A randomised double-blind placebo-controlled trial of minocycline and/or omega-3 fatty acids added to treatment as usual for at risk Mental States: The NAYAB study.

BACKGROUND: Inflammatory mechanisms are thought to contribute to the onset of psychosis in persons with an at-risk mental state (ARMS). We investigated whether the anti-inflammatory properties of minocycline and omega-3 polyunsaturated fatty acids (omega-3), alone or synergistically, would prevent transition to psychosis in ARMS in a randomised, double-blind, placebo-controlled trial in Pakistan. METHODS: 10,173 help-seeking individuals aged 16-35 years were screened using the Prodromal Questionaire-16. Individuals scoring 6 and over were interviewed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) to confirm ARMS. Participants (n = 326) were randomised to minocycline, omega-3, combined minocycline and omega-3 or to double placebo for 6 months. The primary outcome was transition to psychosis at 12 months. FINDINGS: Forty-five (13.8 %) participants transitioned to psychosis. The risk of transition was greater in those randomised to omega-3 alone or in combination with minocycline (17.3.%), compared to 10.4 % in those not exposed to omega-3; a risk-ratio (RR) of 1.67, 95 % CI [0.95, 2.92] p = 0.07. The RR for transitions on minocycline vs. no minocycline was 0.86, 95 % CI [0.50, 1.49] p > 0.10. In participants who did not become psychotic, CAARMS and depression symptom scores were reduced at six and twelve months (mean CAARMS difference = 1.43; 95 % CI [0.33, 1.76] p < 0.01 in those exposed to omega-3. Minocycline did not affect CAARMS or depression scores. INTERPRETATION: In keeping with other studies, omega-3 appears to have beneficial effects on ARMS and mood symptom severity but it increased transition to psychosis, which may reflect metabolic or developmental consequences of chronic poor nutrition in the population. Transition to psychosis was too rare to reveal a preventative effect of minocycline but minocycline did not improve symptom severity. ARMS symptom severity and transition to psychosis appear to have distinct pathogeneses which are differentially modulated by omega-3 supplementation. FUNDING: The study was funded by the Stanley Research Medical Institute.

Culturally adapted motivational interviewing with cognitive behavior therapy and mindfulness-based relapse prevention for substance use disorder in Pakistan (CAMAIB): protocol for a feasibility factorial randomised controlled trial.

BACKGROUND: The use of psychoactive substances significantly impacts the health, social and economic aspects of families, communities and nations. There is a need to develop and test psychological interventions aimed for individuals with substance use disorder (SUD) in lower- and middle-income countries (LMICs), such as in Pakistan. The aim of this exploratory trial is to test the feasibility and acceptability of two culturally adapted psychological interventions in a factorial randomised controlled trial (RCT). METHODS: The proposed project will be conducted in three phases. The first phase of the study will focus on cultural adaptation of the interventions through qualitative interviews with key stakeholders. The second phase will be to refine and produce manually assisted interventions. Third and last stage would be to assess the feasibility of the culturally adapted interventions through a factorial RCT. The study will be carried out in Karachi, Hyderabad, Peshawar, Lahore and Rawalpindi, Pakistan. Recruitment of participants will take place from primary care and volunteer organisations/drug rehabilitation centres. A total of 260 individuals diagnosed with SUD (n = 65) in each of the four arms will be recruited. The intervention will be delivered weekly over a period of 12 weeks in both individual and group settings. Assessments will be carried out at baseline, at 12th week (after completion of intervention) and 24th week post-randomisation. The analysis will determine the feasibility of recruitment, randomisation, retention and intervention delivery. Acceptability of intervention will be determined in terms of adherence to intervention, i.e. the mean number of sessions attended, number of home assignments completed, attrition rates, as well as through process evaluation to understand the implementation process, context, participants' satisfaction, and impact of the study intervention. The health resource use and impact on the quality of life will be established through health economic data. DISCUSSION: This study will provide evidence for feasibility and acceptability of culturally adapted manually assisted psychological interventions for individuals with SUD in the context of Pakistan. The study will have clinical implications if intervention is proven feasible and acceptable. TRIAL REGISTRATION: Name of the registry: ClinicalTrials.gov, Trial registration number: NCT04885569 , Date of registration: 25th April 2021.

