Effectiveness of a culturally tailored text messaging program for promoting cervical cancer screening in accra, Ghana: a quasi-experimental trial.

INTRODUCTION: Despite breakthroughs in cervical cancer detection, resource-constrained countries continue to have a disproportionately high incidence and death rate. Mhealth has been identified as an important tool for increasing cervical cancer screening rates in Sub-Saharan Africa. We determined whether sending Ghanaian women culturally tailored one-way mobile phone SMS text messages about cervical cancer would encourage the uptake of the human papillomavirus (HPV) test. METHODS: From August to November 2016, 88 women aged 18 to 39 living or working in an urban community (Accra, Ghana) participated in a quasi-experimental study. For 8 weeks, 32 SMS messages regarding cervical cancer were developed and sent to the personal phones of intervention arm participants (n = 42). Women in the control group (n = 46) received SMS texts with general health and lifestyle advice. Fischer's exact tests were performed to assess cervical cancer screening uptake and associated reasons for non-uptake between the intervention and control groups (p < 0.05). RESULTS: At the baseline, women differed in terms of ethnicity and wealth. After the intervention, participants' self-reported risk factors for cervical cancer, such as early menarche, usual source of medical treatment, family history of cancer, smoking, and alcohol history, changed. None of the women in the intervention group sought cervical cancer screening after the intervention, but only one (2.2%) of the control arm participants did. Almost all the women (> 95%) agreed that an HPV test was essential and that regular healthcare check-ups could help prevent cervical cancer. Some women believed that avoiding particular foods could help prevent cervical cancer (23.8% intervention vs. 58.7% control, p < 0.001). Time constraints and out-of-pocket expenses were significant barriers to cervical cancer screening. CONCLUSION: A one-way SMS delivered to urban women did not increase cervical cancer screening attendance. The time spent in screening facilities and the lack of coverage by the National Health Insurance Scheme limited screening uptake. We urge for the establishment of screening centers in all healthcare facilities, as well as the inclusion of cervical cancer screening in healthcare programs through cost-sharing.

Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1 variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2 c.778G>A [p.Glu260Lys] manifesting with juvenile ALS. METHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed. RESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that SPTLC2 variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing SPTLC2 variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported SPTLC1 ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in SPTLC1 and SPTCL2-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS. CONCLUSIONS: SPTLC2 is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further.

Coping strategies among adolescents and young adults living with HIV/AIDS in Accra-Ghana.

BACKGROUND: Living with HIV/AIDS is remarkably stressful and has an adverse effect on one's physical and mental health. In Sub-Saharan Africa, the introduction of highly active anti-retroviral therapy has led to an increased number of children with perinatal acquired HIV who are living into adolescence and adulthood. Developing strategies to cope with HIV becomes imperative, especially among these adolescents. The study determined the factors that influence coping strategies among adolescents living with HIV. METHODS: An analytic cross-sectional design was used. A total of 154 adolescents aged 10-19 years living with HIV were systematically sampled at the Fevers Unit of Korle Bu Teaching Hospital from June to December, 2021. The adolescent version of the KidCope tool was used to assess the choice of coping strategies. Stata 16 was used to determine associations between independent variables and the coping strategies identified. Only variables that were significant at p = 0.1 or less in the crude model were used to run the adjusted regression model. The level of significance was set at p = 0.05 with a 95% confidence interval. RESULTS: The mean age of participants was 19.2 ± 0.45 years with 51.9% (80/154) of participants being males. A majority, 57.1% of the participants employed positive coping strategies with 87.0% (135/154) using cognitive restructuring strategy. In an adjusted linear regression model, participants coping strategies were significantly associated with their educational level (p = 0.04) and presence of both parents as caregivers (p = 0.02). CONCLUSION: Participants largely adopted positive coping strategies in managing the disease. Factors that influenced the choice of coping strategies were higher levels of education and the presence of both parents as caregivers. The importance of a good social support structure and pursuing further education needs to be emphasized in counselling adolescents living with HIV as it promotes the choice of positive coping strategies.

