Evaluation of long-term effectiveness of the use of carglumic acid in patients with propionic acidemia (PA) or methylmalonic acidemia (MMA): study protocol for a randomized controlled trial.

INTRODUCTION: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive inborn errors of metabolism characterized by hyperammonemia due to N-acetylglutamate synthase (NAGS) dysfunction. Carglumic acid (Carbaglu®; Orphan Europe Ltd.) is approved by the US Food and Drug Administration (USFDA) for the treatment of hyperammonemia due hepatic NAGS deficiency. Here we report the rationale and design of a phase IIIb trial that is aimed at determining the long-term efficacy and safety of carglumic acid in the management of PA and MMA. METHODS: This prospective, multicenter, open-label, randomized, parallel group phase IIIb study will be conducted in Saudi Arabia. Patients with PA or MMA (≤15 years of age) will be randomized 1:1 to receive twice daily carglumic acid (50 mg/kg/day) plus standard therapy (protein-restricted diet, L-carnitine, and metronidazole) or standard therapy alone for a 2-year treatment period. The primary efficacy outcome is the number of emergency room visits due to hyperammonemia. Safety will be assessed throughout the study and during the 1 month follow-up period after the study. DISCUSSION: Current guidelines recommend conservative medical treatment as the main strategy for the management of PA and MMA. Although retrospective studies have suggested that long-term carglumic acid may be beneficial in the management of PA and MMA, current literature lacks evidence for this indication. This clinical trial will determine the long-term safety and efficacy of carglumic acid in the management of PA and MMA. TRIAL REGISTRATION: King Abdullah International Medical Research Center ( KAIMRC ): (RC13/116) 09/1/2014. Saudi Food and Drug Authority (SFDA) (33066) 08/14/2014. ClinicalTrials.gov (identifier: NCT02426775) 04/22/2015.

Molecular and clinical spectra of FBXL4 deficiency.

F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.

The engagement chasm: Time for competency-based training in employee engagement for healthcare and beyond.

BACKGROUND: Employee disengagement in healthcare and business is currently at unexceptionally high levels worldwide. Disengagement negatively impacts productivity, profitability, efficiency (waste reduction), innovation, quality, customer satisfaction and experience, staff well-being, safety, mortality, staff attendance, and turnover. Despite its serious detrimental impacts, no dedicated competency-based training curriculum exists for engagement as a competency. OBJECTIVE: To develop a competency-based educational curriculum for an Engagement Competency. METHODS: A curricular roadmap comprising the following steps was observed 1. Identifying the desired outcomes needed of trainees. These must help fulfill all the Q12 Gallup survey engagement items. 2. Explicitly defining the required Competencies, Entrustable Professional Activities, and Milestones, 3. Selecting the educational activities, and instructional methods, 4. Selecting the tools to assess progress along the milestones, and finally, 5. Designing an evaluation system to assess the outcomes of the engagement competency program. RESULTS: We developed an Engagement Competency Framework with 7 Entrustable Professional activities "rationally and practically" arranged. These are: Envision E1, Embrace E2, Empower E3, Enlighten E4, Empathize E5, Energize E6, and Evaluate E7 (the 7Es). CONCLUSION: The unfortunate global issue of disengagement in healthcare and in the business arena may be practically tackled by introducing Engagement Competency and training. It should be compulsory for all in the "leadership role". Such training may lead to remarkable performance improvement and a happier, more prosperous, and safer world.

Impact of vaccination on morbidity and mortality in adults hospitalized with COVID-19 during the omicron wave in the Jazan Region, Saudi Arabia.