Reflections on a Physician Assistant Entrance Exam: Does the Profession Need One?

ABSTRACT: Standardized entrance exams are used in many health professions as one way to objectively measure knowledge and facilitate comparisons across student groups. The physician assistant (PA) profession has historically not employed a profession-specific entrance exam, and the idea was never seriously explored until the Physician Assistant College Admissions Test was developed recently by a commercial assessment publisher, with field testing in some volunteer programs in 2018 and the exam's first administration in May of 2020. The 2020 Physician Assistant Education Association Presidents Commission chose to investigate the issues raised by a consensus-derived, PA-specific entrance exam to stimulate more informed discussion on the efficacy of such an exam. While it may have the potential to enhance efficiency in PA admissions and reduce variability in admissions requirements, a PA entrance exam would also likely introduce new challenges, including increased costs, impact on the diversity of the applicant pool, and incongruence with an increasingly holistic admissions process. The biggest barrier would likely be the lack of current consensus on the knowledge, skills, and attributes that matriculants need to be successful in the program and in clinical practice. Development of a consensus-derived PA entrance exam would be a complex, expensive, and time-consuming endeavor, requiring considerable attention to technical issues of psychometric quality, process transparency, and legal defensibility. Changes being made to health professions admissions practices due to the COVID-19 pandemic, including the dropping of test scores as a requirement by some institutions, may make some of the issues raised in this paper more timely than ever.

PULSE-I - Is rePetitive Upper Limb SEnsory stimulation early after stroke feasible and acceptable? A stratified single-blinded randomised controlled feasibility study.

BACKGROUND: Reduction in sensorimotor function of the upper limb is a common and persistent impairment after stroke, and less than half of stroke survivors recover even basic function of the upper limb after a year. Previous work in stroke has shown that repetitive sensory stimulation (RSS) of the upper limb may benefit motor function. As yet, there have been no investigations of RSS in the early-acute period despite this being the time window during which the neuroplastic processes underpinning sensorimotor recovery are likely to occur. METHODS: A single-blinded, stratified, randomised controlled feasibility study was undertaken at two NHS acute trusts to determine the recruitment rate, intervention adherence, and safety and acceptability of an RSS intervention in the early period after stroke. Participants were recruited within 2 weeks of index stroke. Stratified on arm function, they were randomised to receive either 45 min of daily RSS and usual care or usual care alone (UC) for 2 weeks. Changes from baseline on the primary outcome of the Action Research Arm Test (ARAT) to measurements taken by a blinded assessor were examined after completion of the intervention (2 weeks) and at 3 months from randomisation. RESULTS: Forty patients were recruited and randomised (RSS n = 23; UC n = 17) with a recruitment rate of 9.5% (40/417) of patients admitted with a stroke of which 52 (12.5%) were potentially eligible, with 10 declining to participate for various reasons. Participants found the RSS intervention acceptable and adherence was good. The intervention was safe and there were no serious adverse events. CONCLUSIONS: This study indicates that recruitment to a trial of RSS in the acute period after stroke is feasible. The intervention was well tolerated and appeared to provide additional benefit to usual care. In addition to a definitive trial of efficacy, further work is warranted to examine the effects of varying doses of RSS upon arm function and the mechanism by which RSS induces sensorimotor recovery in the acute period after stroke. TRIAL REGISTRATION: ISRCTN, registry no: ISRCTN17422343 ; IRAS Project ID: 215137. Registered on October 2016.

Noncognitive Attributes in Physician Assistant Education.