Correction: Genotypic glucose-6-phosphate dehydrogenase (G6PD) deficiency protects against Plasmodium falciparum infection in individuals living in Ghana.

[This corrects the article DOI: 10.1371/journal.pone.0257562.].

Nationwide Surveillance of Pfhrp2 Exon 2 Diversity in Plasmodium falciparum Circulating in Symptomatic Malaria Patients Living in Ghana.

Reports of increasing false-negative HRP2-based rapid diagnostic test results across Africa require constant monitoring of factors associated with these false-negative outcomes, as failure of this diagnostic tool will have severe consequences on malaria treatment and control programs. This study characterized the extent of genetic diversity in the Plasmodium falciparum histidine-rich protein 2 (Pfhrp2) gene in P. falciparum isolates from symptomatic malaria patients across the regions of Ghana. Exon 2 of Pfhrp2 was amplified from gDNA using polymerase chain reaction. All Pfhrp2-negative samples were subjected to Pf18S rRNA and Pfmsp2 gene amplifications. The amplified Pfhrp2 exon 2 fragments from clonal samples were sent for commercial Sanger sequencing. The type and number of PfHRP2 repeats, classified based on repeat types previously reported, were estimated from the sequence data and compared among geographical regions. About 81% (2,333/2,890) of the original microscopy positive DBS were available and used in this study. The Pfhrp2 exon 2 amplification was successful in 98.5% (2,297/2,333) of the tested samples, with band size ranging from 400 bp to 1,050 bp. A total of 13 out of the 24 previously reported repeat types were identified among the samples, with three samples lacking both type 2 and type 7 repeat motifs. This study suggested that the genetic diversity of Pfhrp2 exon 2 identified in P. falciparum circulating in symptomatic malaria patients in Ghana is unlikely to influence the sensitivity and specificity of HRP2 RDT-based diagnosis.

Nationwide molecular surveillance of three Plasmodium species harboured by symptomatic malaria patients living in Ghana.

BACKGROUND: Clinical presentations of malaria in Ghana are primarily caused by infections containing microscopic densities of Plasmodium falciparum, with a minor contribution from Plasmodium malariae and Plasmodium ovale. However, infections containing submicroscopic parasite densities can result in clinical disease. In this study, we used PCR to determine the prevalence of three human malaria parasite species harboured by suspected malaria patients attending healthcare facilities across the country. METHODS: Archived dried blood spots on filter paper that had been prepared from whole blood collected from 5260 patients with suspected malaria attending healthcare facilities across the country in 2018 were used as experimental material. Plasmodium species-specific PCR was performed on DNA extracted from the dried blood spots. Demographic data and microscopy data for the subset of samples tested were available from the original study on these specimens. RESULTS: The overall frequency of P. falciparum, P. malariae and P. ovale detected by PCR was 74.9, 1.4 and 0.9%, respectively. Of the suspected symptomatic P. falciparum malaria cases, 33.5% contained submicroscopic densities of parasites. For all regions, molecular diagnosis of P. falciparum, P. malariae and P. ovale was significantly higher than diagnosis using microscopy: up to 98.7% (75/76) of P. malariae and 97.8% (45/46) of P. ovale infections detected by PCR were missed by microscopy. CONCLUSION: Plasmodium malariae and P. ovale contributed to clinical malaria infections, with children aged between 5 and 15 years harbouring a higher frequency of P. falciparum and P. ovale, whilst P. malariae was more predominant in individuals aged between 10 and 20 years. More sensitive point-of-care tools are needed to detect the presence of low-density (submicroscopic) Plasmodium infections, which may be responsible for symptomatic infections.

Therapeutic efficacy of dihydroartemisinin-piperaquine combination for the treatment of uncomplicated malaria in Ghana.

