Noma (cancrum oris): A scoping literature review of a neglected disease (1843 to 2021).

BACKGROUND: Noma (cancrum oris) is an ancient but neglected and poorly understood preventable disease, afflicting the most disenfranchised populations in the world. It is a devastating and often fatal condition that requires urgent and intensive clinical and surgical care, often difficult to access as most cases of noma occur in resource-limited settings. We conducted a scoping review of the literature published on noma to understand the size and scope of available research on the disease and identify research gaps that need to be addressed to evolve our understanding of how to address this disease. METHODS: We searched 11 databases and collected primary peer reviewed articles on noma in all languages, the final search was conducted on 24th August 2021. The oldest manuscript identified was from 28th March 1843 and the most recently published manuscript was from 3rd June 2021. Search terms included cancrum oris and noma. Data was extracted using a standardised data extraction tool and key areas of interest were identified. The Preferred Reporting Items for Systemic review and Meta-Analyses requirements were followed. RESULTS: The review included 147 articles, the majority of the studies (n = 94, 64%) were case reports. Most manuscripts (n = 81, 55%) were published in the 2000s, 49 (33%) were from the 1900s and 17 (12%) from the 1800s. The main areas of interest identified were the history and epidemiology of the disease, noma's clinical progression and aetiology, treatment regimens, mortality rates and the risk factors for the development of noma. CONCLUSIONS: Noma has been reported in the literature for hundreds of years; however important gaps in our understanding of the disease remain. Future research should focus on determining the burden and distribution of disease; the true mortality rate, pathogenic cause(s) and the factors that influence prognosis and outcomes after treatment.

Trends in allogeneic haematopoietic cell transplantation for myelofibrosis in Europe between 1995 and 2018: a CMWP of EBMT retrospective analysis.

We performed a retrospective assessment of patient- and transplant-specific characteristics and outcomes for 4142 patients undergoing allogeneic haematopoietic cell transplant for myelofibrosis between 1995 and 2018 across 278 centres. Activity increased steadily across the four analysed eras (<2006, 2006-2010, 2011-2014 and 2015-2018). Median recipient age increased over time between the earliest and most recent cohort (49.4 years (range, 20.1-68) versus 59.3 years (range, 18.1-78.1). Increasing number of patients with a Karnofsky performance status <90 underwent transplant over time. Increased utilisation of matched unrelated donors was apparent (<2006, 22.5% versus 2015-18, 45.2%; p < 0.001). Decreased use of myeloablative conditioning, increased use of busulphan-based platforms and anti-thymocyte globulin was evident. Of note, rates of acute (a)GVHD grade II-IV by day +100 decreased over time (p = 0.027) as did rates of chronic (c) GVHD, predominantly extensive cGVHD (<2006, 36% (31-41%) versus 2015-18, 23% (21-25%); p = 0.001). Overall, significant factors associated with worse overall survival and non-relapse mortality (NRM) remained older age, use of donors other than matched sibling, recipient CMV seropositivity and a lower Karnofsky performance status (<90). Multivariable analysis demonstrated improvements in overall survival and reductions in relapse risk over time with stable NRM rates despite increasing numbers of older, less fit patients and use of unrelated donors.

Why is noma a neglected-neglected tropical disease?

Noma is an orofacial gangrene affecting primarily children living in extreme poverty in remote parts of subtropical and tropical countries. Mortality and disability are high, and survivors often have physical and functional deformities resulting in stigma and isolation. Many healthcare professionals and primary healthcare workers where noma risk factors exist have no knowledge about noma and its implications. Public health measures to improve nutrition, immunizations, sanitation, and access to healthcare and measures to eliminate extreme poverty can lead to the eradication of noma. Research allocation has been insufficient to study the epidemiology, treatment, and prevention of noma. In a recent editorial by Hotez and colleagues in PLOS Neglected Tropical Diseases (NTDs), "What constitutes an NTD?" Noma is not included. The exclusion of noma from NTDs constitutes this preventable childhood disease as a neglected neglected disease. The purpose of this article is the inclusion of noma with the PLOS NTDs. Increased awareness and attention to noma can lead to the eradication of this disease affecting the world's most vulnerable.

Structural brain anomalies in Cri-du-Chat syndrome: MRI findings in 14 patients and possible genotype-phenotype correlations.