Physician assistant (PA) admissions processes have typically given more weight to cognitive attributes than to noncognitive ones, both because a high level of cognitive ability is needed for a career in medicine and because cognitive factors are easier to measure. However, there is a growing consensus across the health professions that noncognitive attributes such as emotional intelligence, empathy, and professionalism are important for success in clinical practice and optimal care of patients. There is also some evidence that a move toward more holistic admissions practices, including evaluation of noncognitive attributes, can have a positive effect on diversity. The need for these noncognitive attributes in clinicians is being reinforced by changes in the US health care system, including shifting patient demographics and a growing emphasis on team-based care and patient satisfaction, and the need for clinicians to help patients interpret complex medical information. The 2016 Physician Assistant Education Association Stakeholder Summit revealed certain behavioral and affective qualities that employers of PAs value and sometimes find lacking in new graduates. Although there are still gaps in the evidence base, some tools and technologies currently exist to more accurately measure noncognitive variables. We propose some possible strategies and tools that PA programs can use to formalize the way they select for noncognitive attributes. Since PA programs have, on average, only 27 months to educate students, programs may need to focus more resources on selecting for these attributes than teaching them.

Accuracy and Efficiency of Recording Pediatric Early Warning Scores Using an Electronic Physiological Surveillance System Compared With Traditional Paper-Based Documentation.

Pediatric Early Warning Scores are advocated to assist health professionals to identify early signs of serious illness or deterioration in hospitalized children. Scores are derived from the weighting applied to recorded vital signs and clinical observations reflecting deviation from a predetermined "norm." Higher aggregate scores trigger an escalation in care aimed at preventing critical deterioration. Process errors made while recording these data, including plotting or calculation errors, have the potential to impede the reliability of the score. To test this hypothesis, we conducted a controlled study of documentation using five clinical vignettes. We measured the accuracy of vital sign recording, score calculation, and time taken to complete documentation using a handheld electronic physiological surveillance system, VitalPAC Pediatric, compared with traditional paper-based charts. We explored the user acceptability of both methods using a Web-based survey. Twenty-three staff participated in the controlled study. The electronic physiological surveillance system improved the accuracy of vital sign recording, 98.5% versus 85.6%, P < .02, Pediatric Early Warning Score calculation, 94.6% versus 55.7%, P < .02, and saved time, 68 versus 98 seconds, compared with paper-based documentation, P < .002. Twenty-nine staff completed the Web-based survey. They perceived that the electronic physiological surveillance system offered safety benefits by reducing human error while providing instant visibility of recorded data to the entire clinical team.

Telomerase in hematologic malignancies.

PURPOSE OF REVIEW: The activation of telomere maintenance pathways has long been regarded as a key hallmark of cancer and this has propelled the development of novel inhibitors of telomerase. In this review, we detail the background biology on telomere maintenance in health and disease, then concentrate on the recent preclinical and clinical development behind targeting telomerase in blood cancers. RECENT FINDINGS: Preclinical and clinical studies have shown that imetelstat, a competitive inhibitor of telomerase, has activity in certain hematologic malignancies, in particular the myeloproliferative neoplasms and acute myeloid leukemia. SUMMARY: Telomerase inhibition has shown remarkable efficacy in myeloid malignancies, and current and future preclinical and clinical studies are necessary to comprehensively investigate its underlying mechanism of action. Future work should identify the potential genetic susceptibilities to telomerase inhibition therapy, and evaluate rational combinations of telomerase inhibitors with chemotherapy and other novel agents. Robust preclinical evaluation is essential to best translate these new agents successfully into our clinical treatment algorithm for myeloid and other blood cancers.

Viridans Group Streptococcal Infections in Children After Chemotherapy or Stem Cell Transplantation: A 10-year Review From a Tertiary Pediatric Hospital.