In 2020, Dihydroartemisinin-Piperaquine (DHAP) was adopted as a second-line antimalarial for treatment of uncomplicated malaria in Ghana following a review of the country's antimalarial medicines policy. Available data obtained in 2007 had shown PCR-uncorrected therapeutic efficacy of 93.3% using a 28-day follow-up schedule. In 2020, the standard 42-day follow-up schedule for DHAP was used to estimate efficacy levels among febrile children aged 6 months to 9 years in three malaria sentinel sites representing the three main ecological zones of the country- savannah, forest, and coastal. PCR genotyping distinguished between recrudescence and re-infection using merozoite surface protein 2 (MSP2)-specific primers for FC27 and 3D7 strains. Per protocol analyses showed day 28 efficacy of 100% in all three sentinel sites with day 42 PCR-corrected efficacy ranging between 90.3% (95% CI: 80.1 - 96.4%) in the savannah zone and 100% in the forest and coastal zones, yielding a national average of 97.0% (95% CI: 93.4 - 98.8). No day 3 parasitemia was observed in all three sites. Prevalence of measured fever (axillary temperature ≥ 37.5°C) declined from 50.0 - 98.8% on day 0 to 7.1-11.5% on day 1 whilst parasitemia declined from 100% on day 0 to 1.2 - 2.3% on day 1. Mean haemoglobin levels on days 28 and 42 were significantly higher than pre-treatment levels in all three sites. We conclude that DHAP is highly efficacious in the treatment of uncomplicated malaria in Ghana. This data will serve as baseline for subsequent DHAP efficacy studies in the country.

Genotypic glucose-6-phosphate dehydrogenase (G6PD) deficiency protects against Plasmodium falciparum infection in individuals living in Ghana.

INTRODUCTION: The global effort to eradicate malaria requires a drastic measure to terminate relapse from hypnozoites as well as transmission via gametocytes in malaria-endemic areas. Primaquine has been recommended for the treatment of P. falciparum gametocytes and P. vivax hypnozoites, however, its implementation is challenged by the high prevalence of G6PD deficient (G6PDd) genotypes in malaria endemic countries. The objective of this study was to profile G6PDd genotypic variants and correlate them with malaria prevalence in Ghana. METHODS: A cross-sectional survey of G6PDd genotypic variants was conducted amongst suspected malaria patients attending health care facilities across the entire country. Malaria was diagnosed using microscopy whilst G6PD deficiency was determined using restriction fragment length polymorphisms at position 376 and 202 of the G6PD gene. The results were analysed using GraphPad prism. RESULTS: A total of 6108 subjects were enrolled in the study with females representing 65.59% of the population. The overall prevalence of malaria was 36.31%, with malaria prevalence among G6PDd genotypic variants were 0.07% for A-A- homozygous deficient females, 1.31% and 3.03% for AA- and BA- heterozygous deficient females respectively and 2.03% for A- hemizygous deficient males. The odd ratio (OR) for detecting P. falciparum malaria infection in the A-A- genotypic variant was 0.0784 (95% CI: 0.0265-0.2319, p<0.0001). Also, P. malariae and P. ovale parasites frequently were observed in G6PD B variants relative to G6PD A- variants. CONCLUSION: G6PDd genotypic variants, A-A-, AA- and A- protect against P. falciparum, P. ovale and P. malariae infection in Ghana.

Diagnosis of Classic Homocystinuria in Two Boys Presenting with Acute Cerebral Venous Thrombosis and Neurologic Dysfunction after Normal Newborn Screening.

