Dose optimization of moxifloxacin and linezolid against tuberculosis using mathematical modeling and simulation

Introduction

There is an urgent need for new anti-tuberculosis (TB) drugs and optimization of current TB treatment. Moxifloxacin and linezolid are valuable options for the treatment of drug-resistant TB; however, it is crucial to find a dose at which these drugs not only show high efficacy but also suppress the development of further drug resistance.

Not all cemented hips are the same: a register-based (NJR) comparison of taper-slip and composite beam femoral stems

Background and purpose — No difference in outcome has been demonstrated comparing cemented taper-slip and composite beam designs in short-term randomised trials; we assessed outcome differences using a registry analysis.

Patients and methods — All cemented stems with > 100 implantations were identified in the National Joint Registry of England and Wales from April 1, 2003 to September 31, 2013 and categorised as taper-slip or composite beam. Survival analyses using Kaplan–Meier and Cox regression were performed.

Results — We identified 292,987 cemented arthroplasties, of which 16% (47,586) were composite beam stems, with taper-slip stems making up the remainder (n = 245,401). There was a statistically significant increased chance of revision in the composite beam group compared with the taper-slip group (1.7% vs 1.3%, p < 0.001) but statistically no significant differences of survival estimates (p = 0.06). When the 2 groups were segregated to delineate the most implanted model in each category, the differences became more profound with the most implanted taper-slip stem (Exeter V40) showing statistically and clinically significant superior 8-year survival: 97.9% compared with 97.6% for all other taper-slip; 97.5% for the most implanted composite beam (Charnley cemented stem); and 97.7% for all other composite beam.

Interpretation — There was an increased incidence of revision for composite beam stems. The most implanted taper-slip stem demonstrated significant survival advantage vs. all other stems.     

Treatment Experiences,Information Needs,Pain and Quality of Life in Men with Metastatic Castrate-resistant Prostate Cancer: Results from the EXTREQOL Study

Aims

Delaying progression, ameliorating symptoms and maintaining quality of life (QoL) are primary aims of treatment for metastatic castrate-resistant prostate cancer (mCRPC). Real-world rather than clinical trial data about symptoms and side-effects are sparse. In EXTREQOL, patients' QoL, pain and information needs were recorded during treatment.

Interpersonal positive reframing in the daily lives of couples coping with breast cancer

Abstract

Objectives: This study examined word use as an indicator of interpersonal positive reframing in daily conversations of couples coping with breast cancer and as a predictor of stress.

Design: The Electronically Activated Recorder (EAR) and Linguistic Inquiry and Word Count (LIWC) were used to examine naturally occurring word use conceptually linked to positive reframing (positive emotion, negative emotion, and cognitive processing words).

Sample: Fifty-two couples coping with breast cancer.

Methods: Couples wore the EAR, a device participants wear, that audio-recorded over one weekend (>16,000 sound files), and completed self-reports of positive reframing (COPE) and stress (Perceived Stress Scale). LIWC, a software program, measured word use.

Findings: Both partners’ word use (i.e., positive emotion and cognitive processing words) was associated with their own reported positive reframing, and spouses’ word use was also indicative of patients’ positive reframing. Results also revealed that, in general, words indicating positive reframing predicted lower levels of stress.

Conclusions: Findings supported the hypothesis that partners—and particularly spouses of breast cancer patients—may assist each other’s coping by positively reframing the cancer experience and other negative experiences in conversation.     

Differentiated Thyroid Cancer in Children: A UK Multicentre Review and Review of the Literature

Aims

To obtain an overview of the management and outcomes of children aged 18 years or younger diagnosed with differentiated thyroid carcinoma of follicular cell origin across the UK, by collecting and analysing data from the limited number of centres treating these patients. This multicentre data might provide a more realistic perspective than single-institution series.

A Canadian Prospective Study of Linkage of Randomized Clinical Trial to Cancer and Mortality Registry Data