OBJECTIVES: To evaluate the impact of coronavirus disease-19 (COVID-19) vaccination on morbidity and mortality in adults hospitalized with COVID-19 during the omicron wave in the Jazan Region, Saudi Arabia. METHODS: A 6-month record-based historical prospective study enrolled COVID-19 adult patients admitted between January and June 2022. Individuals were classified into 3 groups according to their immunity status (immunized, partially immunized, and not immunized). Death, intensive care unit (ICU) admission, and mechanical ventilation were identified as the primary outcomes, collectively referred to as "serious outcomes". On the other hand, the length of hospital stays longer than 5 days was categorized as a secondary outcome. Multiple logistic regression analysis was used to evaluate independent factors and the relationship between the outcomes and vaccination status. RESULTS: Among the 634 COVID-19 patients admitted to Jazan hospitals, 46.4% were fully immunized, 19.7% were partially immunized, and 33.9% were not immunized. Not being immunized was significantly associated with ICU admission (odds ratio [OR]=1.91, 95% confidence interval [CI]: [1.17-3.11]; p=0.009), mechanical ventilation (OR=2.11, 95% CI: [1.25-3.56]; p=0.005), increased length of hospital stays (OR=1.79, 95% CI: [1.24-2.59]; p=0.002), and death (OR=3.03, 95% CI: [1.85-4.98]; p<0.001). CONCLUSION: Our study underscores the importance of a comprehensive approach for managing COVID-19 patients that includes vaccination against the disease.

Divergent responses of pelagic and benthic fish body-size structure to remoteness and protection from humans.

Animal body-size variation influences multiple processes in marine ecosystems, but habitat heterogeneity has prevented a comprehensive assessment of size across pelagic (midwater) and benthic (seabed) systems along anthropic gradients. In this work, we derive fish size indicators from 17,411 stereo baited-video deployments to test for differences between pelagic and benthic responses to remoteness from human pressures and effectiveness of marine protected areas (MPAs). From records of 823,849 individual fish, we report divergent responses between systems, with pelagic size structure more profoundly eroded near human markets than benthic size structure, signifying greater vulnerability of pelagic systems to human pressure. Effective protection of benthic size structure can be achieved through MPAs placed near markets, thereby contributing to benthic habitat restoration and the recovery of associated fishes. By contrast, recovery of the world's largest and most endangered fishes in pelagic systems requires the creation of highly protected areas in remote locations, including on the High Seas, where protection efforts lag.

Real-world effectiveness of COVID-19 vaccines: A retrospective cohort study of vaccinated individuals in Jazan, Saudi Arabia.

BACKGROUND: COVID-19 (Coronavirus Disease 2019) vaccinations are a critical control measure for the coronavirus pandemic that began in 2019. Several COVID-19 vaccines have been developed, and their effectiveness will almost certainly vary. OBJECTIVE: This study aimed to assess how effective two doses of the Pfizer and Oxford-AstraZeneca vaccines were in preventing SARS-CoV-2 infection six months after administration. METHODS: This is a retrospective cohort study of adult individuals from the Jazan Region of Saudi Arabia who received their second dose of the COVID-19 vaccine [Pfizer and Oxford-AstraZeneca (ASZ)] between April and June 2021. The monitoring and follow-up period continued until the end of January 2022. Data were retrieved from the Health Electronic Surveillance Network and National Vaccination Records. Logistic regression was performed to assess the risk of COVID-19 infection among the vaccinated subjects. RESULTS: This study included randomly enrolled 4458 participants in Jazan who received two doses of the COVID-19 vaccine during the research period. The majority of them received the Pfizer vaccine (3136/4458; 70.3%), while the remaining received the ASZ vaccine (1322/4458; 29.7%). The study participants' mean age was 59.7 years, with a male-to-female ratio of 1.9:1.0 (2920:1538). The results showed that the Pfizer and ASZ vaccines' protection against infection decreased from 93.2% and 90.2%, respectively, during the first three months, to 68.5% and 68.1% after a six-month interval. In the current study population, being Saudi Arabian, younger as well as having longer intervals between vaccines or crossing a 6-month period after the second vaccine dose were factors linked to higher rates of breakthrough infections. CONCLUSION: Our findings revealed variations in the efficacy of different COVID-19 vaccine types against COVID-19 breakthrough infections. The Pfizer (mRNA-based) vaccine was found to be relatively more effective than the ASZ (DNA-based) vaccine.

Assessing Continuity of Adherence to Precautionary Measures for COVID-19 among Vaccinated People in Jazan, Saudi Arabia.