INTRODUCTION: Cri-du-Chat Syndrome (CdCS) is a genetic condition due to deletions showing different breakpoints encompassing a critical region on the short arm of chromosome 5, located between p15.2 and p15.3, first defined by Niebuhr in 1978. The classic phenotype includes a characteristic cry, peculiar facies, microcephaly, growth retardation, hypotonia, speech and psychomotor delay and intellectual disability. A wide spectrum of clinical manifestations can be attributed to differences in size and localization of the 5p deletion. Several critical regions related to some of the main features (such as cry, peculiar facies, developmental delay) have been identified. The aim of this study is to further define the genotype-phenotype correlations in CdCS with particular regards to the specific neuroradiological findings. PATIENTS AND METHODS: Fourteen patients with 5p deletions have been included in the present study. Neuroimaging studies were conducted using brain Magnetic Resonance Imaging (MRI). Genetic testing was performed by means of comparative genomic hybridization (CGH) array at 130 kb resolution. RESULTS: MRI analyses showed that isolated pontine hypoplasia is the most common finding, followed by vermian hypoplasia, ventricular anomalies, abnormal basal angle, widening of cavum sellae, increased signal of white matter, corpus callosum anomalies, and anomalies of cortical development. Chromosomal microarray analysis identified deletions ranging in size from 11,6 to 33,8 Mb on the short arm of chromosome 5. Then, we took into consideration the overlapping and non-overlapping deleted regions. The goal was to establish a correlation between the deleted segments and the neuroradiological features of our patients. CONCLUSIONS: Performing MRI on all the patients in our cohort, allowed us to expand the neuroradiological phenotype in CdCS. Moreover, possible critical regions associated to characteristic MRI findings have been identified.

Stress in Parents of Children With Genetically Determined Leukoencephalopathies: A Pilot Study.

Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index-4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index-4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

Approche diagnostique et thérapeutique de la vasculopathie polypoïdale choroïdienne. Recommandations de la Fédération France Macula.

PURPOSE: To update the medical literature on the diagnostic and therapeutic approach to polypoidal choroidal vasculopathy (PCV) and to propose a treatment algorithm in agreement with French market approval, supported by the France Macula Federation (FFM). METHODS: Literature review and expert opinion. RESULTS: The diagnosis of PCV is based on multimodal imaging, including indocyanine green angiography (ICGA), which is considered the gold standard for the diagnosis of PCV. Regarding the therapeutic management of PCV, the FFM recommends treating PCV first-line either by monotherapy with intra-vitreal anti-vascular endothelial growth factor (anti-VEGF) injections, or by a combined treatment of photodynamic therapy (PDT) with Verteporfin and intra-vitreal anti-VEGF injections, depending on the location of the PCV.

Optical coherence tomography angiography features of choroidal neovascularization secondary to angioid streaks.

PURPOSE: To characterize the features of choroidal neovascularization (CNV) secondary to angioid streaks (AS) with optical coherence tomography angiography (OCT-A) and to assess its sensitivity in CNV detection in this particular context. METHODS: Consecutive patients, both with treatment-naïve and recurrent CNV associated with angioid streaks were prospectively analyzed. All patients underwent macular imaging by fluorescein angiography (FA), indocyanine green angiography (ICGA), spectral-domain (SD)-OCT, and OCT-A (AngioVue, Optovue, Optovue Inc., Freemont, CA, USA). OCT-A detection rate of CNV associated to AS was evaluated by two independent observers. We studied the association between OCT-A feature and either exudative or active status using Fisher exact test. RESULTS: A total of 32 eyes of 18 consecutive patients were included in the analysis. OCT-A was able to detect CNV associated with angioid streaks in 87.5 % (28/32) eyes. OCT-A phenotypes of CNV were classified into interlacing pattern in 9 eyes, pruned vascular tree pattern in 7 eyes, and combined pattern in 12 eyes (Interuser agreement: 0.871 ± 0.071). CNV were not detectable in 4/32 eyes. There was a statistically significant association between the presence in OCT-A of densely ramified networks with both previous treatment status in the last 6 months (p < 0.001) and with exudative signs on SD-OCT (p = 0.014). CONCLUSION: OCT-A appears as a sensitive tool for detection of CNV secondary to AS. The interlacing pattern was significantly associated with active and exudative features.

Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy.

Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report 2 patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5, but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Biochemical analysis confirmed a complex I deficiency, and whole-exome sequencing revealed a homozygous mutation in NDUFA2 (c.134A>C, p.Lys45Thr). Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole-exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2 (c.134A>C, p.Lys45Thr; c.225del, p.Asn76Metfs*4). Only 1 other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2.

Milk products in the dietary management of childhood undernutrition - a historical review.