Homocystinuria, caused by cystathionine ß-synthase deficiency, is a rare inherited disorder involving metabolism of methionine. Impaired synthesis of cystathionine leads to accumulation of homocysteine that affects several organ systems leading to abnormalities in the skeletal, cardiovascular, ophthalmic and central nervous systems. We report a 14-month-old and a 7-year-old boy who presented with neurologic dysfunction and were found to have cerebral venous sinus thromboses on brain magnetic resonance imaging (MRI)/magnetic resonance venogram (MRV) and metabolic and hypercoagulable work-up were consistent with classic homocystinuria. The 14-month-old boy had normal newborn screening. The 7-year-old boy initially had an abnormal newborn screen for homocystinuria but second tier test that consisted of total homocysteine was normal, so his newborn screen was reported as normal. With the advent of expanded newborn screening many treatable metabolic disorders are detected before affected infants and children become symptomatic. Methionine is the primary target in newborn screening for homocystinuria and total homocysteine is a secondary target. Screening is usually performed after 24-48 h of life in most states in the US and some states perform a second screen as a policy on all tested newborns or based on when the initial newborn screen was performed. This is done in hopes of detecting infants who may have been missed on their first screen. In the United Kingdom, NBS using dried blood spot is performed at 5 to 8 days after birth. It is universally known that methionine is a poor target and newborn screening laboratories have used different cutoffs for a positive screen. Reducing the methionine cutoff increases the sensitivity but not necessarily the specificity of the test and increasing the cutoff will miss babies who may have HCU whose levels may not be high enough to be detected at their age of ascertainment. It is not clear whether adjusting methionine level to decrease the false negative rates combined with total homocysteine as a second-tier test can be used effectively and feasibly to detect newborns with HCU. Between December 2005 and December 2020, 827,083 newborns were screened in Kentucky by MS/MS. Kentucky NBS program uses the postanalytical tools offered by the Collaborative Laboratory Integrated Reports (CLIR) project which considers gestational age and birthweight. One case of classical homocystinuria was detected and two were missed on first and second tier tests respectively. The newborn that had confirmed classical homocystinuria was one of twenty-three newborns that were referred for second tier test because of elevated methionine (cutoff is >60 µmol/L) and/or Met/Phe ratio (cutoff is >1.0); all 23 dried blood spots had elevated total homocysteine. One of the subjects of this case report had a normal methionine on initial screen and the other had a normal second-tier total homocysteine level. The performance of methionine and total homocysteine as screening analytes for homocystinuria suggest that it may be time for newborn screening programs to consider adopting next generation sequencing (NGS) platforms as alternate modality of metabolic newborn screening. Because of cost considerations, newborn screening programs may not want to adopt NGS, but the downstream healthcare cost incurred due to missed cases and the associated morbidity of affected persons far exceed costs to newborn screen programs. Since NGS is becoming more widely available and inexpensive, it may be feasible to change testing algorithms to use Newborn Metabolic NGS as the primary mode of testing on dry blood specimens with confirmation with biochemical testing. Some commercial laboratories have Newborn Screening Metabolic gene panel that includes all metabolic disorders on the most comprehensive newborn screening panel in addition to many other conditions that are not on the panel. A more targeted NGS panel can be designed that may not cost much and eventually help avoid the pitfalls associated with delayed diagnosis and cost of screening.

Impact of malaria diagnostic refresher training programme on competencies and skills in malaria diagnosis among medical laboratory professionals: evidence from Ghana 2015-2019.

BACKGROUND: The quality of malaria test results is crucial for optimal patient treatment and care. The Ghana Health Service is successfully shifting from presumptive clinical diagnosis and treatment of malaria to the Test, Treat and Track (T3) initiative. In line with the initiative, the National Malaria Control Programme (NMCP) set out to improve the capacity of medical laboratory professionals in Ghana through a five-day Malaria Diagnostic Refresher Training (MDRT) to build competencies and skills in malaria diagnosis, especially in the three components of microscopy: parasite detection, species identification and parasite quantification. This study evaluates the impact of the training on malaria microscopy. METHODS: The training which was based on the World Health Organization basic malaria microscopy training guide employed presentations and practical approaches to malaria diagnosis. A total number of 765 medical laboratory professionals from various health facilities across the country were trained every other year from 2015 to 2019 and were included in this evaluation. Evaluation of this training was done using pre-test and post-test microscopy scores. The Negative Binomial fixed effect model was used in determining the overall effect of the training in improving the competencies of the participants on malaria microscopy. RESULTS: The ability of the medical laboratory professionals to correctly detect malaria parasites increased significantly from a median score of 64% prior to the training to 87% after the training (p < 0.001). The competencies of the medical laboratory scientists to correctly identify malaria parasite species and quantify the number of malaria parasites increased significantly from a median score of 17% and 20% pre-test to 78% and 50% post-test, respectively (p < 0.001). The results showed that participants' competency level and skill to perform malaria microscopy (species identification, parasite quantification and detection of malaria parasites) increased by approximately two folds after the training compared to the no-training scenario (adjusted rate ratio = 2.07, 95% CI 2.01-2.13, p < 0.001). CONCLUSION: The MDRT programme significantly improved participants' performance of malaria microscopy over a short period of time.

