Qualitative measures that assess functional disability and quality of life in ALS.

BACKGROUND: Selection of appropriate trial endpoints and outcome measures is particularly important in rare disease and rapidly progressing disease such as amyotrophic lateral sclerosis (ALS) where the challenges to conducting clinical trials, are substantial: patient and disease heterogeneity, limited understanding of exact disease pathophysiology, and lack of robust and available biomarkers. To address these challenges in ALS, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised version (ALSFRS-R) was developed and has become a key primary endpoint in ALS clinical trials to assess functional disability and disease progression, often replacing survival as a primary outcome. However, increased understanding of the ALS disease journey and improvements in assistive technology for ALS patients have exposed issues with the ALSFRS-R, including non-linearity, multidimensionality and floor and ceiling effects that could challenge its continued utility as a primary outcome measure in ALS clinical trials. Recently, other qualitative scale measures of functioning disability have been developed to help address these issues. With this in mind, we conducted a literature search aimed at identifying both established and promising new measures for potential use in clinical trials. METHODS: We searched PubMed, Google, Google Scholar, and the reference sections of key studies to identify papers that discussed qualitative measures of functional status for potential use in ALS studies. We also searched clinicaltrials.gov to identify functional status and health-related quality of life (HRQoL) measures that have been used in ALS interventional studies. RESULTS: In addition to the ALSFRS-R, we identified several newer qualitative scales including ALSFRS-EX, ALS-MITOS, CNS-BFS, DALS-15, MND-DS, and ROADS. Strengths and limitations of each measure were identified and discussed, along with their potential to act as a primary or secondary outcome to assess patient functional status in ALS clinical trials. CONCLUSION: This paper serves as a reference guide for researchers deciding which qualitative measures to use as endpoints in their ALS clinical trials to assess functional status. This paper also discusses the importance of including ALS HRQoL and ALS cognitive screens in future clinical trials to assess the value of a new ALS therapy more comprehensively.

A Descriptive Review of Global Real World Evidence Efforts to Advance Drug Discovery and Clinical Development in Amyotrophic Lateral Sclerosis.

Understanding patient clinical progression is a key gateway to planning effective clinical trials and ultimately enabling bringing treatments to patients in need. In a rare disease like amyotrophic lateral sclerosis (ALS), studies of disease natural history critically depend on collaboration between clinical centers, regions, and countries to enable creation of platforms to allow patients, caregivers, clinicians, and researchers to come together and more fully understand the condition. Rare disease registries and collaborative platforms such as those developed in ALS collect real-world data (RWD) in standardized formats, including clinical and biological specimen data used to evaluate risk factors and natural history of disease, treatment patterns and clinical (ClinROs) and patient- reported outcomes (PROs) and validate novel endpoints. Importantly, these data support the development of new therapeutics by supporting the evaluation of feasibility and design of clinical trials and offer valuable information on real-world disease trajectory and outcomes outside of the clinical trial setting for comparative purposes. RWD may help to accelerate therapy development by identifying and validating outcome measures and disease subpopulations. RWD can also make potential contributions to the evaluation of the safety and effectiveness of new indications for approved products and to satisfy post-approval regulatory and market access requirements. There is a lack of amalgamated information on available registries, databases, and other sources of real-world data on ALS; thus, a global review of all available resources was warranted. This targeted review identifies and describes ALS registries, biobanks and collaborative research networks that are collecting and synthesizing RWD for the purposes of increasing patient awareness and advancing scientific knowledge with the hope of expediting future development of new therapies.

Creating medical and drug code lists to identify cases in primary care databases.

This paper demonstrates how compilation of medical and drug code lists for outcomes or exposures of interest for studies using primary care databases can be carried out efficiently using Stata. Use of Stata do-files to record and execute the commands provides good documentation and ease of replication of the procedure.

A comparison of father and mother report of child behaviour on the Strengths and Difficulties Questionnaire.

