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Background: Hereditary transthyretin-mediated (hATTR) amyloidosis a hereditary, multi-systemic and life-threatening disease resulting in neuropathy and cardiomyopathy. In the APOLLO study, patisiran, an investigational RNAi therapeutic targeting hepatic TTR production resulted in significant improvement in neuropathy and QoL compared to placebo and was generally well tolerated. Methods: APOLLO, a Phase 3 study of patisiran vs. placebo (NCT01960348) prespecified a cardiac subpopulation (n=126 of 225 total) that included patients with baseline left ventricular (LV) wall thickness ≥ 13mm and no medical history of aortic valve disease or hypertension. Cardiac measures included structure and function by electrocardiography, changes in NT-proBNP and 10-MWT gait speed. Results: At 18 months, patisiran treatment resulted in a mean reduction in LV wall thickness of 1 mm (p=0.017) compared to baseline, which was associated with significant improvements relative to placebo in LV end diastolic volume (+8.31 mL, p=0.036), global longitudinal strain (-1.37%, p=0.015) and NT-proBNP (55% reduction, p=7.7 x 10-8) (Figure 1). Gait speed was also improved relative to placebo (+0.35 m/sec, p=7.4 x 10-9). Rate of death or hospitalization was lower with patisiran. mNIS+7 results in the cardiac subpopulation will also be presented. Conclusions: These data suggest patisiran has the potential to halt or reverse cardiac manifestations of hATTR amyloidosis.
The development of nutritional strategies to improve microbial homeostasis and gut health of piglets post-weaning is required to mitigate the high prevalence of post-weaning diarrhea and subsequent growth checks typically observed during the weaning transition. Therefore the objective of this study was to determine the effect of supplementing piglet creep and nursery feed with a yeast-derived mannan-rich fraction (MRF) on piglet growth performance, cecal microbial profiles, and jejunal morphology and gene expression. Ten litters of piglets (n=106) were selected on postnatal day (PND) 7 and assigned to diets with or without MRF (800 mg/kg) until weaning (n=5 litters/treatment; initial weight 3.0±0.1 kg). On PND 21, 4 piglets per litter (n=40) were selected and weaned into the nursery where they remained on their respective diets until PND 42. A two-phase feeding program was used to meet nutrient requirements, and pigs were switched from phase 1 to phase 2 on PND 28. Feed intake and piglet weights were recorded on PND 7, 14, 21, 28, 35 and 42. On PND 28 and 42, ten piglets per treatment were euthanized to collect intestinal tissue and digesta. Piglets supplemented with MRF had 21.5% greater (P<0.05) average daily feed intake between PND 14-21. However, MRF supplementation did not affect piglet growth performance compared to control. On PND 28, jejunal villus height was 16.8% greater (P<0.05) in piglets consuming MRF supplemented diets. Overall microbial community structure in cecal digesta on PND 28 tended to differ in pigs supplemented with MRF (P=0.076; analysis of similarities (ANOSIM)) with increased (P<0.05) relative abundance of Paraprevotellaceae genera YRC22 and CF231, and reduced (P<0.05) relative abundance of Sutterella and Prevotella. Campylobacter also tended to reduce (P<0.10) in MRF supplemented piglets. On PND 28 differential gene expression in jejunal tissue signified an overall effect of supplementing MRF to piglets. Downstream analysis of gene expression data revealed piglets supplemented with MRF had enriched biological pathways involved in intestinal development, function and immunity, supporting the observed improvement in jejunal villus architecture on PND 28. On PND 42 there was no effect of MRF supplementation on jejunal morphology or overall cecal microbial community structure. In conclusion, supplementing Actigen™, a MRF, to piglets altered cecal microbial community structure and improved jejunal morphology early post-weaning on PND 28, which is supported by enrichment of intestinal development pathways.
