A novel semi-automated method of tracking fetal movements.

We have designed software that can "look" at recorded ultrasound sequences. We analyzed fifteen video sequences representing recorded ultrasound scans of nine fetuses. Our method requires a small amount of user labelled pixels for processing the first frame. These initialize GrowCut, a background removal algorithm, which was used for separating the fetus from its surrounding environment (segmentation). For each subsequent frame, user input is no longer necessary as some of the pixels will inherit labels from the previously processed frame. This results in our software's ability to track movement. Two sonographers rated the results of our computer's 'vision' on a scale from 1 (poor fit) to 10 (excellent fit). They assessed tracking accuracy for the entire video as well as segmentation accuracy (the ability to identify fetus from non-fetus) for every 100th processed frame. There was no appreciable deterioration in the software's ability to track the fetus over time.

Dietary intervention for oral allergy syndrome as a treatment in orofacial granulomatosis: a new approach?

BACKGROUND: Orofacial granulomatosis (OFG) is a chronic granulomatous condition of the mouth, face and lips. Recent work demonstrates a high rate of atopy and silver birch sensitisation from skin prick testing (SPT). Oral allergy syndrome (OAS) is an acute oro-pharyngeal IgE mediated reaction, triggered by foods that cross react with pollens, most commonly silver birch. The aim of this study was to determine if patients with OFG and positive SPT to common OAS associated pollens responded to avoidance of cross reactive foods. METHODS: Patients with OFG and positive SPT to silver birch, grass, mugwort, ragweed and latex were required to avoid cross reacting foods, for 6 weeks and, in those who responded, for a total of 12 weeks. All had standardized oral examinations and were given severity scores (SS) at each appointment. RESULTS: Twenty two of 47 (47%) patients had one or more positive SPT and 13/22 completed 6 weeks on the diet. No difference was seen in SS between weeks 0 (14.62 ± 11.16) and 6 (13.31 ± 10.33; P = 0.656). Six of 14 (43%) had significantly improved SS (week 0; 19.17 ± 12.95, week 6; 10.83 ± 4.99, P = 0.027). Five completed 12 weeks and no further improvement was seen (week 6; 11 ± 5.57, week 12; 10.4 ± 9.94; P = 0.068). Two patients required no further treatments. CONCLUSIONS: On an intention to treat basis, only 2/14 patients improved and required no further intervention. Whilst this diet cannot be recommended routinely, the improvement seen in some patients raises questions about the role of OAS in patients with OFG.

Development of a low phenolic acid diet for the management of orofacial granulomatosis.

BACKGROUND: Orofacial granulomatosis (OFG) is a rare disease of unknown cause. A cinnamon- and benzoate-free diet is successful in up to 72% of patients. Phenolic acids are among the chemical constituents restricted in this diet, which avoids some but not all of these structurally similar compounds. The present study aimed to: (i) develop a novel diet low in phenolic acids; (ii) implement this in a small clinical trial; and (iii) assess its nutritional adequacy. METHODS: A literature review identified 10 papers quantifying phenolic acids from which 91 10-mg phenolic acid exchanges were devised. A phenolic acid exclusion diet with precautionary micronutrient supplementation was designed and implemented in 10 patients. Phenolic acids were excluded for 6 weeks and were reintroduced at a rate of one exchange every second day for 6 weeks. Wilcoxon matched pairs tests analysed disease outcomes measured by an oral disease severity scoring tool at weeks 0, 6 and 12. Nutritional adequacy was assessed, excluding micronutrient supplementation, at weeks 0 and 6, and compared intakes with dietary reference values. RESULTS: The diet was nutritionally inadequate for a range of micronutrients. Seven of 10 patients responded. Mean [standard deviation (SD)] severity scores improved from week 0-6 [20.8 (9.39) and 10.1 (5.72); P = 0.009] and were maintained in five patients who completed the reintroduction [6.6 (3.13) and 7.2 (5.54); P = 0.713]. CONCLUSIONS: A low phenolic acid diet with micronutrient supplementation holds promise of a novel dietary treatment for OFG. Further work is required in larger studies to determine long-term outcomes.

Substantially reduced pre-patent parasite multiplication rates are associated with naturally acquired immunity to Plasmodium falciparum.

Naturally acquired immunity to Plasmodium falciparum's asexual blood stage reduces parasite multiplication at microscopically detectable densities. The effect of natural immunity on initial prepatent parasite multiplication during the period following a new infection has been uncertain, contributing to doubt regarding the utility of experimental challenge models for blood-stage vaccine trials. Here we present data revealing that parasite multiplication rates during the initial prepatent period in semi-immune Gambian adults are substantially lower than in malaria-naive participants. This supports the view that a blood-stage vaccine capable of emulating the disease-reducing effect of natural immunity could achieve a detectable effect during the prepatent period.