To date there has been no comparison of father and mother report on the Strengths and Difficulties Questionnaire (SDQ), a standardised measure of child behaviour used widely in the UK in clinical practice and research. The objectives of the study were to investigate differences and agreement between parents on the various SDQ domains of child behaviour. Parents of 4-6 years olds were recruited via 13 UK general practices, and completed the SDQ and measures on depression, parenting, couple relationship, alcohol use and demographics. Parental SDQ ratings were compared. The SDQ was completed by 248 parent dyads. Mother and father ratings were correlated, however fathers reported higher mean scores than mothers for externalising behaviours. Higher reporting by fathers was related to alcohol misuse, the couple relationship, fathering, and father employment. Fathers did not report significantly more abnormal behaviours than mothers except for hyperactivity. There was high interparental agreement on normal/borderline behaviours (94.8-98.3% agreement), but lower agreement on abnormal behaviours (7.7-37.9%). There was higher interparental agreement on male rather than female children, but fathers were four times more likely to report hyperactivity among their boys compared with girls. Using combined parental reports in clinical settings would enhance the sensitivity of identifying children requiring clinical attention for their problem behaviours.

Intellectual Property and biodiversity: interplay.

Potentially divergent objectives and thereby obligations under the Convention on Biodiversity and Trade-Related Aspects of Intellectual Property Rights Agreement are also reflected in respective domestic legislations in India. The review article focuses on Biological Diversity Act, 2002 vis-à-vis Patents Act, 1970 of India with intricacies involved thereunder. Authors have analyzed the obligations under these domestic legislations. The article goes on to make a few suggestions to aid effective implementation of both the statutes. The scope of this review article is limited in two aspects; first, it speaks only about Indian landscape and second, it discusses about interplay of biodiversity law only with respect to patent law instead of all the domestic Intellectual Property enactments of India.

Toward the Ultimate Limit of Connectivity in Quantum Dots with High Mobility and Clean Gaps.

Colloidal quantum dots (CQDs) are highly versatile nanoscale optoelectronic building blocks, but despite their materials engineering flexibility, there is a considerable lack of fundamental understanding of their electronic structure as they couple within thin films. By employing a joint experimental-theoretical study, we reveal the impact of connectivity in CQD assemblies, going beyond the single CQD picture. High-resolution transmission electron microscopy (HR-TEM) demonstrates connectivity motifs across different CQD sizes and length scales and provides the necessary perspective to build robust computational models to systematically study the achievable degree of connectivity in these materials. We focused on state-of-the-art surface ligand treatments, taking into account both the degree of connectivity and nanocrystal orientation, and performed ab initio simulations within the phonon-assisted hopping regime. Importantly, both the TEM studies and our simulation results revealed morphological and electronic defects that could dramatically reduce optoelectronic performance, and yet would not have been captured within a single CQD model that neglects connectivity. We calculate carrier mobility in the presence of such defect states and conclude that the best-achievable CQD assemblies for optoelectronics will require a modest degree of fusing via the {001} facet, followed by atomic ligand passivation to generate a clean band gap and unprecedentedly high charge transport.

Association between therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors and risk of ileus: a cohort study.

BACKGROUND: Three cases of ileus have been published among dipeptidyl peptidase-4 (DPP-4) inhibitor users in Japan. The purpose of this study was to estimate and compare incidence rates of ileus among alogliptin users and users of other DPP-4 inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and voglibose. METHODS: We used the Medical Data Vision database in Japan to conduct a retrospective cohort study among type 2 diabetes mellitus (T2DM) patients who were new users of alogliptin, other DPP-4 inhibitors, GLP-1 receptor agonists, or voglibose between 1 April 2010 and 30 April 2014. The primary outcome was an incident diagnosis of ileus. Kaplan-Meier survival curves were used to estimate ileus events over time. Adjusted Poisson regression models were used to estimate incidence rate ratios (IRR) for ileus and 95 % confidence intervals (CI) by comparing alogliptin users to users of the other study drugs. RESULTS: We identified 82,386 patients with T2DM. In the adjusted model, there was no difference in risk of ileus among patients exposed to alogliptin compared with patients exposed to other DPP-4 inhibitors (IRR 1.15, 95 % CI 0.75-1.75) or GLP-1 receptor agonists (IRR 0.42, 95 % CI 0.14-1.20). The risk of ileus was significantly lower among patients exposed to alogliptin compared with patients exposed to voglibose (IRR 0.55, 95 % CI 0.35-0.88). CONCLUSIONS: The independent risk of ileus among new users of alogliptin did not significantly differ compared with new users of other DPP-4 inhibitors or GLP-1 receptor agonists but was significantly lower than new users of voglibose.