Although low birth weight (LBW) increases the risk for type 2 diabetes (T2DM), the relationship between high birth weight (HBW) and T2DM is less definitive and largely confined to North American Indigenous populations. We re-examined the relationship between LBW (<2500 g) and HBW (>4000 g) and both T2DM and gestational diabetes (GDM) among First Nations and non-First Nations women in Saskatchewan. We analyzed new data for female subjects from a 2001 case-control study that led to our hefty fetal phenotype hypothesis. Using survival analysis techniques and a validated algorithm for identifying diabetes in health care administrative data, we followed a 1950–1984 birth cohort of 2003 women until March 31, 2013. Cox regression analysis determined the time to occurrence of first episode of GDM and diagnosis of T2DM by birth weight and ethnicity. First Nations women with HBW demonstrated a greater risk for developing both T2DM [hazard ratios (HR) 1.568; 95% confidence interval (CI) 1.188, 2.069] and GDM (HR 1.468; 95% CI 1.016, 2.121) than those with normal birth weight (NBW). Non-First Nations women with LBW had a greater risk of developing GDM than those with NBW (HR 1.585; 95% CI 1.001, 2.512). HBW is a risk factor for GDM and T2DM among First Nations women. This is likely due to exposure of these women to their own mothers’ diabetic pregnancies or gestational impaired glucose tolerance. This inter-generational amplification of T2DM risk mediated through prenatal exposures appears to play a substantial role in the epidemic of T2DM among First Nations peoples.
Perfectionism has been argued to have both positive and negative aspects. Negative perfectionism has a robust positive correlation with psychopathology. This study explored the personality pattern of a group of clinical participants and a group of athletes in relation to positive and negative perfectionism. The results indicated negative perfectionism is related to neuroticism and agreeableness in both clinical and non-clinical groups. Negative perfectionism was most strongly associated with low agreeableness but had no significant relationship with conscientiousness or extraversion in the clinical sample. In the athlete sample, higher negative perfectionism was most strongly related to higher neuroticism but was also associated with lower extraversion and conscientiousness. In order to more fully understand these relationships and their clinical implications, more studies using validated measures of positive and negative perfectionism with larger samples are required. It would be useful to determine if personality factors of agreeableness and competence could be increased in order to ameliorate the distress associated with negative perfectionism.
This article reports an evaluation of the officer selection procedures of the Papua New Guinea Defence Force based on the performance of 195 officers. Results indicate that a linear combination of selection variables, including psychometric measures, academic achievement, interview impressions, and hands-on performance tests, was not predictably related to the criterion measure of officer performance. Post-hoc validation checks suggest that only one of the psychometric tests used in selection meets basic construct validation criteria and that the criterion measure of officer performance is unreliable. No evidence was found to support the predictive validity of selection procedures.
Background: Clinical perfectionism is a transdiagnostic process that has been found to maintain eating disorders, anxiety disorders and depression. Cognitive behavioural models explaining the maintenance of clinical perfectionism emphasize the contribution of dichotomous thinking and resetting standards higher following both success and failure in meeting their goals. There has been a paucity of research examining the predictions of the models and motivation to change perfectionism. Motivation to change is important as individuals with clinical perfectionism often report many perceived benefits of their perfectionism; they are, therefore, likely to be ambivalent regarding changing perfectionism. Aims: The aim was to compare qualitative responses regarding questions about motivation to change standards and cognitions regarding failure to meet a personal standard in two contrasting groups with high and low negative perfectionism. Negative perfectionism refers to concern over not meeting personal standards. Method: A clinical group with a range of axis 1 diagnoses who were elevated on negative perfectionism were compared to a group of athletes who were low on negative perfectionism. Results: Results indicated that the clinical group perceived many negative consequences of their perfectionism. They also, however, reported numerous benefits and the majority stated that they would prefer not to change their perfectionism. The clinical group also reported dichotomous thinking and preferring to either keep standards the same or reset standards higher following failure, whilst the athlete group reported they would keep standards the same or set them lower. Conclusions: The findings support predictions of the cognitive behavioural model of clinical perfectionism.
The effect of Ni doping on the Co site of the binary skutterudite CoSb3 is investigated. We measured resistivity, Hall effect, magnetoresistance, thermopower, thermal conductivity, and magnetization of a series of samples of the form Co1-xNixSb3 with x in the range x=0 to x=0.01. We find that Ni takes the tetravalent state Ni4+, assumes the d6 electronic configuration for the lower energy non-bonding orbitals, and gives an electron to the conduction band. Ni doping dramatically suppresses the thermal conductivity, changes the temperature dependence of the thermopower, and increases the carrier concentration. Low temperature anomalies in thermopower, Hall coefficient and magnetoresistance are found.
Background: The aim of this study is to determine whether B12 replacement would ameliorate cognitive and psychiatric symptoms in elderly subjects with dementia and low serum B12 levels.