Spontaneous pneumomediastinum in two young women.

SUMMARY: Spontaneous pneumomediastinum (SPM) is a rare benign condition which must be differentiated from secondary pneumomediastinum due to chest trauma, abscess formation or Boerhaave's syndrome. We present two young women with SPM due to chronic self-induced vomiting and starvation associated with psychosis and pregnancy-associated vomiting respectively. This report highlights the exclusionary diagnostic pathway, the principles of conservative management and the need for a tailored multidisciplinary approach to enhance patient recovery and prevent future recurrence.

Retain rural doctors: Burnout, depression and anxiety in medical doctors working in rural KwaZulu-Natal Province, South Africa.

BACKGROUND: There is a need to retain medical doctors in rural areas to ensure equitable access to healthcare for rural communities. Burnout, depression and anxiety may contribute to difficulty in retaining doctors. Some studies have found high rates of these conditions in medical doctors in general, but there is little research available on their prevalence among those working in the rural areas of South Africa (SA). OBJECTIVES: To determine the prevalence of burnout, depression and anxiety in doctors working in rural district hospitals in northern KwaZulu-Natal (KZN) Province, SA, and to explore the associated sociodemographic and rural work-related factors. METHODS: We performed a quantitative descriptive cross-sectional study in three districts in northern KZN among medical doctors working at 15 rural district hospitals during August and September 2020. The prevalences of burnout, depression and anxiety were measured using the Maslach Burnout Inventory, the Patient Health Questionnaire-9 and the Generalized Anxiety Disorder 7-item questionnaire, respectively. The sociodemographic and rural occupational profiles were assessed using a questionnaire designed by the authors. Descriptive statistics were used to analyse the data. RESULTS: Of 96 doctors who participated in the study, 47.3% (n=44) were aged between 24 and 29 years and 70.8% (n=68) had worked in a rural setting for <5 years. Of the participants, 68.5% (n=61) were considered to have burnout. The screening tests for depression and anxiety were positive for 35.6% (n=31) and 23.3% (n=20) of participants, respectively. Burnout alone was significantly associated with female gender (84.8%; n=39) (χ2=11.65, df=1, p=0.01). Burnout (χ2=8.14, df=3, p=0.04) and anxiety (χ2=12.96, df=3, p<0.01) were both significantly associated with occupational rank, with 85.2% (n=23) of community service medical officers (CSMOs) reporting the former and 29.6% (n=8) screening positive for generalised anxiety disorder. Burnout (χ2=7.61, df=1, p=0.01), depression (χ2=5.49, df=1, p=0.02) and anxiety (χ2=4.08, df=1, p=0.04) were all shown to be significantly associated with doctors planning to leave the public sector in the next 2 years. CONCLUSIONS: Our study found high rates of burnout, depression and anxiety in rural doctors in northern KZN, all of which were associated with the intention to leave the public sector in the next 2 years. Of particular concern was that CSMOs as a group had high burnout and anxiety rates and female gender was associated with burnout. We recommend that evidence-based solutions are urgently implemented to prevent burnout and retain rural doctors.

Transnasal humidified rapid-insufflation ventilatory exchange ('THRIVE') in the coronavirus disease 2019 pandemic.

BACKGROUND: Since the start of the coronavirus disease 2019 pandemic, transnasal humidified rapid-insufflation ventilatory exchange ('THRIVE') has been classified as a high-risk aerosol-generating procedure and is strongly discouraged, despite a lack of conclusive evidence on its safety. METHODS: This study aimed to investigate the safety of transnasal humidified rapid-insufflation ventilatory exchange usage and its impact on staff members. A prospective study was conducted on all transnasal humidified rapid-insufflation ventilatory exchange cases performed in our unit between March and July 2020. RESULTS: During the study period, 18 patients with a variety of airway pathologies were successfully managed with transnasal humidified rapid-insufflation ventilatory exchange. For each case, 7-10 staff members were present. Appropriate personal protective equipment protocols were strictly implemented and adhered to. None of the staff involved reported symptoms or tested positive for coronavirus disease 2019, up to at least a month following their exposure to transnasal humidified rapid-insufflation ventilatory exchange. CONCLUSION: With strictly correct personal protective equipment use, transnasal humidified rapid-insufflation ventilatory exchange can be safely employed for carefully selected patients in the current pandemic, without jeopardising the health and safety of the ENT and anaesthetic workforce.