Chemistry and Structure of Graphene Oxide via Direct Imaging.

Graphene oxide (GO) and reduced GO (rGO) are the only variants of graphene that can be manufactured at the kilogram scale, and yet the widely accepted model for their structure has largely relied on indirect evidence. Notably, existing high-resolution transmission electron microscopy (HRTEM) studies of graphene oxide report long-range order of sp(2) lattice with isolated defect clusters. Here, we present HRTEM evidence of a different structural form of GO, where nanocrystalline regions of sp(2) lattice are surrounded by regions of disorder. The presence of contaminants that adsorb to the surface of the material at room temperature normally prevents direct observation of the intrinsic atomic structure of this defective GO. To overcome this, we use an in situ heating holder within an aberration-corrected TEM (AC-TEM) to study the atomic structure of this nanocrystalline graphene oxide from room temperature to 700 °C. As the temperature increases to above 500 °C, the adsorbates detach from the GO and the underlying atomic structure is imaged to be small 2-4 nm crystalline domains within a polycrystalline GO film. By combining spectroscopic evidence with the AC-TEM data, we support the dynamic interpretation of the structural evolution of graphene oxide.

The association of paternal mood and infant temperament: A pilot study.

Maternal depression is associated with adverse child development, but little is known about the effects of paternal depression. This pilot study estimated the prevalence of paternal depression and mood state, and assessed the relationship between paternal mood and infant temperament. The participants in the study were 98 fathers of newborn babies. Fathers were initially screened for depressed mood (Hospital anxiety and depression scale, and Edinburgh postnatal depression scale), and at 6 months parental mood, infant temperament, couple relationship quality, alcohol use, adverse life events, parenting, and demographics were recorded. Infant fussiness was analysed in relation to paternal mood and other contextual factors using multiple regression. Of the 98 fathers, 48 (49%) completed depression-screening measures. Of these 48 fathers, 4 (8%) reported depressive symptoms above the cut-off for case definition. A total of 48% (N=19) completed measures at follow-up. In the adjusted model, higher paternal depression scores, more traditional attitudes towards fathering, and increased recent life events were related to higher infant fussiness scores; and better couple relationship quality was related to lower fussiness scores. This study showed that 1 in 12 fathers had depressed mood, and lower mood was associated with negative infant temperament. Since the findings of this feasibility study were based on a small sample size the association of paternal mood and child development merits further study using a larger sample of fathers.

A national survey in England of the routine examination of the newborn baby.

OBJECTIVE: To identify current practices for the initial routine examination of healthy newborn babies, and determine the extent to which midwives are carrying out this examination. DESIGN AND PARTICIPANTS: Postal questionnaires were sent to consultant paediatricians and midwifery managers in all maternity units in England. Questionnaires were also sent to the 12 universities in England which run the N96 post-registration course in the examination of the newborn baby. FINDINGS: Questionnaires were returned from 197 (86%) maternity units. Senior house officers examined in 83% (160/193) a median of 92% of babies; 44% (74/167) had at least one midwife (median of two) with qualifications to carry out the examination and in 31% (51/167) some examinations were conducted by a midwife. However, a third of midwives with this qualification carried out no examinations, and nationally only about 2% of babies were examined by a midwife. Rates of referral by midwives and senior house officers were similar. Examinations were carried out between four and 48 hours from birth; most units considered six hours an acceptable minimum. An estimated 1% of babies were transferred home without routine examination; the GP was responsible for most (83-93%) of these babies' examinations; midwives for 10-23%; and senior house officers in hospital for 4-7%. Twelve per cent (23/194) of units carried out a second examination prior to discharge. Most respondents were in favour of midwives carrying out the examinations provided they were adequately trained. CONCLUSIONS: Many of the consultant paediatricians and midwifery managers stated that suitably trained midwives could routinely examine the healthy newborn baby; however, many currently N96 trained midwives were examining few or no babies. An extension of training would be needed were midwife examination to become general policy.

