Pharmacological modulation of AMPA receptors rescues specific impairments in social behavior associated with the A350V Iqsec2 mutation.

In this study we tested the hypothesis that pharmacological modulation of glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in the Iqsec2 gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in the IQSEC2 gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. Using a battery of social behavioral tasks, we found that A350V Iqsec2 mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with a single dose of PF-4778574. We conclude that social behavior deficits associated with the A350V Iqsec2 mutation may be rescued by enhancing AMPAR mediated synaptic transmission.

Prisoners' access to HIV services in southern Malawi: a cross-sectional mixed methods study.

BACKGROUND: The prevalence of Human Immunodeficiency Virus (HIV) among prisoners remains high in many countries, especially in Africa, despite a global decrease in HIV incidence. Programs to reach incarcerated populations with HIV services have been implemented in Malawi, but the success of these initiatives is uncertain. We explored which challenges prisoners face in receiving essential HIV services and whether HIV risk behavior is prevalent in prisons. METHODS: We conducted a mixed-methods (qualitative and quantitative), cross-sectional study in 2018 in six prisons in Southern Malawi, two large central prisons with on-site, non-governmental organization (NGO) supported clinics and 4 smaller rural prisons. Four hundred twelve prisoners were randomly selected and completed a structured questionnaire. We conducted in-depth interviews with 39 prisoners living with HIV, which we recorded, transcribed and translated. We used descriptive statistics and logistic regression to analyze quantitative data and content analysis for qualitative data. RESULTS: The majority of prisoners (93.2%) were male, 61.4% were married and 63.1% were incarcerated for 1-5 years. Comprehensive services were reported to be available in the two large, urban prisons. Female prisoners reported having less access to general medical services than males. HIV risk behavior was reported infrequently and was associated with incarceration in urban prisons (adjusted odds ratio [aOR] 18.43; 95% confidence interval [95%-CI] 7.59-44.74; p = < 0.001) and not being married (aOR 17.71; 95%-CI 6.95-45.13; p = < 0.001). In-depth interviews revealed that prisoners living with HIV experienced delays in referrals for more severe illnesses. Prisoners emphasized the detrimental impact of poor living conditions on their personal health and their ability to adhere to antiretroviral therapy (ART). CONCLUSIONS: Malawian prisoners reported adequate knowledge about HIV services albeit with gaps in specific areas. Prisoners from smaller, rural prisons had suboptimal access to comprehensive HIV services and female prisoners reported having less access to health care than males. Prisoners have great concern about their poor living conditions affecting general health and adherence to ART. These findings provide guidance for improvement of HIV services and general health care in Malawian institutionalized populations such as prisoners.

Systematic Review of Hypertension and Diabetes Burden, Risk Factors, and Interventions for Prevention and Control in Malawi: The NCD BRITE Consortium.

Recent studies have found an increasing burden of noncommunicable diseases in sub-Saharan Africa. A compressive search of PubMed, Medline, EMBASE, and the World Health Organization Global Health Library databases was undertaken to identify studies reporting on the prevalence, risk factors, and interventions for hypertension and diabetes in Malawi. The findings from 23 included studies revealed a high burden of hypertension and diabetes in Malawi, with estimates ranging from 15.8% to 32.9% and from 2.4% to 5.6%, respectively. Associated risk factors included old age, tobacco smoking, excessive alcohol consumption, obesity, physical inactivity, high salt and sugar intake, low fruit and vegetable intake, high body mass index, and high waist-to-hip ratio. Certain antiretroviral therapy regimens were also associated with increased diabetes and hypertension risk in human immunodeficiency virus patient populations. Nationwide, the quality of clinical care was generally limited and demonstrated a need for innovative and targeted interventions to prevent, control, and treat noncommunicable diseases in Malawi.

Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial.

BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted. METHODS: Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162. FINDINGS: Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery. INTERPRETATION: This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy. FUNDING: Abbott (previously St Jude Medical).

Commentary. Transcranial Magnetic Stimulation: Does It Matter Where or What or Whom You Target?

Repetitive transcranial magnetic stimulation is a promising treatment for depression and possibly for other psychiatric disorders. Clinical trials show a small but significant benefit compared with sham treatment. Occasional patients respond dramatically, as witnessed in the 2 cases presented here of patients with depersonalization symptoms. The guest discussant, Dr Joshua Berman, analyzes the challenges of finding individualized treatment parameters that could make repetitive transcranial magnetic stimulation more predictably effective.

Building a knowledge translation platform in Malawi to support evidence-informed health policy.