BACKGROUND: Adherence to behavioral respiratory hygiene practices is essential in preventing the transmission of COVID-19, especially given the appearance of new variants of the COVID-19 virus. This study estimated the pre- and post-vaccination levels of adherence to COVID-19 preventive behavioral measures among vaccinated people. METHODS: This cross-sectional study assessed the sociodemographics and preventive behavioral measures, and pre- and post-vaccination data, via a questionnaire. Paired t-tests and Chi-squared tests were used to assess the variation in adherence levels. RESULTS: Of the 480 participants, 57.9% were male, and 30.4% were aged between 30 and 39 years of age. After vaccination, there was a statistically significant decline in adherence to all the assessed behavioral protective measures (p < 0.05). Being 50 years old or older, female, a healthcare worker, and a smoker were associated with higher adherence levels compared with other groups in the same categories. CONCLUSIONS: A change in the behavior of the community members regarding COVID-19 after receiving the vaccination and a reduction in adherence to respiratory hygiene practices was observed. This indicates the importance of raising awareness about the possibility of reinfection with COVID-19 despite the vaccination, and the importance of behavioral respiratory hygiene for the prevention and control of COVID-19.

Progressive Ataxia and Neurologic Regression in RFXANK-Associated Bare Lymphocyte Syndrome.

OBJECTIVE: To identify the genetic cause of a late-onset immunodeficiency and subacute progressive neurodegenerative disease affecting cognition, motor, visual, and cerebellar systems in a patient with a family history of 2 younger siblings with an early-onset immunodeficiency disease. METHODS: Physical examinations, immunologic, brain MRI, whole-exome sequencing, and segregation studies were used to identify the genetic and neuroimmunologic etiology of disease in this family. RESULTS: We identified a homozygous loss-of-function (LOF) mutation (c.271+1G>C) in the RFXANK gene in the index patient and one of his younger affected siblings. Biallelic mutations in the RFXANK gene are known to cause bare lymphocyte syndrome (BLS) type II, complementation group B. The clinical and immunologic investigations were consistent with a clinical diagnosis of BLS type II. MRI demonstrated global cerebral and cerebellar atrophy with white matter signal changes in the index case. CONCLUSIONS: In addition to BLS type II, our study has expanded and further characterized the phenotype associated with the LOF of RFXANK to include progressive neurodegenerative disease. Our study also provides evidence for the impact of LOF on brain development and function. Thus, early bone marrow transplantation, as a standard of care for BLS, could prove to be protective against the neurologic phenotypes in this group of patients.

Long-term effectiveness of carglumic acid in patients with propionic acidemia (PA) and methylmalonic acidemia (MMA): a randomized clinical trial.

BACKGROUND: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare, autosomal recessive inborn errors of metabolism that require life-long medical treatment. The trial aimed to evaluate the effectiveness of the administration of carglumic acid with the standard treatment compared to the standard treatment alone in the management of these organic acidemias. METHODS: The study was a prospective, multicenter, randomized, parallel-group, open-label, controlled clinical trial. Patients aged ≤ 15 years with confirmed PA and MMA were included in the study. Patients were followed up for two years. The primary outcome was the number of emergency room (ER) admissions because of hyperammonemia. Secondary outcomes included plasma ammonia levels over time, time to the first episode of hyperammonemia, biomarkers, and differences in the duration of hospital stay. RESULTS: Thirty-eight patients were included in the study. On the primary efficacy endpoint, a mean of 6.31 ER admissions was observed for the carglumic acid arm, compared with 12.76 for standard treatment, with a significant difference between the groups (p = 0.0095). Of the secondary outcomes, the only significant differences were in glycine and free carnitine levels. CONCLUSION: Using carglumic acid in addition to standard treatment over the long term significantly reduces the number of ER admissions because of hyperammonemia in patients with PA and MMA.

Ghrelin, resistin and insulin in obese diabetic women in Wad-Madani, Sudan.