Amodiaquine dosage and tolerability for intermittent preventive treatment to prevent malaria in children.

Sulfadoxine-pyrimethamine with amodiaquine (SP-AQ) is a highly efficacious regimen for intermittent preventive treatment to prevent malaria in children (IPTc), but the amodiaquine component is not always well tolerated. We determined the association between amodiaquine dosage by body weight and mild adverse events (AEs) and investigated whether alternative age-based regimens could improve dosing accuracy and tolerability, using data from two trials of IPTc in Senegal, one in which AQ dose was determined by age and the other in which it was determined by weight category. Both dosage strategies resulted in some children receiving AQ doses above the recommended therapeutic range. The odds of vomiting increased with increasing amodiaquine dosage. In one study, incidence of fever also increased with increasing dosage. Anthropometric data from 1,956 children were used to predict the dosing accuracy of existing and optimal alternative regimens. Logistic regression models describing the probability of AEs by dosage were used to predict the potential reductions in mild AEs for each regimen. Simple amendments to current AQ dosing schedules based on the child's age could substantially increase dosing accuracy and thus improve the tolerability of IPTc using SP-amodiaquine in situations where weighing the child is impractical.

Telephone follow-up to improve glycaemic control in patients with Type 2 diabetes: systematic review and meta-analysis of controlled trials.

OBJECTIVE: To examine the impact of telephone follow-up interventions on glycaemic control in patients with Type 2 diabetes. METHODS: This was a systematic review and meta-analysis of randomized controlled trials using The Cochrane Library, including the Cochrane central register of controlled trials; MEDLINE, EMBASE, PsycINFO and CINHAL, together with citation searching. The included studies were randomized controlled trials examining the effect of a telephone follow-up intervention on glycaemic control in patients with Type 2 diabetes. All the included trials were subject to critical appraisal. Data were extracted on study design, characteristics of patients, exact nature of the telephone intervention and details of comparison. Pooled standardized effects were calculated for the primary outcome. Glycaemic control was measured by HbA(1c) . RESULTS: HbA(1c) levels reported in the reviewed studies were pooled using random effects models. The standardized effect of telephone follow-up was equivocal, with endpoint data showing weighted mean differences of -0.44 (95% CI -0.93 to 0.06) (Z = -1.72, P=0.08) in favour of the telephone follow-up intervention. Subgroup analysis of more intensive interventions (interactive follow-up with health professional plus automated follow-up or non-interactive follow-up) showed (n=1057) a significant benefit in favour of the treatment group, with a standardized mean difference of -0.84 (95% CI -1.67 to 0.0) (Z=1.97, P=0.05), indicating that more intensive (targeted) modes of follow-up may have better effects on glycaemic control. CONCLUSIONS: The analysis suggested that telephone follow-up interventions following a more intensive targeted approach could have a positive impact on glycaemic control for Type 2 diabetes.

Use of transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) to facilitate the management of subglottic stenosis in pregnancy.

Subglottic stenosis is a rare condition. Diagnosis is often delayed as symptoms are attributed to other causes, such as asthma. This problem may be compounded in pregnancy when dyspnoea may be attributed to normal physiological changes. In respiratory compromise, surgical intervention may be required and airway management is challenging as endotracheal intubation may be traumatic or, in severe cases, impossible. Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) is a novel open-airway apnoeic technique using high-flow nasal oxygen. It does not expose the patient to the risks of jet ventilation, nor does it require the placement of an airway device to effectively oxygenate the patient. In pregnancy, elevation of maternal carbon dioxide is of particular concern as it may result in a worsening fetal acidosis. While THRIVE has been shown to provide some clearance of carbon dioxide, a patent airway is required for it to function effectively. In this case report we describe the management of a pregnant patient who underwent balloon dilatation for severe subglottic stenosis at 23 weeks' gestation using THRIVE and we summarise the evidence supporting the use of this new technique in pregnant women.

Gastric and small intestinal ileus as a cause of acute colic in the post parturient mare.