In a prospective study, we sought to determine acceptability of linkage of administrative and clinical trial data among Canadian patients and Research Ethics Boards (REBs). The goal is to develop a more harmonized approach to data, with potential to improve clinical trial conduct through enhanced data quality collected at reduced cost and inconvenience for patients. On completion of the original LY.12 randomized clinical trial in lymphoma ({"type":"clinical-trial","attrs":{"text":"NCT00078949","term_id":"NCT00078949"}}NCT00078949), participants were invited to enrol in the Long-term Innovative Follow-up Extension (LIFE) component. Those consenting to do so provided comprehensive identifying information to facilitate linkage with their administrative data. We prospectively designed a global assessment of this innovative approach to clinical trial follow-up including rates of REB approval and patient consent. The pre-specified benchmark for patient acceptability was 80%. Of 16 REBs who reviewed the research protocol, 14 (89%) provided approval; two in Quebec declined due to small patient numbers. Of 140 patients invited to participate, 115 (82%, 95% CI 76 to 88%) from across 9 Canadian provinces provided consent and their full name, date of birth, health insurance number and postal code to facilitate linkage with their administrative data for long-term follow-up. Linkage of clinical trial and administrative data is feasible and acceptable. Further collaborative work including many stakeholders is required to develop an optimized secure approach to research. A more coordinated national approach to health data could facilitate more rapid testing and identification of new effective treatments across multiple jurisdictions and diseases from diabetes to COVID-19.     

Degree of Bystander-Patient Relationship and Prehospital Care for Opioid Overdose

Abstract

Background

Across the spectrum of patient care for opioid overdose, an important, yet frequently overlooked feature is the bystander, or witness to the overdose event. For other acute medical events such as cardiac arrest and stroke, research supports that the presence of a bystander is associated with better outcomes. Despite the similarities, however, this well-established conceptual framework has yet to be applied in the context of overdose patient outcomes. The objective of this study was to assess the association between the nature of the bystander-patient relationship and prehospital care measures in patients being treated for opioid overdose.     

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study

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Effects of short birth spacing on birth-order differences in child stunting: Evidence from India

Do firstborn children have a height advantage? Empirical findings have found mostly that, yes, second or higher-order children often lag behind firstborns in height outcomes, especially in developing countries. However, empirical investigations of birth-order effects on child height overlook the potential impact that birth spacing can have. We provide an explanation for the negative birth-order effect on stunting outcomes for young Indian children and show it is driven by short preceding-birth spacing. We find that firstborn children are taller than children of higher birth order: The height-for-age gap for third (or higher)-order children is twice the gap for children second in birth order. However, this pattern is observed when spacing between later-born children and their immediate elder siblings is fewer than 3 y. Interestingly, the firstborn height advantage disappears when later-born children are born at least 3 y after their elder siblings. Thus, our findings indicate that spacing length between children explains differences in height, over birth order. Although India’s family planning policy has resulted in a substantial reduction in total fertility, its achievement in spacing subsequent births has been less impressive. In showing that spacing can alleviate or aggravate birth-order effects on attained height, our study fills an evidence gap: Reducing fertility alone may not be sufficient in overcoming negative birth-order effects. To reduce the detrimental effects of birth order on child stunting, policy responses—and therefore research priorities—require a stronger focus on increasing the time period between births.

