Clinical trials in pediatric ALS: a TRICALS feasibility study.

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information

WHO 2010 Guidelines for Prevention of Mother-to-Child HIV Transmission in Zimbabwe: Modeling Clinical Outcomes in Infants and Mothers

The Zimbabwean national prevention of mother-to-child HIV transmission (PMTCT) program provided primarily single-dose nevirapine (sdNVP) from 2002-2009 and is currently replacing sdNVP with more effective antiretroviral (ARV) regimens.Published HIV and PMTCT models, with local trial and programmatic data, were used to simulate a cohort of HIV-infected, pregnant/breastfeeding women in Zimbabwe (mean age 24.0 years, mean CD4 451 cells/µL). We compared five PMTCT regimens at a fixed level of PMTCT medication uptake: 1) no antenatal ARVs (comparator); 2) sdNVP; 3) WHO 2010 guidelines using "Option A" (zidovudine during pregnancy/infant NVP during breastfeeding for women without advanced HIV disease; lifelong 3-drug antiretroviral therapy (ART) for women with advanced disease); 4) WHO "Option B" (ART during pregnancy/breastfeeding without advanced disease; lifelong ART with advanced disease); and 5) "Option B+:" lifelong ART for all pregnant/breastfeeding, HIV-infected women. Pediatric (4-6 week and 18-month infection risk, 2-year survival) and maternal (2- and 5-year survival, life expectancy from delivery) outcomes were projected.Eighteen-month pediatric infection risks ranged from 25.8% (no antenatal ARVs) to 10.9% (Options B/B+). Although maternal short-term outcomes (2- and 5-year survival) varied only slightly by regimen, maternal life expectancy was reduced after receipt of sdNVP (13.8 years) or Option B (13.9 years) compared to no antenatal ARVs (14.0 years), Option A (14.0 years), or Option B+ (14.5 years).Replacement of sdNVP with currently recommended regimens for PMTCT (WHO Options A, B, or B+) is necessary to reduce infant HIV infection risk in Zimbabwe. The planned transition to Option A may also improve both pediatric and maternal outcomes

Overcoming phase 1 delays: the critical component of obstetric fistula prevention programs in resource-poor countries

<p>Abstract</p> <p>Background</p> <p>An obstetric fistula is a traumatic childbirth injury that occurs when labor is obstructed and delivery is delayed. Prolonged obstructed labor leads to the destruction of the tissues that normally separate the bladder from the vagina and creates a passageway (fistula) through which urine leaks continuously. Women with a fistula become social outcasts. Universal high-quality maternity care has eliminated the obstetric fistula in wealthy countries, but millions of women in resource-poor nations still experience prolonged labor and tens of thousands of new fistula sufferers are added to the millions of pre-existing cases each year. This article discusses fistula prevention in developing countries, focusing on the factors which delay treatment of prolonged labor.</p> <p>Discussion</p> <p>Obstetric fistulas can be prevented through contraception, avoiding obstructed labor, or improving outcomes for women who develop obstructed labor. Contraception is of little use to women who are already pregnant and there is no reliable screening test to predict obstruction in advance of labor. Improving the outcome of obstructed labor depends on prompt diagnosis and timely intervention (usually by cesarean section). Because obstetric fistulas are caused by tissue compression, the time interval from obstruction to delivery is critical. This time interval is often extended by delays in deciding to seek care, delays in arriving at a hospital, and delays in accessing treatment after arrival. Communities can reasonably demand that governments and healthcare institutions improve the second (transportation) and third (treatment) phases of delay. Initial delays in seeking hospital care are caused by failure to recognize that labor is prolonged, confusion concerning what should be done (often the result of competing therapeutic pathways), lack of women’s agency, unfamiliarity with and fear of hospitals and the treatments they offer (especially surgery), and economic constraints on access to care.</p> <p>Summary</p> <p>Women in resource-poor countries will use institutional obstetric care when the services provided are valued more than the competing choices offered by a pluralistic medical system. The key to obstetric fistula prevention is competent obstetrical care delivered respectfully, promptly, and at affordable cost. The utilization of these services is driven largely by trust.</p

Arousal States, Symptoms, Behaviour, Sleep and Body Temperature

Autonomic arousal (or affective states, e.g. stress, anxiety), symptoms (e.g. fatigue, pain), sleep-disrupting behaviour (e.g. physical inactivity, electronic device use, TV watching, shift work) and medications are linked to impaired sleep and, in many cases, overweight/obesity. Further, in many cases, the phenomena are linked to an elevated BT, and in some cases, a high nocturnal BT, although there is a lack of specific research pertaining to nocturnal BT and the relationship between BT and chronic pain. A relative hyperthermia at night is known to interfere with sleep onset, possible via a phase-shift in the sleep-wake cycle. However, an elevated BT can additionally lead to activation of the inflammatory response system (e.g. cytokine secretion), which may represent another possible mechanism by which the aforementioned states, symptoms, disorders and behaviour can develop