REASONS FOR PERFORMING STUDY: Ileus (functional obstruction of aboral gastrointestinal transit) is an uncommon cause of gastrointestinal dysfunction and colic in the horse. A number of specific conditions have been previously reported in association with ileus. This report describes the recognition of primary gastric and small intestinal ileus of undetermined cause in a series of post parturient mares. OBJECTIVES: To describe the clinical features, treatment and outcome of a series of episodes of primary gastric and small intestinal ileus. METHODS: A retrospective study was performed of colic episodes seen in an equine practice in Newmarket, UK over a 6 year period (2002-2007). RESULTS: Seventeen episodes of gastric and small intestinal ileus were identified, which occurred in 15 horses. All episodes occurred in post parturient mares. No previously reported cause of ileus was identified in any of the episodes. Fifteen of the 17 episodes received medical treatment (medical support and nasogastric decompression) and, in addition, surgical decompression was performed in 9 episodes. Two mares were subjected to euthanasia before treatment due to the presence of gastric rupture and the remaining 13 mares survived with a follow-up period of at least 10 months. Two mares suffered a further episode of gastric and small intestinal ileus, one 4 days and the other 2 years after the initial episode. CONCLUSIONS: Gastric and small intestinal ileus of, as yet, unknown aetiology appears to be a potential cause of acute colic in the post parturient mare. The outcome following treatment by decompression is good.

Model-based drug development.

The low productivity and escalating costs of drug development have been well documented over the past several years. Less than 10% of new compounds that enter clinical trials ultimately make it to the market, and many more fail in the preclinical stages of development. These challenges in the "critical path" of drug development are discussed in a 2004 publication by the US Food and Drug Administration. The document emphasizes new tools and various opportunities to improve drug development. One of the opportunities recommended is the application of "model-based drug development (MBDD)." This paper discusses what constitutes the key elements of MBDD and how these elements should fit together to inform drug development strategy and decision-making.

Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial.

BACKGROUND: It is recommended that children aged 3 months to five years of age living in areas of seasonal transmission in the sub-Sahel should receive Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) during the malaria transmission season. The purpose of this study was to evaluate the safety of SMC with SPAQ in children when delivered by community health workers in three districts in Senegal where SMC was introduced over three years, in children from 3 months of age to five years of age in the first year, then in children up to 10 years of age. METHODS: A surveillance system was established to record all deaths and all malaria cases diagnosed at health facilities and a pharmacovigilance system was established to detect adverse drug reactions. Health posts were randomized to introduce SMC in a stepped wedge design. SMC with SPAQ was administered once per month from September to November, by nine health-posts in 2008, by 27 in 2009 and by 45 in 2010. RESULTS: After three years, 780,000 documented courses of SMC had been administered. High coverage was achieved. No serious adverse events attributable to the intervention were detected, despite a high level of surveillance. CONCLUSIONS: SMC is being implemented in countries of the sub-Sahel for children under 5 years of age, but in some areas the age distribution of cases of malaria may justify extending this age limit, as has been done in Senegal. Our results show that SMC is well tolerated in children under five and in older children. However, pharmacovigilance should be maintained where SMC is implemented and provision for strengthening national pharmacovigilance systems should be included in plans for SMC implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00712374.

Good Practices in Model-Informed Drug Discovery and Development: Practice, Application, and Documentation.

This document was developed to enable greater consistency in the practice, application, and documentation of Model-Informed Drug Discovery and Development (MID3) across the pharmaceutical industry. A collection of "good practice" recommendations are assembled here in order to minimize the heterogeneity in both the quality and content of MID3 implementation and documentation. The three major objectives of this white paper are to: i) inform company decision makers how the strategic integration of MID3 can benefit R&D efficiency; ii) provide MID3 analysts with sufficient material to enhance the planning, rigor, and consistency of the application of MID3; and iii) provide regulatory authorities with substrate to develop MID3 related and/or MID3 enabled guidelines.

Correction: Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial.

[This corrects the article DOI: 10.1371/journal.pone.0162563.].

[Acceptability of indoor residual spraying in the Central-Western of Senegal]. / Étude de l'acceptabilité de l'aspersion intradomiciliaire d'insecticide à effet rémanent dans le centre-ouest du Sénégal.

The recent decline of malaria transmission in central-western of Senegal after a scaling up of control measures gives an open window for interventions toward malaria elimination. As a consequence, malaria transmission is now occurring as hotspots. The aim of the project is to evaluate whether target control measures combining indoor residual spraying (IRS) with chemoprophylaxis can virtually eliminate malaria in hotspots. Targeted villages located in four (4) health districts (Mbour, Fatick, Niakhar and Bambey) were sprayed in august 2013 with Actellic® 300 CS (Pirimiphosmethyl). Our objective in this study is to evaluate the acceptability of IRS in the population. IRS is a very complex intervention that requires strong adhesion of populations. After its implementation, 370 households have been interviewed. The results of this survey showed good acceptability of IRS using Actellic® 300 CS, with 97.8% of beneficiaries who declared that IRS is good and even excellent for the community. Despite inconveniences that may arise during intervention, including the preparation of structures to be treated, 98% of respondents were not disturbed in their daily activities. 98.6% of responders declared that sprayers were working with professionalism and almost all households (99.7%) are willing to accept IRS next year. The survey revealed a good acceptability of indoor residual spraying in hot spots located in central-western of Senegal; spraying with Actellic® 300 CS did not cause a problem to the targeted populations. Finally, there is great satisfaction in the population due a huge reduction of mosquito nuisances.

Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development.

The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.

Maternal plasma viral RNA levels determine marked differences in mother-to-child transmission rates of HIV-1 and HIV-2 in The Gambia. MRC/Gambia Government/University College London Medical School working group on mother-child transmission of HIV.

OBJECTIVES: To determine the rates of, and risk factors for, mother-to-child transmission (MCT) of HIV-1 and HIV-2 infection in The Gambia. DESIGN: A blinded, prospective, community-based cohort study of 29.549 pregnant women attending the eight largest antenatal clinics in The Gambia. METHODS: Women were tested for HIV-1 and HIV-2 infection. Infected subjects and a group of HIV-seronegative women were followed with their babies until 18 months after delivery. Maternal CD4 cell count percentages were measured before and 18 months after delivery, and the antenatal plasma viral load was determined. Babies were tested for HIV by the polymerase chain reaction and/or serology at 2, 9 and 18 months of age. RESULTS: The study enrolled 144 women positive for HIV-1 and 294 for HIV-2 plus 565 seronegative pregnant women: the mean antenatal percentage CD4 cell counts of 96 HIV-1-positive, 223 HIV-2-positive and 125 HIV-seronegative mothers were 31% [95% confidence interval (CI) 28-33], 41% (95% CI 39-42) and 47% (95% CI 45-49), respectively. The geometric mean antenatal plasma viral load of 94 HIV-1-infected women was 15,100 copies x 10(3) ml (95% CI 10,400-19,000) which was much higher than that of 60 randomly selected HIV-2-infected women, which was 410 copies x 10(3) ml (95% CI 150-910) (P < 0.001). The estimated transmission rate of HIV-1 was 24.4% (95% CI 14.6-33.9) and that of HIV-2 was 4.0% (95% CI 1.9-7.4). Five of 17 HIV-1-positive and three of eight HIV-2-positive babies were infected after 2 months of age. Birth in the rainy season [odds ratio (OR) 2.9; 95% CI 1.2-7.2], a low postnatal CD4 cell percentage (OR for a 10% fall 2.4; 95% CI 1.1-5.1) and a high maternal plasma viral load (OR for a 10-fold increase 2.9; 95% CI 1.1-7.8) were risk factors for transmission that applied equally to both viruses. CONCLUSION: Low maternal HIV-2 RNA levels, which on average are 37-fold less than in HIV-1 infection, relate to the low MCT rate of HIV-2.

Maternal HIV-1 and HIV-2 infection and child survival in The Gambia.

OBJECTIVE: To compare the survival of children born to HIV-1 or HIV-2 seropositive mothers with that of children born to HIV-seronegative mothers and to evaluate risk factors for mortality. DESIGN: Physician-blinded prospective study. METHODS: One hundred and one HIV-1-seropositive, 243 HIV-2-seropositive pregnant women, and 468 HIV-seronegative women (control group) matched by age, parity, and health centre, were followed up in a study of mother-to-child transmission of HIV. Mothers and children were seen at 2 and 6 months of age and subsequently followed at 3-monthly intervals up to 18 months of age. HIV infection in children was diagnosed by polymerase chain reaction at 2, 9 or 18 months and by antibody assays at 18 months. RESULTS: Fifteen per cent of children born to HIV-1-infected mothers died compared with 7% of children born to HIV-2-infected mothers [hazard ratio, 2.3; 95% confidence interval (CI), 1.1-4.7; P = 0.02], and 6% of HIV-seronegative mothers (hazard ratio, 2.6; 95% CI, 1.4-5.0; P = 0.003). Six of the 17 children known to be HIV-1 infected died compared with none among the eight HIV-2-infected children (P = 0.13). High proviral load in the babies, high antenatal maternal RNA plasma viral load, and maternal death increased child mortality significantly. CONCLUSIONS: More children born to HIV-1-infected mothers died in comparison with those born to HIV-2-infected mothers or to mothers from the control group. This effect was due to excess death in HIV-1-infected infants which was associated with a high viral load in the affected mother and child.