Malaria parasitaemia and mRDT diagnostic performances among symptomatic individuals in selected health care facilities across Ghana.

BACKGROUND: Parasitological diagnosis generates data to assist malaria-endemic countries determine their status within the malaria elimination continuum and also inform the deployment of proven interventions to yield maximum impact. This study determined prevalence of malaria parasitaemia and mRDT performances among febrile patients in selected health care facilities across Ghana. METHODS: This study was a cross-sectional survey conducted in the previously 10 regions of Ghana from May to August 2018. Each patient suspected to have uncomplicated malaria was tested using microscopy and two malaria rapid diagnostic tests (mRDTs): routinely used CareStart™ Malaria HRP2 (Pf) and SD Bioline Malaria Ag Pf (HRP2/pLDH). Main outcome variables were malaria slide and CareStart™ Malaria HRP2 (Pf) positivity rates; and diagnostic accuracy of CareStart™ Malaria HRP2 (Pf) and SD Bioline Malaria Ag Pf (HRP2/pLDH) using microscopy as "gold standard". RESULTS: Overall parasite positivity rates were 32.3% (6266/19402) by mRDT and 16.0% (2984/18616) by microscopy, with Plasmodium falciparum mono-infection accounting for 98.0% of all infections. The odds of parasitaemia by microscopy was significantly lower among female patients compared with males (OR = 0.78; 95% CI: 0.66-0.91), and among patients with history of previous antimalarial intake compared with those with no such history (OR = 0.72; 95% CI: 0.54-0.95). Overall sensitivity of CareStart™ Malaria HRP2 (Pf) was statistically similar to that of the HRP2 band of SD Bioline Malaria Ag Pf (HRP2/pLDH) combo kit (95.4%; 95% CI: 94.6-96.1 vs 94.3%; 95% CI: 93.4-95.1; p = 0.065) but significantly higher than the pLDH band (89.3%; 95% CI: 88.1-90.4; p < 0.001). The same pattern was observed for negative predictive value. CONCLUSIONS: Malaria control interventions should be targeted at the general population, and history of antimalarial intake considered a key predictor of malaria slide negativity. Furthermore, HRP2-based mRDTs remain effective diagnostic tool in the management of suspected uncomplicated malaria in the country.

Contribution of P. falciparum parasites with Pfhrp 2 gene deletions to false negative PfHRP 2 based malaria RDT results in Ghana: A nationwide study of symptomatic malaria patients.

INTRODUCTION: False-negative malaria rapid diagnostic test (RDT) results amongst symptomatic malaria patients are detrimental as they could lead to ineffective malaria case management. This study determined the nationwide contribution of parasites with Pfhrp2 and Pfhrp 3 gene deletions to false negative malaria RDT results in Ghana. METHODS: This was a cross sectional study where whole blood (~2 ml) was collected from patients presenting with malaria symptoms at 100 health facilities in all the regions in Ghana from May to August 2018. An aliquot of the blood was used to prepare thin and thick blood smears, filter paper blood spots (DBS) and spot a PfHRP 2 RDT kit. The remaining blood was separated into plasma and blood cells and stored at -20°C. Plasmodium parasite density and species identity was estimated from the blood smears. Plasmodium falciparum specific 18S rRNA PCR, merozoite surface protein (msp 1) and glutamate rich protein (glurp) gene PCR were used to identify P. falciparum positive samples, which were subjected to Pfhrp 2/3 exon1-2 and exon2 genotyping. RESULTS: Of the 2,860 microscopically P. falciparum positive patients analyzed, 134 (4.69%) had false negative P. falciparum specific RDT results. Samples for PCR analysis was available for 127 of the false negative patients, and the analysis identified 116 (91.3%) as positive for P. falciparum. Only 58.1% (79/116) of the false negative RDT samples tested positive by msp 1 and glurp PCR. Genotyping of exon 1-2 and exon 2 of the Pfhrp 2 gene identified 12.9% (10/79) and 39.5% (31/79) of samples respectively to have deletions. Genotyping exon 1-2 and exon 2 of the Pfhrp 3 gene identified 15.2% (12/79) and 40.5% (32/79) of samples respectively to have deletions. Only 5% (4/79) of the false negative samples had deletions in both exon 1-2 and exon 2 of the Pfhrp 2 gene. Out of the 49 samples that tested positive for aldolase by luminex, 32.6% (16/49) and) had deletions in Pfhrp 2 exon 2 and 2% (1/49) had deletions in both exon 2 and exon 1-2 of the Pfhrp 2 gene. CONCLUSIONS: The low prevalence of false negative RDT test results provides assurance that PfHRP 2 based malaria RDT kits remain effective in diagnosing symptomatic malaria patients across all the Regions of Ghana. Although there was a low prevalence of parasites with deletions in exon 2 and exon 1-2 of the Pfhrp 2 gene the prevalence of parasites with deletions in Pfhrp 2 exon 2 was about a third of the false negative RDT results. The need to ensure rapid, accurate and reliable malaria diagnosis requires continuous surveillance of parasites with Pfhrp 2 gene deletions.