Viridans Group Streptococci (VGS) are associated with high mortality rates in febrile neutropenia; yet there are no recent European pediatric studies to inform antimicrobial therapy. The aim of this study was to describe the characteristics, outcome, and resistance patterns of children with VGS bacteremia (VGSB) undergoing treatment of malignancy or hematopoietic stem cell transplant. Patients aged 0 to 18 years, admitted to a tertiary pediatric hemato-oncology center with VGSB, from 2003 to 2013, were included in the study. All data were collected retrospectively from medical records. A total of 54 bacteremic episodes occurred in 46 patients. The most common underlying diagnosis was relapsed acute lymphoblastic leukemia. Streptococcus mitis was the most frequent organism. A total of 30% of isolates were resistant to penicillin and 100% sensitive to vancomycin. There were 8 episodes (14.8%) of Viridans Group Streptococcal Shock Syndrome; 6 resulted in admission to intensive care and 3 of these patients died of multiorgan failure. The potentially fatal nature of VGSB is confirmed. The high risk in relapsed acute lymphoblastic leukemia is of note. Research is needed to develop risk-stratification scores that identify children at risk of Viridans Group Streptococcal Shock Syndrome to guide empirical antimicrobial therapy in febrile neutropenia.

Self-reported anxiety and sleep problems in people with epilepsy and their association with quality of life.

Comorbidities are common in epilepsy, and their role in quality of life (QOL) is receiving increasing scrutiny. Considerable attention has been focused on the role of depression, the most common comorbidity, with rather less attention paid to its frequent concomitant, anxiety, and other conditions known to be at increased prevalence among people with epilepsy (PWE) when compared to the general population. In this paper, we report findings from a UK-based survey in which we examined self-reporting of two common comorbidities, anxiety and sleep problems, factors associated with them, and their role in QOL in people with and without epilepsy. Data were obtained via mailed questionnaires, supplemented by an internet survey, from PWE and age- and gender-matched controls. Based on self-reported symptoms, PWE were at higher risk of anxiety and sleep problems. Contributory factors for anxiety included poorer general health, worry about seizures, and self-reported antiepileptic drug (AED) side effects. Good social support emerged as protective for anxiety in PWE. Nighttime sleep problems were very common even in controls but were further elevated in PWE. Antiepileptic drug adverse events emerged as an important contributory factor for sleep problems. Trait anxiety emerged as significant for defining overall QOL, and its importance over state anxiety supports the notion of anxiety in PWE as a primarily premorbid condition. In contrast, sleep quality was not consistently predictive of QOL. Our study has important implications for clinical management, emphasizing the need for a holistic approach to address wider patient-reported problems as well as any epilepsy-specific ones.

Psychiatric morbidity in chronic respiratory disorders in an Indian service using GMHAT/PC.

OBJECTIVE: The study aimed to assess psychiatric morbidity in stable chronic respiratory disorders and to examine the pattern of psychiatric illness in specific respiratory disorders in Northern India. METHODS: All consecutive patients with stable chronic respiratory illnesses who attended the respiratory disease clinic were recruited in the study. Their healthy attendants were interviewed as a control group. The research clinician, trained in the use of the Global Mental Health Assessment Tool, Primary Care Version (GMHAT/PC), interviewed all the participants. The respiratory consultant made the respiratory illness diagnosis. The data were analyzed comparing the patient and the control group by using relative risk and adjusted odds ratios. RESULTS: Of 391 patients with respiratory illness, 44.8% had a mental illness identified by GMHAT/PC interview compared with 24.3% of 177 attendants (controls). Anxiety (20.6%), depression (13.2%) and obsessive compulsive disorders (4.6%) were the most frequently identified mental disorders in the respiratory disease group. Chronic obstructive pulmonary disease and bronchial asthma when combined with rhinitis had a significantly higher prevalence of comorbid mental illness than those illnesses alone. CONCLUSION: Patients with chronic respiratory illness have high mental health comorbidity. Physicians and practitioners can be trained to identify mental illness using computer-assisted tools such as GMHAT/PC (which is easy to use by clinicians and well accepted by patients). A holistic approach of providing care to such patients may improve their overall outcome and quality of life.

Valproic acid combined with cytosine arabinoside in elderly patients with acute myeloid leukemia has in vitro but limited clinical activity.

