were proportional to body weight (WT), as expressed by CL/F in males (liters/h) = 0.0358 + 0.00374 × WT (kg). CL/F in females was 39% greater than that in males. Steady-state concentrations of diazoxide were similar following twice- and 3 times-daily dosing when the total daily doses were comparable. A patient whose serum diazoxide concentration exceeded 100 μg/mL over a 4-month period developed hyperglycemia. No significant correlation was observed between severity of hirsutism and diazoxide concentration. Conclusion: We have proposed for the first time a population pharmacokinetic model for diazoxide in children with HI. The potential risk of diabetes mellitus and/or hyperglycemia increases when serum concentrations of diazoxide exceed 100 μg/mL.

The room temperature magnetostriction of polycrystalline Fe100– x Cr x alloys annealed at 800 °C was investigated as a function of Cr content varying from 10 to 30 at.% Cr. All alloys exhibited a single bcc $\alpha $ -Fe–Cr phase with a disordered A2 structure. With increasing Cr concentration, the grain shape became very elongated. The greatest total magnetostriction value of $70 \times 10^{-6}$ was obtained in the direction of the elongated grains for 30% of Cr. We also investigated the effect of B addition on the magnetostriction and structural properties of the alloy Fe80Cr20. Although the addition of B was expected to form the Fe2B phase, the B-added Fe–Cr alloy forms a ternary phase (Fe z Cr1– z )2B ( $0 ), a weak magnetic phase.

Background Increasing evidence suggests that the impact of community-acquired pneumonia (CAP) extends beyond discharge from the hospital and the acute phase of illness. We sought to characterize mortality and hospital readmission across the adult age span and spectrum of comorbidities. Methods A retrospective cohort design and data from Optum’s de-identified Integrated Claims-Clinical dataset (2009-2018) were employed. Study population comprised all adults who, between 1.1.2013 and 12.31.2017, had ≥ 1 acute-care hospitalization for CAP; each qualifying CAP hospitalization separated by ≥ 365 days was included as a unique observation in analyses. Study outcomes included acute-care hospital readmission for any reason and death for any reason. Hospital readmission was ascertained during the 360-day period following discharge from the CAP hospitalization; death was ascertained during the CAP hospitalization as well as during the same 360-day period. Cumulative rates of mortality and readmission were summarized for all patients as well as subgroups defined on age and comorbidity profile (i.e., healthy, at-risk, high-risk). Results Study population totaled 37,006 patients who contributed 38,809 CAP hospitalizations; mean age was 71 years, 51% were female, and 88% had an at-risk (33%) or high-risk (55%) condition. Hospital readmission was 12.5% during the 30-day post-discharge period, and 42.3% during the 360-day post-discharge period. Mortality was 3.5% in hospital, 8.2% from admission to 30 days post-discharge, and 17.7% from admission to 360 days post-discharge. Mortality rates increased with age and severity of comorbidity profile; readmission rates were highest for persons aged 65-74 years and high-risk persons. Rates of readmission and mortality among adults hospitalized for CAP Conclusion All-cause mortality up to 1 year following hospital admission for CAP was substantial, and was associated with increasing age and worsening comorbidity profile. Both readmission and mortality were greater at all ages in high-risk and at-risk groups compared with their healthy counterparts. Strategies that prevent pneumonia and/or the pathophysiologic changes that follow CAP, especially among individuals with comorbid conditions, have the potential to reduce morbidity and mortality following CAP as well as healthcare costs associated with readmission. Disclosures Reiko Sato, PhD, Pfizer, Inc (Employee, Shareholder) Derek Weycker, PhD, Pfizer Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Melody Shaff, BA, Pfizer, Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Ahuva Hanau, BS, Pfizer, Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Alexander Lonshteyn, PhD, Pfizer, Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Stephen I. Pelton, MD, Merck vaccine (Consultant, Grant/Research Support)Pfizer (Consultant, Grant/Research Support)Sanofi Pasteur (Consultant, Other Financial or Material Support, DSMB)Seqirus Vaccine Ltd. (Consultant)