A randomised controlled trial of maternal satisfaction with the routine examination of the newborn baby at three months post birth.

OBJECTIVE: to determine whether any differences in maternal satisfaction with the examination of a newborn baby between midwives and junior paediatricians are maintained over a three-month period. DESIGN, SETTING AND PARTICIPANTS: randomised controlled trial. Eight hundred and twenty-six mother and baby pairs in a district general hospital in South East England were randomised to a junior paediatrician or a midwife for the routine examination. Four hundred and eighty-six mothers completed a maternal satisfaction questionnaire on day-one and again three-months later. Maternal satisfaction with the examination was analysed in relation to randomised group, process and background variables. FINDINGS: high satisfaction with the examination was reported by most mothers (day-one: 82%; three-months: 79%). At day-one, mothers whose babies were examined by a midwife were more satisfied with the examination (crude odds ratio (OR) for the lowest tertile of satisfaction 0.49, 95% CI 0.32-0.73). However, after controlling for provision of health education during the examination (e.g. discussing feeding, sleeping and skin care) and continuity of care provided, maternal satisfaction was no longer related to status of examiner (adjusted OR 0.83, 95% CI 0.52-1.33). Three months later, there was no significant difference in maternal satisfaction with midwife and junior paediatrician examinations of the newborn baby (crude OR 0.89, 95% CI 0.58-1.37). Discussion of health-care issues by the examiner during the examination was significantly related to increased satisfaction even at three-months. Three month ratings of low satisfaction with the examination were most strongly predicted by current maternal depressive mood, even when other factors were adjusted for (adjusted OR 2.58, 95% CI 1.19-5.59). KEY CONCLUSIONS: from the mother's perspective, the quality of midwife examination is at least as satisfactory as that of junior paediatricians and this perception is maintained over a three-month period. Satisfaction can be significantly enhanced if the examiner provides information on behavioural and health-care issues. The examination of the newborn baby provides an important window of opportunity for sharing information on newborn behaviour and care issues.

Incidence of maternal and paternal depression in primary care: a cohort study using a primary care database.

OBJECTIVE: To examine incidence, trends, and correlates of parental depression in primary care from 0 to 12 years of child age. DESIGN: Prospective cohort study. SETTING: Primary care records from more than 350 general practices in The Health Improvement Network database from 1993 to 2007. PARTICIPANTS: A total of 86 957 mother, father, and child triads identified in The Health Improvement Network database by linking mothers and babies and then identifying an adult household man. Depressed parents were identified using Read code entries for depression and antidepressant prescriptions. MAIN EXPOSURES: Child age, parental age at the birth, and area deprivation quintile. MAIN OUTCOME MEASURES: Incidence rates for maternal and paternal episodes of depression. RESULTS: Overall incidences of depression from the birth of the child up to age 12 years were 7.53 per 100 person-years for mothers and 2.69 per 100 person-years for fathers. Depression was highest in the first year post partum (13.93 and 3.56 per 100 person-years among mothers and fathers, respectively). By 12 years of child age, 39% of mothers and 21% of fathers had experienced an episode of depression. A history of depression, lower parental age at the birth of the child, and higher social deprivation were associated with a higher incidence of parental depression. CONCLUSIONS: Parents are at highest risk for depression in the first year after the birth of their child. Parents with a history of depression, younger parents, and those from deprived areas are particularly vulnerable to depression. There is a need for appropriate recognition and management of parental depression in primary care.