Methods: A test group (n = 28) of nursing home residents with low serum B12 levels (<250 pg/mL) and a matched comparison group (n = 28) with normal serum B12 levels (>300 pg/mL) were evaluated by blinded raters while the test group received intramuscular (IM) B12 replacement therapy. All subjects were assessed at baseline, 8 weeks, and 16 weeks with the Dementia Rating Scale, Brief Psychiatric Rating Scale, and Geriatric Depression Scale.
Results: Although B12 replacement produced significant improvement in hematologic and metabolic parameters, it yielded no significant effect on cognitive or psychiatric variables. A few subjects evidenced notable individual treatment responses; however, these were not statistically more frequent than in the normal B12 group.
Conclusions: These results suggest that B12 replacement is unlikely to benefit cognitive or psychiatric symptoms in the vast majority of elderly dementia patients with low serum B12 levels.
Schema-focused therapy (SFT) and transference-focused psychotherapy (TFP)
for borderline personality disorder were recently compared in a
randomised multicentre trial.
To assess the societal cost-effectiveness of SFT v. TFP in treating
borderline personality disorder.
Costs were assessed by interview. Health-related quality of life was
measured using EQ-5D. Outcomes were costs per recovered patient (recovery
assessed with the Borderline Personality Disorder Severity Index) and
costs per quality-adjusted life-year (QALY).
Mean 4-year bootstrapped costs were $37826 for SFT and $46 795 for TFP
(95% uncertainty interval for difference −21 775 to 3546); QALYs were
2.15 for SFT and 2.27 for TFP (95% UI −0.51 to 0.28). The percentages of
patients who recovered were 52% and 29% respectively. The SFT
intervention was less costly and more effective than TFP (dominant), for
recovery; it saved $90457 for one QALY loss.
Despite the initial slight disadvantage in QALYs, there is a high
probability that compared with TFP, SFT is a cost-effective treatment for
borderline personality disorder.
Children with motor coordination problems are known to have emotional difficulties and poor social skills. The current study investigated whether children with poor motor ability have poor emotion recognition skills, and whether these could be linked to problems in social behaviour. It was hypothesized that difficulties in empathic ability might be related to the poor visuo-spatial processing ability identified in children with developmental coordination disorder (as defined by the American Psychiatric Association). The relationship between motor coordination, emotion recognition, and social behaviour was examined in a sample of 234 children (113 males, 121 females; mean age 9y 7mo, [SD 1y 8mo] age range 6y 8mo to 12y 11mo). From this sample two groups of 39 children each (17 females, 22 males), one group with motor difficulties (mean age 9y 11mo [SD 2y], range 6y 11mo to 12y 11mo) and the other of control children (mean age 10y [SD 1y 11mo], range 6y 11mo to 12y 11mo), matched for age and sex, were compared using a set of six emotion recognition scales that measured both verbal and perceptual aspects of empathic ability. Children with motor difficulties were found to perform more poorly on scales measuring the ability to recognize static and changing facial expressions of emotion. This difference remained even when visuo-spatial processing was controlled. When controlling for emotion recognition and visuo-spatial organization, a child's motor ability remained a significant predictor of social behaviour.
For the conduct of controlled clinical trials, epidemiologic surveys or even of medical practice of varieties of peripheral neuropathy, the usefulness, error rate and cost-effectiveness of scannable case-report forms has not been studied. Materials and
The overall performance, the frequency of the problems identified and corrected, and the time saved from use of a standard paper case report form was evaluated in multicenter treatment trials, single center epidemiologic surveys and in our neurologic practice. The paper case report form (Clinical Neuropathy Assessment [CNA]) for pen entry at study medical centers for patient, disease and demographic information (Lower Limb Function [LLF] and Neuropathy Impairment Score [NIS]) can be faxed to a core Reading and Quality Assurance Center where the form and data is electronically and interactively evaluated and corrected, if needed, by participating medical centers before electronic entry into database.
Observations and conclusions:
1) The approach provides a standard, scannable paper case report form for pen entry of neuropathy symptoms, impairments and disability at the bedside or in the office which is retained as a source document at the participating medical center but a facsimile can be transferred instantaneously, its data can be programmed, interactively evaluated, modified and stored while maintaining an audit trail; 2) it allowed efficient and accurate reading, transfer, analysis, and storage of data of more than 15,000 forms used in multicenter trials; 3) in 500 consecutive CNA evaluations, software programs identified and facilitated interactive corrections of omissions, discrepancies, and disease and study inconsistencies, introducing only a few readily identified and corrected entry errors; and 4) use of programmed, as compared to non-programmed assessment, was more accurate than double keyboard entry of data and was approximately five times faster.