With the support of the World Health Organization's Evidence-Informed Policy Network, knowledge translation platforms have been developed throughout Africa, the Americas, Eastern Europe, and Asia to further evidence-informed national health policy. In this commentary, we discuss the approaches, activities and early lessons learned from the development of a Knowledge Translation Platform in Malawi (KTPMalawi). Through ongoing leadership, as well as financial and administrative support, the Malawi Ministry of Health has strongly signalled its intention to utilize a knowledge translation platform methodology to support evidence-informed national health policy. A unique partnership between Dignitas International, a medical and research non-governmental organization, and the Malawi Ministry of Health, has established KTPMalawi to engage national-level policymakers, researchers and implementers in a coordinated approach to the generation and utilization of health-sector research. Utilizing a methodology developed and tested by knowledge translation platforms across Africa, a stakeholder mapping exercise and initial capacity building workshops were undertaken and a multidisciplinary Steering Committee was formed. This Steering Committee prioritized the development of two initial Communities of Practice to (1) improve data utilization in the pharmaceutical supply chain and (2) improve the screening and treatment of hypertension within HIV-infected populations. Each Community of Practice's mandate is to gather and synthesize the best available global and local evidence and produce evidence briefs for policy that have been used as the primary input into structured deliberative dialogues. While a lack of sustained initial funding slowed its early development, KTPMalawi has greatly benefited from extensive technical support and mentorship by an existing network of global knowledge translation platforms. With the continued support of the Malawi Ministry of Health and the Evidence-Informed Policy Network, KTPMalawi can continue to build on its role in facilitating the use of evidence in the development and refinement of health policy in Malawi.

Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial.

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22-68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.

Task-shifting and prioritization: a situational analysis examining the role and experiences of community health workers in Malawi.

BACKGROUND: As low- and middle-income countries face continued shortages of human resources for health and the double burden of infectious and chronic diseases, there is renewed international interest in the potential for community health workers to assume a growing role in strengthening health systems. A growing list of tasks, some of them complex, is being shifted to community health workers' job descriptions. Health Surveillance Assistants (HSAs) - as the community health worker cadre in Malawi is known - play a vital role in providing essential health services and connecting the community with the formal health care sector. The objective of this study was to understand the performed versus documented roles of the HSAs, to examine how tasks were prioritized, and to understand HSAs' perspectives on their roles and responsibilities. METHODS: A situational analysis of the HSA cadre and its contribution to the delivery of health services in Zomba district, Malawi was conducted. Focus groups and interviews were conducted with 70 HSAs. Observations of three HSAs performing duties and work diaries from five HSAs were collected. Lastly, six policy-maker and seven HSA supervisor interviews and a document review were used to further understand the cadre's role and to triangulate collected data. RESULTS: HSAs performed a variety of tasks in addition to those outlined in the job description resulting in issues of overloading, specialization and competing demands existing in the context of task-shifting and prioritization. Not all HSAs were resistant to the expansion of their role despite role confusion and HSAs feeling they lacked adequate training, remuneration and supervision. HSAs also said that increasing workload was making completing their primary duties challenging. Considerations for policy-makers include the division of roles of HSAs in prevention versus curative care; community versus centre-based activities; and the potential specialization of HSAs. CONCLUSION: This study provides insights into HSAs' perceptions of their work, their expanding role and their willingness to change the scope of their practice. There are clear decision points for policy-makers regarding future direction in policy and planning in order to maximize the cadre's effectiveness in addressing the country's health priorities.

Effect of atropine dose on heart rate during electroconvulsive therapy.

INTRODUCTION: Transient bradycardia during the stimulation phase of electroconvulsive therapy (ECT) is a well-known clinical observation. The optimal dose of atropine needed to prevent bradycardia has not been determined. This study was designed to investigate the effect of low doses of atropine on heart rate during ECT. METHODS: Patients who received at least 2 different doses of atropine over their series of right unilateral ECT were included in the analysis. The anesthetic consisted of 0, 0.2, 0.3, or 0.4 mg of atropine, methohexital, and succinylcholine. Heart rate was measured by the RR interval, the time between sequential R waves on the electrocardiogram. Analysis was performed using logistic multivariate regression and repeated-measures multivariate analysis of variance. RESULTS: One hundred eighteen ECT sessions were identified from 19 patients. Patients were grouped into 4 groups by atropine dose (0, 0.2, 0.3, or 0.4 mg) with 9, 33, 13, and 63 ECT sessions identified for each dose, respectively. Patients who received atropine had significantly less bradycardia after electrical stimulus and a faster heart rate through the seizure than patients who did not receive atropine. There was no significant difference in heart rate between patients receiving 0.2, 0.3, and 0.4 mg of atropine at any time point. There was no significant difference in heart rate at time points after the seizure conclusion in any group of patients. CONCLUSION: Low-dose atropine results in significantly less bradycardia after electrical stimulus. There was no significant difference in heart rate across low doses of atropine.