Major paternal depression and child consultation for developmental and behavioural problems.

BACKGROUND: It is well established that maternal depression is associated with enhanced child consultation for developmental and behaviour problems, but there is a dearth of research on paternal depression and child outcome. AIM: To assess the association of major paternal depressed mood and child consultation for developmental and behaviour problems. DESIGN OF STUDY: Cross-sectional study. SETTING: General practices in London and Hertfordshire, UK. METHOD: Fathers of children aged 4-6 years were recruited via 13 general practices. A sample of 248 biological father and mother dyads completed measures on depressive syndrome (Patient Health Questionnaire), child consultations with health professionals for developmental and behaviour problems, fathering, couple relationship quality, alcohol misuse, other psychiatric impairment, and sociodemographic factors. RESULTS: Eight out of 248 fathers (3%) had a major depressive syndrome. Sixty-five out of 247 (26%) fathers reported they were responsible for taking their child to see the doctor at least half the time compared with mothers. Children of fathers with a major depressive syndrome were almost nine times more likely to have consulted a health professional for speech and language problems (adjusted odds ratio [OR] = 8.67, 95% confidence interval [CI] = 1.99 to 37.67, P = 0.004) and seven times more likely to have consulted for externalising behaviour problems (adjusted OR = 6.98, 95% CI = 1.00 to 48.76, P = 0.05). CONCLUSION: Children of fathers with major depression were more likely to consult for speech and language problems and externalising behaviour problems. A longitudinal study is recommended to identify causal mechanisms.

Associations between paternal depression and behaviour problems in children of 4-6 years.

Maternal depression is associated with adverse child development, however little is known about paternal depression and child outcome. The aim of this study was to estimate the prevalence of paternal depression and assess its association with abnormal child behaviours among 4- 6-year-olds. Parents of 4- 6-years-olds were recruited via general practices and completed measures on child behaviour (Strengths and Difficulties Questionnaire), depression (Patient Health Questionnaire), and other covariates. The association of major and other paternal depressive syndrome with mother reported child behaviour was analysed. Eight percent (29/365) of fathers had depression (3.3 and 4.77% a major and other depressive syndrome, respectively). Major but not other paternal depressive syndrome was associated with an 8 and 36 times greater likelihood of child prosocial behaviour problems and peer problems respectively.

A feasibility study on recruiting fathers of young children to examine the impact of paternal depression on child development.

Fathers are underrepresented in research on mental health and child outcome. We tested a range of methods of recruitment of fathers to establish feasibility and recruitment rates to obtain a sample for a study on paternal depression and child development. The study took place in North London. Fathers of children aged 6 years and under were approached via: general practice surgeries by post and by face-to-face contact with attendees; child health surveillance clinics face-to-face or via their partners and via hospital postnatal wards face-to-face or by post. Researcher time and associated costs were monitored for each method, and symptoms of depression and anxiety measured using the Hospital Anxiety and Depression Scale (HADS). Face-to-face recruitment of fathers on the postnatal ward generated the highest return rate of HADS (28/37; 76%), followed by postal recruitment through general practice (41%;124/303). Lower response rates were observed with postal recruitment via postnatal wards (31%), recruitment in child health surveillance clinics (20%) and approaching attendees in general practice (16%). Twelve percent (23/194) and 30% (58/194) of fathers respectively reported depression and anxiety above the cut-off for case-definition. Costs were calculated on pro-rata researcher time. Costs of recruiting one participant ranged from 3 pounds sterling (general practice postal) to 11.75 pounds sterling (child health surveillance clinics), however the general practice attender method was disproportionately expensive (52.50 pounds sterling). This feasibility study shows that it is possible to recruit fathers to mental health studies and provides clear guidance on planning, costing and the expected levels of recruitment for future studies on fathers of young children.