A trial of 11 video-conferenced teaching sessions for residents in pediatric cardiology was performed by the 7 training programs in Canada in order to share expertise in specialized areas, to expose trainees to educational telemedicine, and to acquaint residents with other programs and personnel. Topics included cardiac pathology, arrhythmias, magnetic resonance imaging, fetal physiology, pulmonary hypertension, and cardiomyopathy. The sessions were evaluated by 93 residents by questionnaire for content and technology. Session content was highly rated. Videoconference picture quality was highly rated, but sound quality and visual aids were rated as neutral or unsatisfactory by a significant minority,related to problems with several early sessions, subsequently corrected. 60% of respondents rated the videoconferences as good as live presentations. Presenters were generally satisfied although they required some adjustments to videoconferencing. The average cost per session was $700 Canadian. Videoconferencing of resident educational sessions was generally well accepted by most presenters and residents, and the trial has formed the basis for a national network. Adequate organizational time, and careful attention to audiovisual needs, are most important. Videoconference guidelines are suggested for presenters based on this experience.
To report on an open trial of intravenous methylprednisolone (IV MP) in nondiabetic lumbosacral radiculoplexus neuropathy (LSRPN).
Lumbosacral radiculoplexus neuropathy is a subacute, unilateral or asymmetric syndrome of pain, weakness, and paresthesia of the lower extremity, which is attributed to ischemic injury from microvasculitis in lumbosacral roots, plexus, and nerves.
Eleven nondiabetic patients with worsening LSRPN were treated - ten with infusions of IV MP (1 gm/wk) for 8 to 16 weeks and one with an equivalent dosage of oral prednisone. The main endpoints evaluated were: 1) the Neuropathy Impairment Score (NIS), and 2) the Neuropathy Symptoms and Change (NSC) scores.
The median age of our patients was 67 years, range 49 to 86 years. Seven patients were women. All 11 patients reported improvement during treatment - nine reported marked improvement. The median NIS improved from 42 points (range 9 to 106 points) before treatment, to 20 points (range 5 to 57 points) (p = 0.005) after treatment. Pain was completely resolved in four patients and much improved in seven. The change subscore and the severity subscore of the NSC were statistically significantly improved after treatment. Prior to treatment, all patients had significant weakness with six confined to wheelchairs and four using mechanical devices to aid in ambulation. After treatment, the weakness was markedly improved in nine patients; only one still required a wheelchair and six walked independently (p = 0.03).
1) In LSRPN, pain and neurological deficits improved (often dramatically) with IVMPtreatment. 2) Although our results should be interpreted with caution since this trial is uncontrolled, IV MP may favorably affect the natural history of LSRPN. 3) The results are sufficiently promising to provide a rationale for prospective, sham controlled, double blind trials.
Two experiments were performed to examine the effects of immunoneutralizing PMSG at the onset of oestrus on the reproductive performance of sows. In experiment 1, 12 multiparous sows received 750 i.u. PMSG at weaning and six sozus acted as controls and were injected with saline. At 84 h after PMSG injection, all sows received an injection of 500 i.u. human chorionic gonadotropin (hCG) and six of the PMSG-treated sows also received an injection of 750 i.u. of a monoclonal anti-PMSG serum. The ovaries of all sows were examined by real time ultrasonography at 60-min intervals from 36 to 48 h after hCG injection for evidence of ovulation. In sows observed to ovulate, there was no significant effect of treatment on the interval from hCG injection to the start of ovulation, the duration of ovulation or subsequent litter size. In experiment 2, 253 primiparous sows received injections at weaning of 750 i.u. PMSG (no. = 134), 400 i.u. PMSG plus 200 i.u. hCG (no. = 69) or served as controls (no. = 50). At breeding, 67 of the PMSG-treated sows received an injection of 750 i.u. of monoclonal anti-PMSG serum.
More gonadotropin-treated than control sows were bred by 7 days after weaning (P < 0·05). Farrowing rates were higher in sows receiving the PMSG followed by anti-PMSG and PMSG plus hCG than in controls (P < 0·05), with those receiving PMSG alone being intermediate. There was no effect of treatment on subsequent litter sizes. These data indicate that the reproductive performance of primiparous sows may be improved by gonadotropin administration at the time of weaning. However, there was no advantage to using any particular hormone combination or anti-PMSG.