Developing a hospital quality improvement initiative in Lesotho.

PURPOSE: Hospital-based quality improvement (QI) programs are becoming increasingly common in developing countries as a sustainable method of strengthening health systems. The aim of this paper is to present the results and lessons learned from a QI program in a large, rural, district hospital in Lesotho, Southern Africa. DESIGN/METHODOLOGY/APPROACH: Over a 15-month period, a locally-relevant, hospital-wide QI program was developed and implemented. The QI program consisted of: planning meetings with district and hospitals staff; creation of multi-disciplinary QI teams; establishment of a QI steering committee; design and implementation of a locally appropriate QI curriculum; and monthly consultation from technical advisers. Initial QI programming was developed in three distinct areas: maternity care, out-patient care, and referral systems. FINDINGS: Partogram documentation in the maternity department increased by 78 percent, waiting time for critically ill patients in the out-patient department was reduced by 84 percent, and emergency referral times were reduced by 58 percent. ORIGINALITY/VALUE: The design and early implementation of QI programs should focus on easily achievable, locally-relevant improvement projects. It was found that early successes helped to fuel further QI gains and the authors believe that the work building sustainable QI skill sets within hospital staff could be useful in the future when attempting to tackle larger national-level quality of care indicators. The findings add to the existing evidence suggesting that an increased use of locally-relevant quality improvement programming could help strengthen health care systems in low resource settings.

Electroconvulsive therapy for the treatment of refractory mania.

We present the case of a patient with treatment-refractory mania. The patient had been tried on numerous medications, to which she either did not respond well or on which she developed severe side effects, However, the patient improved rapidly when treated with unilateral electropercussive therapy (ECT) following a court order. We outline the legal barriers that have been raised against the use of ECT in patients with mania, who often refuse treatment, and the irony that ECT can be safer than medications for some patients. ECT is underutilized in mania but deserves more frequent consideration. (Journal of Psychiatric Practice. 2011;17:61-66).

Design, implementation, and evaluation of a computerized system to communicate with patients with limited native language proficiency in the perioperative period.

BACKGROUND: Effective communication with patients having limited proficiency in the native language of anesthesia care providers during the perioperative period is often challenging. We describe how we developed, implemented, and evaluated a computerized system to convey frequently used prerecorded phrases related to perioperative anesthesia care in the languages we most often encounter in such patients. METHODS: Phrases were chosen through a consensus process among anesthesia department members. These included routine sayings used to inform patients about what they should anticipate, what interventions we are performing, and how they can participate. Common questions requiring a "yes" or "no" answer were also identified. We recorded these phrases using native speakers who were both knowledgeable medically and familiar with the culture of the patients to provide accurate translations. We developed a software application that categorically grouped the phrases and allowed care providers to select a phrase and play the associated sound file to the patient and deployed the program on our touchscreen-enabled anesthesia information management system workstations. A convenience sample of obstetrical patients speaking a Chinese dialect with whom the language program was used were asked to complete an anonymous questionnaire, translated into Chinese, about their experience. Ninety-five percent lower confidence limits (LCLs) were calculated for response proportions. RESULTS: We approached 25 parturients with varying levels of English comprehension, and all agreed to use the language program. Each used it throughout her interaction with the anesthesia care providers during labor and delivery, and all patients completed the survey. Acceptance of the process was high, with all patients indicating that they would like to use it again were they to return for another procedure requiring anesthesia. Eighty-eight percent (LCL = 73%) indicated that having instructions in their native language made them feel more relaxed, whereas the experience was neutral in the remainder. Comprehension of the phrases presented was high, with 96% (LCL = 83%) indicating that they understood all instructions. Ninety-six percent (LCL = 83%) of patients indicated that they would be likely to refer friends and family to our institution based on the availability of this device. CONCLUSIONS: Although patient safety likely could be improved by use of a communication device such as the one we developed, our study was insufficiently powered to be able to measure this potential improvement. The process we describe should be useful wherever anesthesia care providers are not able to communicate in the same language as their patients.

Cholinergic circuits and signaling in the pathophysiology of schizophrenia.

Central cholinergic signaling has long been associated with aspects of memory, motivation, and mood, each affected functions in neuropsychiatric disorders such as schizophrenia. In this chapter, we review evidence related to the core hypothesis that dysregulation of central cholinergic signaling contributes to the pathophysiology of schizophrenia. Although central cholinergic circuits are resistant to simplification-particularly when one tries to parse the contributions of various classes of cholinergic receptors to disease related phenomena--the potential role of ACh signaling in Schizophrenia pathophysiology deserves careful consideration for prospective therapeutics. The established role of cholinergic circuits in attentional tuning is considered along with recent work on how the patterning of cholinergic activity may modulate corticostriatal circuits affected in schizophrenia.