Laboratory evaluation of homocysteine remethylation disorders and classic homocystinuria: Long-term follow-up using a cohort of 123 patients.

The homocystinurias, caused by defects of remethylation and cystathionine-beta-synthase (CBS) deficiency, are characterized by elevated homocysteine and abnormal methionine levels. Various treatments, including injectable hydroxycobalamin and oral betaine, aim to reduce homocysteine toxicity and normalize methionine, but only limited biochemical data has been reported assessing biochemical response to treatment. We analyzed laboratory results in 812 plasma samples from 56 patients with remethylation disorders and 67 patients with CBS deficiency. Total plasma homocysteine (tHcys) decreased with therapy, but rarely normalized regardless of treatment, with highest levels seen in CBS (116 ±â€¯79 µmol/L) and MTHFR (102 ±â€¯56 µmol/L) deficiencies. In CBS deficiency, tHcys correlated positively with methionine (rs = 0.51, p < 0.0001) and inversely with cystine (rs = -0.57, p < 0.0001) consistent with a metabolic block downstream of homocysteine. In patients with remethylation disorders, methionine was mostly normal on therapy, and inversely correlated with tHcys (rs = -0.57, p < 0.0001) demonstrating effectiveness of hydroxycobalamin and/or betaine in stimulating tHcys remethylation. Betaine also significantly increased sarcosine from its pre-treatment level on average 19-fold in remethylation disorders and 3-fold in CBS deficiency, with sarcosine > 5 µmol/L being 97% sensitive and 95% specific for betaine therapy. These results show that existing therapies improve sulfur amino acid metabolism without completely normalizing it and that sarcosine can determine compliance to betaine supplementation.

Emicizumab Associated Rhabdomyolysis in Hemophilia A.

Emicizumab is increasingly the front-line treatment for patients with Hemophilia A with or without inhibitors. Rhabdomyolysis is a syndrome of muscle necrosis and release of intracellular muscle constituents into the circulation. Creatine kinase (CK) levels are typically markedly elevated, and muscle pain and myoglobinuria may be present. The severity of illness ranges from asymptomatic elevations in serum muscle enzymes to life-threatening disease associated with extreme enzyme elevations, electrolyte imbalances, acute kidney injury and disseminated intravascular coagulation. We present a case of an African American male with severe hemophilia A and history of factor VIII inhibitor, maintained on emicizumab prophylaxis, who developed rhabdomyolysis with a symptomatic hyperCKemia. To date, there is no known link between rhabdomyolysis to emicizumab. This report brings to light the possibility of symptomatic rhabdomyolysis as a potential side effect of emicizumab after moderate exertional activity.

Heme and sensory neuropathy: insights from novel mutations in the heme exporter feline leukemia virus subgroup C receptor 1.