Child undernutrition continues to be a problem in low-and middle-income countries, and adversely affects child survival and well being (1). While child undernutrition is gauged by several indicators, stunting—a key marker of chronic undernutrition obtained by comparing child height with that of children in the same age group in a healthy reference population—is at the forefront of discussion because of its vast prevalence across all developing regions and its important consequences for health and development. Almost all of stunting takes place in the first 1,000 d from conception to 2 y of age, but its consequences follow throughout adulthood. These consequences are largely irreversible, making stunting an extremely critical condition (2, 3). Children who are stunted are vulnerable to disease and mortality during childhood and run a much higher risk of developing deficits in later-life outcomes, including in adult height, cognitive and intellectual ability, and as a consequence, on schooling attainment, productivity, and earnings (4–10). Furthermore, if stunting is accompanied by excessive weight gain later in childhood, there is an increased risk of developing adult obesity and nutrition-related chronic diseases, including cardiovascular disease, stroke, and type 2 diabetes in adult life (see, for example, ref. 6). In addition, stunted girls carry additional risk of having adverse pregnancy outcomes and reproductive complications as adults, leading to detrimental intergenerational effects (11, 12). Nevertheless, stunting is preventable, and reducing it is an important component of overall development for the well being of children.In recognition of the high social and economic costs of stunting, efforts are ongoing to address this public health issue, including programs aimed at reducing poverty and inequality, improving dietary intake and access to healthcare services, and improving the hygiene environment. Childhood stunting has declined by 35% from a global estimate of 253 million in 1990, with over 90 million children protected from suboptimal growth and a large number of child deaths prevented. However, this decrease is small relative to the overall burden, as over 161 million children under 5 y were reported to be stunted in 2011 (13). Furthermore, there is a large disparity in numbers across regions, with the highest number of over 69 million stunted children living in South Asia and with India bearing 90% of this regional burden (14). Thus, although stunting levels have been reduced, the progress has been both uneven and suboptimal (15). There is need to develop strategies, policies, and programs tailored to local conditions, which in turn require a case-by-case approach to identify what other conditions may be predisposing children to poor height in certain regions, and also, within regions.Birth order—an indicator of a child’s position in the age hierarchy of siblings—has been used time and again to explain variation in height outcomes in children. Children born to the same parents share the same genetic make-up; yet, the order in which they are born exposes them to different biological and behavioral environments (16, 17). Through differences in health endowments and parental investments, birth order often affects the health and nutritional outcomes of children. Hence, birth-order effects reflect differences in the unshared environment within a family. The literature on child stunting has provided significant evidence from across countries that children of lower birth order are at an advantage, compared to children of higher birth order. Firstborn children are taller compared to those born subsequently, and this height advantage increases sharply over the higher order of birth of siblings. Explanations for the firstborn height advantage have addressed issues, such as better health endowments of the firstborn at birth and parental favoritism toward some offspring over others—usually the eldest son—generating more prenatal and postnatal investments, greater time investment in child care, longer duration of breastfeeding, and also affecting the desire for having more children (18–24).However, an important factor in assessing the birth-order effects on child health and nutritional outcomes is the length of interval between two consecutive births: That is, birth spacing. A wealth of studies have shown that a short length of birth spacing is associated with higher risk of maternal mortality and adverse subsequent birth outcomes, such as child mortality, preterm birth, small for gestational age, and low birthweight, though the degree to which the relationship holds varies substantially across countries (25–29). These associations stem from the biological factor commonly referred to as maternal depletion syndrome (26, 30). Closely spaced pregnancies may not allow sufficient time for the mother to restore her depleted micronutrient and macronutrient stores from the previous birthing, which in turn may reduce her ability to provide a favorable fetal growth environment in subsequent pregnancies and sufficient breast milk production postdelivery. Literature also suggests short birth spacing is associated with suboptimal parental care practices, which adversely affect the health and nutritional outcomes of siblings born close to each other. For example, the birth of a new baby may reduce the parental care time devoted to older siblings, as well as result in poor postnatal investment; similarly, a new pregnancy may reduce or curtail breast milk production, which may lead to suboptimal feeding for older siblings.While the aforementioned channels show the potential for longer birth spacing to influence nutritional outcomes of children more positively, especially for the later born, empirical inquiry into the spacing order linkages is limited. We believe that birth order and height linkage can be better understood by examining the interaction between birth order and birth spacing. Using an illustrative example of India in this paper, we demonstrate that the negative association between increasing birth order and child height is driven by the short length of interval between births. We link height-for-age standardized scores (HAZ) of children under 5 y, recorded in the latest Indian Demographic and Health Survey (DHS), to an indicator of birth order, disaggregated by the length of preceding birth spacing. When birth order is considered alone, we find that firstborn children on average are taller than children of higher birth order. This result is consistent with previous research on birth order. However, we discover noteworthy changes in the patterns of the HAZ gap between firstborn and subsequent children on combining birth order with preceding birth spacing. We find that the firstborn height advantage is significant if birth spacing between the higher-order child and its immediate elder sibling is less than 3 y, and this advantage gets steeper with increasing order of birth; that is, the height advantage for firstborns, compared to children from third or higher-order births, is almost twice the height advantage for firstborns, compared to children of second-birth order. Interestingly, if the birth spacing between the higher birth-order child and its immediate elder sibling is 3 or more years, the firstborn height advantage disappears and becomes insignificant. This is true with respect to the gap for all higher birth-order children. Thus, higher birth-order children, on average, are as tall as firstborn children if they are appropriately spaced. Our results emphasize the importance of time between births in determining height outcomes of young children, over birth order, and demonstrate how spacing length may weaken or strengthen the birth-order effect on child height. Designing and implementing policies and interventions that affect knowledge and attitude toward healthy spacing could significantly impact the health, nutrition, and accomplishments of young children.However, we emphasize at the outset that our analysis is exploratory in nature. An ideal dataset for comparing height outcomes across birth orders would require longitudinal data, recording all pregnancies conceived by a woman with predelivery and postdelivery information related to healthcare, as well as feeding practices for every living child. Because of the absence of datasets that cover all these aspects, we rely on DHS data, which are closely but imperfectly suited to the question at hand. The nature of DHS is such that anthropometry is recorded only for children below 5 y, and for many healthcare and dietary intake variables the information is collected only for the youngest child born to the mother. Hence, the reduced sample size and data limitations preclude our ability to establish causality. However, the large sample size is sufficient to assess subgroup and interaction effects. We address several possible biases or limitations of using survey data with additional analyses.