The present narrative review outlines the use of milk products in infant and young child feeding from early history until today and illustrates how research findings and technical innovations contributed to the evolution of milk-based strategies to combat undernutrition in children below the age of 5 years. From the onset of social welfare initiatives, dairy products were provided by maternal and child health services to improve nutrition. During the last century, a number of aetiological theories on oedematous forms of undernutrition were developed and until the 1970s the dogma of protein deficiency was dominant. Thereafter, a multifactorial concept gained acceptance and protein quality was emphasised. During the last decades, research findings demonstrated that the inclusion of dairy products in the management of severe acute malnutrition is most effective. For children suffering from moderate acute malnutrition the evidence for the superiority of milk-based diets is less clear. There is an unmet need for evaluating locally produced milk-free alternatives at lower cost, especially in countries that rely on imported dairy products. New strategies for the dietary management of childhood undernutrition need to be developed on the basis of research findings, current child feeding practices, socio-cultural conditions and local resources. Exclusive and continued breast-feeding supported by community-based nutrition programmes using optimal combinations of locally available complementary foods should be compared with milk product-based interventions.

[Management of wet AMD in France in 2015]. / Prise en charge de la DMLA exsudative en France en 2015.

PURPOSE AND CONTEXT: Intravitreal administration of anti-VEGF agents, available in France since 2007, allows stabilization and improvement in visual acuity in wet age-related macular degeneration (AMD). In the past few years, the management of this disease has evolved in terms of both diagnostic methods and treatment schedules, which have been adapted to the pathophysiology of AMD. The goal of this survey, performed in a representative sample of French ophthalmologists, was to describe the evolution of medical practices one year after a similar survey (Massé et al., J Fr Ophtalmol 2016; 39: 40-7). METHOD: The survey was performed from December, 2014 to March, 2015 in 191 ophthalmologists (53 general ophthalmologists and 98 retina specialists) with an on-line questionnaire. This questionnaire was designed by a committee of ophthalmologists to describe practices concerning screening, diagnosis, treatment and follow-up of wet AMD. RESULTS: An initial intravitreal injection of an anti-VEGF agent was usually performed within 10 days after the diagnosis of wet AMD by 98% of ophthalmologists and within 5 days by 63%. The treatment protocols favored by retina specialists were pro re nata (PRN) for 58%, Observe and Plan for 25% and Treat and Extend for 17%. Bilateral intravitreal injections were performed on the same day by 46% of retina specialists, mostly for the convenience of the patient and because of the low infectious risk. The initial protocol was maintained by one third of retina specialists throughout the course of treatment, while two thirds of them reported that they reassessed the protocol on average after 5 months. CONCLUSION: This survey on the practices of the ophthalmologists in wet AMD highlights an improvement in the time course of patient management and an evolution of treatment schedules toward individualized protocols.

[Individualized management of patients with exudative AMD, IOI protocol: Injection-observational-individualization]. / Prise en charge individualisée des patients atteints de DMLA exsudative, le protocole IOI : injection­observation­individualisation.

Wet macular degeneration remains a major cause of visual impairment in people over 55years. Through a group of experts belonging to the Federation France Macula, we review the treatment of wet AMD and provide recommendation with a 3 phases protocol called IOI.

Noma: Overview of a Neglected Disease and Human Rights Violation.

Noma is an orofacial gangrene affecting malnourished children and mainly observed in tropical countries, particularly sub-Saharan Africa. Epidemiological data on noma are scarce, but a current estimate of the global incidence is 30,000-40,000 cases per year, with a mortality rate of approximately 85% and a burden of disease calculated to be a loss of 1-10 million disability-adjusted life years. The etiology of noma is multifactorial with malnutrition as an ever present factor, often in combination with concomitant diseases, such as measles, malaria, and human immunodeficiency virus (HIV), and poor oral hygiene. The pathogenesis is a fast-spreading, noncontagious gangrenous infection occurring in the face, often preceded by acute necrotizing gingivitis, and stomatitis. Rare microbiological studies suggest an opportunistic infection caused by an imbalance in normal intraoral microorganisms. Prevention lies in food security, measles vaccination, prevention of malaria and HIV, including the early detection and treatment of necrotizing gingivitis and stomatitis. Early treatment with antibiotics may prevent gangrene or reduce its extent. Late treatment consists of surgical rehabilitation, which is often complex. However, access to medical care is very limited for noma patients due to the extremely poor conditions in which they live that are frequently located in remote rural areas. The authors support the United Nations Human Rights Council Resolution 19/7 adopted on March 22, 2012 "The right to food," and advocate for the inclusion of noma on the list of neglected tropical diseases to encourage more medical and institutional attention for this often lethal or very mutilating infectious gangrene.

The Role of Breastfeeding in the Prevention of Childhood Malnutrition.