Elderly patients with acute myeloid leukemia (AML) have a poor prognosis. The authors examined the in vitro and clinical activity of the histone deacetylase inhibitor valproic acid (VA) combined with cytosine arabinoside (AraC) in elderly patients with AML unsuited to intensive therapy. For the in vitro studies, primary AML cells from 11 patients were treated with AraC and VA and analyzed for apoptosis, cytostatic effects, differentiation and acetyl histone H3 induction. VA (alone and with AraC) enhanced apoptosis and induced acetyl histone H3. VA inhibited cell proliferation. For the clinical trial, 15 patients were treated with VA and subcutaneous AraC and assessed for toxicity and response. No complete or partial remissions were achieved. In conclusion, VA has in vitro activity against AML and has additional activity with AraC. However, in this study, this combination demonstrated limited clinical activity in elderly patients with AML.

Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses.

OBJECTIVES: To determine the incremental net health benefits of dabigatran etexilate 110 mg and 150 mg twice daily and warfarin in patients with non-valvular atrial fibrillation and to estimate the cost effectiveness of dabigatran in the United Kingdom. DESIGN: Quantitative benefit-harm and economic analyses using a discrete event simulation model to extrapolate the findings of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study to a lifetime horizon. SETTING: UK National Health Service. Population Cohorts of 50,000 simulated patients at moderate to high risk of stroke with a mean baseline CHADS(2) (Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes mellitus, previous Stroke/transient ischaemic attack) score of 2.1. MAIN OUTCOME MEASURES: Quality adjusted life years (QALYs) gained and incremental cost per QALY of dabigatran compared with warfarin. RESULTS: Compared with warfarin, low dose and high dose dabigatran were associated with positive incremental net benefits of 0.094 (95% central range -0.083 to 0.267) and 0.146 (-0.029 to 0.322) QALYs. Positive incremental net benefits resulted for high dose dabigatran in 94% of simulations versus warfarin and in 76% of those versus low dose dabigatran. In the economic analysis, high dose dabigatran dominated the low dose, had an incremental cost effectiveness ratio of £23,082 (€26,700; $35,800) per QALY gained versus warfarin, and was more cost effective in patients with a baseline CHADS(2) score of 3 or above. However, at centres that achieved good control of international normalised ratio, such as those in the UK, dabigatran 150 mg was not cost effective, at £42,386 per QALY gained. CONCLUSIONS: This analysis supports regulatory decisions that dabigatran offers a positive benefit to harm ratio when compared with warfarin. However, no subgroup for which dabigatran 110 mg offered any clinical or economic advantage over 150 mg was identified. High dose dabigatran will be cost effective only for patients at increased risk of stroke or for whom international normalised ratio is likely to be less well controlled.

Patient restraint positions in a psychiatric inpatient service.

AIM: The use of physical intervention on psychiatric inpatient units continues to be a source of debate and controversy. Some studies and national clinical guidelines have identified particular restraint positions as both dangerous and undesirable. The following study attempts to identify clinical variables that may make physical restraint in a particular position more likely. METHOD: A cross-sectional survey design was adopted and data was obtained from a violence and aggression audit form used by the trust. This form has 122 items to be completed by staff within 72 hours of an episode of patient aggression or self-harm. Ten variables were selected for scrutiny on the basis of their potential clinical importance. RESULTS: The survey found that prone restraint was significantly associated with others reporting the patient's imminent violence and high-intensity observation after the incident. Supine restraint was significantly associated with the patient being withdrawn and/or refusing to communicate prior to the episode and with a high severity incident rating after the incident. CONCLUSION: If we work on the premise that restraint in the prone position is less desirable than interventions undertaken with the patient in the supine position, this study clearly suggests that we have an opportunity to influence the nature of intervention through quite minimal changes to training programmes. It is important that any change in emphasis around intervention does not create a sense that controlled descent to the floor is inevitable. The principle of its use as a 'last resort in the event of loss of control on the feet' has to be maintained.