Hereditary sensory and autonomic neuropathies (HSANs) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system mainly characterized by impaired nociception and autonomic dysfunction. We previously identified heme metabolism as a novel pathway contributing to sensory neurons maintenance and nociception. Indeed, we reported mutations in the feline leukemia virus subgroup C receptor 1 (FLVCR1) gene in individuals affected by HSAN. FLVCR1 gene encodes for 2 heme export proteins, FLVCR1a (plasma membrane) and FLVCR1b (mitochondria), crucially involved in the regulation of cellular heme homeostasis. Here, we report on 2 additional patients carrying novel biallelic mutations in FLVCR1 translation initiation codon (c.2T>C; p.(Met1Thr) and c.3G>T; p.(Met1Ile)). We overexpressed the c.2T>C; p.(Met1Thr) mutant in human cell lines and we describe its impact on protein structure and function in comparison with other HSAN-related mutations. We found that the mutation interferes with translation in 2 different ways: by lowering levels of translation of wild-type protein and by inducing translation initiation from a downstream in-frame ATG, leading to the production of an N-terminal truncated protein that is retained in the endoplasmic reticulum. The impact of different kinds of mutations on FLVCR1a localization and structure was also described. The identification of novel FLVCR1 mutations in HSAN reinforces the crucial role of heme in sensory neuron maintenance and pain perception. Moreover, our in vitro findings demonstrate that heme export is not completely lost in HSAN patients, thus suggesting the possibility to improve FLVCR1 expression/activity for therapeutic purposes.

Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy.

BACKGROUND: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations. METHODS: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature. RESULTS: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells. CONCLUSIONS: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition of the cardinal features of this condition will facilitate diagnosis of this complex neurologic disorder.

Diarrhoea morbidity patterns in Central Region of Ghana.

INTRODUCTION: Diarrhoea diseases remain a major public health threat with nearly 1.7 billion cases annually worldwide occurring in all age groups. In Ghana diarrhoea kills about 14,000 children under five years annually. We therefore analysed data to determine the morbidity pattern of diarrhoea diseases in the Central Region of Ghana. METHODS: Health facility morbidity data was reviewed from 2008-2012. Monthly data on diarrhoeal diseases were extracted from District Health Information Management System database by sex, age group and districts. Data for bloody diarrhoea were extracted from monthly surveillance report forms. Data was analysed descriptively and expressed as frequencies and proportionate morbidity rates (pmr). Aberrations were determined using C2 threshold. RESULTS: The total cases of all morbidity from 2008 to 2012 were 7,642,431. Diarrhoea diseases formed 4% (306854/7642431) of total morbidity. Children under one year (pmr= 8.4%) and males (pmr= 4.4%) were the most affected. Bloody diarrhea formed 2.2% (6835/306854) of diarrhoea cases with 0.7 %(45/6835) laboratory confirmed. Diarrhoea cases peaked from January to March throughout the study period with highest frequency 9.3% (28511/306854) in June. The mean monthly distribution of diarrhoea cases was 25571.17±1389.91. Poorest districts had significantly lower odds of getting bloody diarrhoea than non-poorest districts OR = 0.73 (95%CI = 0.70-0.77). CONCLUSION: Diarrhoea characterized 4% of total morbidity presenting at health facilities in the region from 2008 to 2012. The diarrhoea morbidity rate decreased with increased age. Diarrhoea was higher among non poorest districts. The rate was highest in the month of June over the five year period. Bloody diarrhoea cases were mostly untested. We recommended that stool samples should be taken for laboratory testing for bloody diarrhoea cases.

Fetal alcohol spectrum disorders: guidance for recognition, diagnosis, differential diagnosis and referral.

FASDs are the most common preventable cause of developmental and intellectual disabilities in the United States and yet can easily be overlooked in pediatric and adolescent practices. Early diagnosis, presence of developmental and educational services, and a nurturing home environment have been associated with decreased occurrence of secondary disabilities such as substance use and criminal involvement.23 Therefore, it is important for providers to know how to go about the identification, diagnostic, and evaluation process. Pediatric care clinicians should be knowledgeable about the diagnostic criteria for fetal alcohol syndrome and know common differentiating conditions. Furthermore, they should be able to recognize other disorders on the spectrum, and in doing so, they should facilitate appropriate referral, initial management, and coordination of care.