Breastfeeding has an important role in the prevention of different forms of childhood malnutrition, including wasting, stunting, over- and underweight and micronutrient deficiencies. This chapter reviews research that demonstrates how improved breastfeeding rates have the potential to improve childhood nutrition, with associated impacts on infectious and noninfectious disease prevention. The unique composition of breastmilk, the importance of breastfeeding in infectious disease prevention, the iron status of breastfed infants, and breastfeeding's protective effect on overweight and obesity are discussed based on currently available research. Early and tailored dietary counseling is needed to improve maternal diets, which can affect the nutritional status of breastmilk. Promotion and support of breastfeeding are important to prevent childhood morbidity and mortality. A review of the literature reveals key factors shown to be effective in improving breastfeeding rates, especially including legislation to control the marketing of breastmilk substitutes. In conclusion, breastfeeding is shown to be the best natural resource to improve childhood nutrition throughout the world.

fMRI brain response during sentence reading comprehension in children with benign epilepsy with centro-temporal spikes.

INTRODUCTION: Children with benign epilepsy with centro-temporal spikes (BECTS) often have language problems. Abnormal epileptic activity is found in central and temporal brain regions, which are involved in reading and semantic and syntactic comprehension. Using functional magnetic resonance imaging (fMRI), we examined reading networks in BECTS children with a new sentence reading comprehension task involving semantic and syntactic processing. METHOD: Fifteen children with BECTS (age=11y 1m ± 16 m; 12 boys) and 18 healthy controls (age=11 y 8m ± 20 m; 11 boys) performed an fMRI reading comprehension task in which they read a pair of syntactically complex sentences and decided whether the target sentence (the second sentence in the pair) was true or false with respect to the first sentence. All children also underwent an exhaustive neuropsychological assessment. RESULTS: We demonstrated weaknesses in several cognitive domains in BECTS children. During the sentence reading fMRI task, left inferior frontal regions and bilateral temporal areas were activated in BECTS children and healthy controls. However, additional brain regions such as the left hippocampus and precuneus were activated in BECTS children. Moreover, specific activation was found in the left caudate and putamen in BECTS children but not in healthy controls. Cognitive results and accuracy during the fMRI task were associated with specific brain activation patterns. CONCLUSION: BECTS children recruited a wider network to perform the fMRI sentence reading comprehension task, with specific activation in the left dorsal striatum. BECTS cognitive performance differently predicted functional activation in frontal and temporal regions compared to controls, suggesting differences in brain network organisation that contribute to reading comprehension.

A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly.

We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. L-Serine is essential for neuronal survival and differentiation. Indeed, L-serine biosynthesis disorders affect brain development and cause severe ID. In the brain, L-serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of L-serine into neurons and the release of glia-borne L-serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of L-serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID.

Ranibizumab for exudative age-related macular degeneration: A five year study of adherence to follow-up in a real-life setting.

PURPOSE: To analyze adherence to follow-up over 5 years in patients treated with intravitreal ranibizumab for exudative age-related macular degeneration (AMD) in a tertiary health care center. To investigate factors associated with failure to continue follow-up. METHODS: Retrospective chart review of all consecutive patients with exudative AMD, who received their first intravitreal ranibizumab injection at the Créteil Intercommunal University Hospital Eye Clinic between October 1, 2006 and March 31, 2007. Patient clinical characteristics at baseline and at the last follow-up visit were recorded. Distance from home to hospital was measured for each patient. A multiple-choice telephone survey was conducted for patients lost to follow-up to determine the main reasons for failure to continue follow-up. RESULTS: Two hundred and one patients were included. The rate of loss to follow-up over the 5-year period was 57% (115/201). Fifty-eight patients lost to follow-up completed the questionnaire. The main reasons reported by patients for follow-up discontinuation were long distance from home to hospital (51.7%, 30/58), subjective dissatisfaction with the benefits of intravitreal injections (34.5%, 20/58), and the excessive burden of periodic follow-up visits (24.1%, 14/58). Three factors were significantly associated with follow-up discontinuation: high age at baseline (82.2 vs. 76.5 years, P<0.001), poor best-corrected visual acuity (BCVA) at baseline (42.5 vs. 51.0 letters, P=0.020), and long distance from home to hospital (132 vs. 17.1km, P<0.001). CONCLUSION: In this study, adherence to follow-up over 5 years was poor. Age and BCVA at baseline and distance from home to hospital were independently associated with long-term adherence.

Noma: neglected, forgotten and a human rights issue.

Noma, an orofacial gangrene and opportunistic infection, affects primarily malnourished children living in extreme poverty. Neglected, forgotten, unknown by most health workers, noma results in death, disfigurement and disability of some of the world's most vulnerable children. Noma is a biological indicator of multiple human rights violations, including the right to food. International support and national attention in countries with noma are lacking. The end of neglect of noma can lead to the elimination of this horrific childhood disease.