Background Mobility is a cornerstone of healthy aging. Pneumonia may impact mobility through damage to physiological systems as well as increased inflammation, which has been associated with reduced physical functioning. The objective of this study was to assess the impact of pneumonia on objectively measured physical functioning in a sample of older adults. Methods This was a post-hoc analysis of the Lifestyle Interventions and Independence for Elders (LIFE) Study provided by the National Institute on Aging’s AgingResearchBiobank. Participants with pre-existing mobility concerns aged 70-89 years were randomized to physical activity or health education interventions. Outcomes included the ability to complete a 400-meter walk and gait speed (meters/second, m/s) and were assessed every 6 months from baseline up to 42 months. New health events were assessed at each visit including overall pneumonia events and pneumonia hospitalizations. Repeated measures regression models evaluated the ability to walk 400-meters and gait speed as separate outcomes controlling for age, sex, race, education, past medical history, the occurrence of other health events, and a cumulative deficit frailty index. Results There were 1,635 LIFE Study participants with N=9,872 follow-up measures during the study period. Among these, 174 (10.6%) had a pneumonia event which included 96 hospitalization events. Those with pneumonia events during follow-up were mostly similar to those without pneumonia events at baseline, except for higher prevalence of past hospitalizations and respiratory problems. Any pneumonia event was associated with an adjusted mean gait speed of 0.67 (0.63-0.71) m/s vs. 0.70 (0.66-0.73) m/s in those without pneumonia and 0.60 (0.55-0.64) in those with pneumonia hospitalization. Similarly, pneumonia events were associated with 84% [odds ratio = 1.84 (1.45-2.23)] and pneumonia hospitalizations with 200% [odds ratio = 3.00 (2.48-3.52)] increases in the odds of not being able to walk 400-meters compared to those without pneumonia events. Conclusion Pneumonia-related health events were associated with subsequent reduced mobility measured by 400-meter walk tests and gait speed. Preventing pneumonia may be an important component of maintaining physical functioning in older adults. Disclosures Joshua Brown, PharmD, PhD, Pfizer, Inc (Consultant, Grant/Research Support) Reiko Sato, PhD, Pfizer, Inc (Employee, Shareholder) John Morley, MD, Pfizer, Inc (Consultant)

Background: Recent studies of community-acquired pneumonia (CAP) have recognized acute cardiac complications—such as myocardial infarction, arrhythmia, or congestive heart failure (CHF)—as frequent complications during the acute process. As well, a prolonged vulnerability to exacerbations of underlying comorbidities—such as CHF and COPD—has been observed following CAP. We hypothesized that young adults with underlying asthma could also be adversely impacted over a prolonged time period following CAP.Methods: Using a retrospective matched-cohort design and data from a US private healthcare claims repository (>15 M persons annually), we selected all adults 18–49 years of age with evidence of asthma as their only comorbidity for inclusion in the source population. Then, from the source population, we matched one comparison patient to each CAP patient based on index date, age, sex, and selected markers for health status (eg, history of asthma-related healthcare encounters), and evaluated subsequent outpatient and inpatient encounters for asthma exacerbations.Results: Asthma exacerbations were identified twice as often in the 12 months subsequent to acute CAP. Cumulative incidence proportions for asthma exacerbations requiring hospitalization or emergency department care after 12 months of follow-up were 19.9% for those previously hospitalized with CAP versus 9.0% for matched comparison patients (difference, 10.9%; p

Background The risk of community-acquired pneumonia (CAP) increases with age and significantly impacts morbidity and mortality in the elderly population. The burden of illness and cost of preventing CAP has not been compared to other serious diseases. Methods This retrospective analysis used claims data from 2014 to 2015 and compared hospitalizations for CAP, myocardial infarction (MI), stroke, and osteoporotic fractures (OF) in adults aged ≥65 years enrolled in a Medicare Advantage insurance plan. Individuals who had not already been hospitalized for one of these conditions and did not have evidence of long-term care were included in the study. Hospitalizations for each condition were described by length of stay, readmissions, mortality, and total costs. Preventive measures included vaccinations for CAP and medications for MI, stroke, and OF. Results A total of 1,949,352 individuals were included in the cohort. In 2015, the rate of CAP-related hospitalizations was the highest at 846.7 per 100,000 person-years compared to 405 for MI, 278.9 for stroke, and 343.9 for OF. Vaccination costs for CAP were $40.2 million including $14.1 million for pneumococcal and $26.1 million for influenza vaccines. The cost of preventive medications for MI and stroke reached over $661 million and OF totaled $169 million. Conclusions Although CAP has a higher burden of hospitalization and total costs than MI, stroke, and OF in the elderly population, prevention efforts were disproportionately smaller for CAP. Prioritization of CAP prevention is needed to substantially reduce the burden of CAP.