BACKGROUND: Obesity in the Sudan is increasing at alarming rate with the tendency of reaching an epidemic proportion in women. It is commonly associated with type 2 diabetes (T2D). Some adipokine hormones such as resistin are associated with obesity. OBJECTIVES: To study how the levels of resistin, ghrelin and insulin are associated with obesity,fat distribution and (T2D) and to ascertain any interrelationships between them. SUBJECTS AND METHODS: 150 women, age ≥18 years old, resident in Wad-Madani town, Sudan were participated in the study. They were divided into 3 groups according to body mass index (BMI) value: I (normal weight), II (overweight) and III (obese diabetic). Fasting serum resistin and ghrelin concentrations were measured using ELISA method. Insulin levels were determined by radioimmunoassay(RIA). RESULTS: The mean±SD levels of resistin 5.80±4.91ng/mL,Ghrelin107.60±26.67pg/M and Insulin 11.92±8.54mLU/ml in obese diabetic were found to be greater than in normal or overweight women. In normal weight values were 3.07±2.15 ng/mL 83.30±13.38pg/mL, and 6.62±6.77mLU/ml for resistini, ghrelin and Insulin, respectively. Values for overweight women 3.64±2.63 pg/mL 90±17.35 pg/mL and 8.13±7.54 mLU/ml for resistin, ghrelin and insulin respectively. CONCLUSIONS AND RECOMMENDATIONS: Increased BMI, waist circumference (WC) and hormones (ghrelin and resistin) were associated with insulin resistance. Further studies are needed to accept or refute these findings.

Schizophrenia: Impact of psychopathology, faith healers and psycho-education on adherence to medications.

BACKGROUND: Many patients suffering from psychosis are nonadherent to their medications. Nonadherence can range from treatment refusal to irregular use or partial change in daily medication doses. AIM: To investigate whether symptom dimensions, post-discharge care plans and being involved with faith healer affect the adherence to treatment in patients with schizophrenia. METHOD: A total of 121 patients with schizophrenia were examined 6 weeks post-discharge from the inpatient unit and assessed for full, partial or nonadherence to medication. RESULTS: There was a significant association between family involvement and partial adherence and between community team involvement post-discharge and full adherence to medications. Psycho-education was a predictor for adherence to medications, persecutory delusions and lack of insight predicted partial adherence, while being involved with faith healers predicted nonadherence. CONCLUSION: Adherence to medications and socio-demographic variables are independent. This study demonstrated that nonadherence or partial adherence to medications is associated with lack of insight and persecutory delusions. Psycho-education could improve the adherence to medication compliances.

Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial.

BACKGROUND: SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa. METHODS: A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments. RESULTS: In sequential analyses with 49-51 patients per arm, initial cure was 85% (95% CI: 73-92) in all arms. At D210, definitive cure was 87% (95% CI: 77-97) for AmBisome + SSG, 77% (95% CI 64-90) for AmBisome + miltefosine and 72% (95% CI 60-85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults. CONCLUSION: No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov, number NCT01067443.

Lifestyle modification programs in polycystic ovary syndrome: systematic review and meta-analysis.

CONTEXT: Polycystic ovary syndrome (PCOS) is a prevalent disorder that affects women of childbearing age and may be related to obesity and insulin resistance. OBJECTIVE: The purpose of this systematic review was to appraise the evidence of the impact of lifestyle modification (LSM) interventions on outcomes of women with PCOS. DATA SOURCES: Sources included Ovid Medline, OVID Embase, OVID Cochrane Library, Web of Science, Scopus, PsycINFO, and CINAHL (up to January 2011). STUDY SELECTION: We included randomized controlled trials that enrolled woman of any age with PCOS who received LSM and compared them against women who received no intervention, minimal intervention, or metformin. DATA EXTRACTION: Two authors performed the data extraction independently. DATA SYNTHESIS: We included 9 trials enrolling 583 women with a high loss to follow-up rate, lack of blinding, and short follow-up. Compared with minimal intervention, LSM significantly reduced fasting blood glucose (weighted mean difference, -2.3 mg/dL; 95% confidence interval, -4.5 to -0.1, I² = 72%, P = .04) and fasting blood insulin (weighted mean difference, -2.1 µU/mL, 95% confidence interval, -3.3 to -1.0, I² = 0%, P < .001). Changes in body mass index were associated with changes in fasting blood glucose (P < .001). Metformin was not significantly better than LSM in improving blood glucose or insulin levels. We found no significant effect of LSM on pregnancy rate, and the effect on hirsutism was unclear. CONCLUSIONS: The available evidence suggests that LSM reduces fasting blood glucose and insulin levels in women with PCOS. Metformin has similar effects. Translation of these short-term effects to patient-important outcomes, beyond diabetes prevention, remains uncertain.