Early-onset gout and rare deficient variants of the lactate dehydrogenase D gene.

OBJECTIVES: To investigate whether the lactate dehydrogenase D (LDHD) gene deficiency causes juvenile-onset gout. METHODS: We used whole-exome sequencing for two families and a targeted gene-sequencing panel for an isolated patient. d-lactate dosages were analysed using ELISA. RESULTS: We demonstrated linkage of juvenile-onset gout to homozygous carriage of three rare distinct LDHD variants in three different ethnicities. In a Melanesian family, the variant was (NM_153486.3: c.206C>T; rs1035398551) and, as compared with non-homozygotes, homozygotes had higher hyperuricaemia (P = 0.02), lower fractional clearance of urate (P = 0.002), and higher levels of d-lactate in blood (P = 0.04) and urine (P = 0.06). In a second, Vietnamese, family, very severe juvenile-onset gout was linked to homozygote carriage of an undescribed LDHD variant (NM_153486.3: c.1363dupG) leading to a frameshift followed by a stop codon, p.(AlaGly432fsTer58). Finally, a Moroccan man, with early-onset and high d-lactaturia, whose family was unavailable for testing, was homozygous for another rare LDHD variant [NM_153486.3: c.752C>T, p.(Thr251Met)]. CONCLUSION: Rare, damaging LDHD variants can cause autosomal recessive early-onset gout, the diagnosis of which can be suspected by measuring high d-lactate levels in the blood and/or urine.

Two-year clinico-biological feedback in Overseas France and French-speaking territories during Covid-19 pandemic / Retour d'expériences clinico-biologiques en Outre-mer et en Francophonie après deux années de pandémie Covid-19

The French Society of Clinical Biology (SFBC) set up a working group "Biochemical markers of Covid-19" whose main objective is to review, analyse and monitor biological prescriptions according to the patient's care path. This study covers all public and private sectors of medical biology in metropolitan France and overseas and extends to the French-speaking world. We present a summary of feedbacks after 2 years of the pandemic. At the early stage of Covid-19, with regard to the regions surveyed, a common symptomatology with local zoonosis (dengue fever, zika, malaria, leptospirosis, etc.) complicates the diagnosis of Covid-19. At a more advanced stage, it is a question of managing an influx of patients suffering from acute respiratory distress syndrome. In this case, the biology is then simpler and delocalized medical biology devices have proven their effectiveness. As a result, ICU clinicians can better manage the frequent comorbidities encountered in these regions: obesity, diabetes, chronic renal failure, cardiovascular diseases.

La Société française de biologie clinique (SFBC) a mis en place un groupe de travail « Marqueurs biochimiques de Covid-19 ¼ dont l'objectif principal est de revoir, d'analyser et de suivre les prescriptions biologiques en fonction du parcours de soins du patient. Cette étude couvre tous les secteurs publics et privés de la biologie médicale en métropole et en Outre-mer et s'étend à la Francophonie. Nous présentons une synthèse des retours d'expériences après 2 ans de pandémie. Au stade précoce de la Covid-19, pour les régions interrogées, une symptomatologie commune avec des zoonoses locales (dengue, zika, paludisme, leptospirose…) complique le diagnostic de la Covid-19. À un stade plus avancé, il s'agit de gérer un afflux de patients atteints de syndrome de détresse respiratoire aiguë. La biologie est alors plus simple, et les dispositifs de biologie médicale délocalisée ont prouvé leur efficacité. De ce fait, les réanimateurs peuvent mieux gérer les comorbidités fréquentes rencontrées dans ces régions : obésité, diabète, insuffisance rénale chronique ou maladies cardiovasculaires.

Hidden administration of 5-APB in a dancing club of New Caledonia documented by urine analysis: about 3 cases.

1-Benzofuran-5-ylpropan-2-amine or 5-APB is a new psychoactive substance (NPS) with empathic effects close to ecstasy (MDMA). Although 5-APB has been observed in fatality cases, the drug has not yet been reported in the context of hidden administration for behaviour impairment, also known as drug-facilitated crime. Such a situation was recently observed on 3 separate occasions in the same dancing club of New Caledonia. It involves 3 women, aged 27, 29, and 33 years who presented, after having drunk a cocktail, anxiety, abnormal movements of the inferior jaw, and aggressiveness. No memory loss was noticed. About 12 h after the event, a urine specimen was collected in the 3 cases. Comprehensive toxicology was requested and only 5-APB was identified, at 6, 8, and 14 ng/mL. Urine ethanol tested negative, which is consistent with the limited intake before the event occurred. These results have demonstrated that NPS are circulating in New Caledonia, which was not previously reported, and that 5-APB, like ecstasy, can be used to modify the behaviour of a subject, as it can be done by a chemical weapon.

[Management of a global health crisis: first COVID-19 disease feedback from Overseas and French-speaking countries medical biologists]. / Gestion d'une crise sanitaire mondiale : premiers retours d'expérience de biologistes médicaux d'Outre-mer et de francophonie face au COVID-19.

The French society of clinical biology "Biochemical markers of COVID-19" has set up a working group with the primary aim of reviewing, analyzing and monitoring the evolution of biological prescriptions according to the patient's care path and to look for markers of progression and severity of the disease. This study covers all public and private sectors of medical biology located in metropolitan and overseas France and also extends to the French-speaking world. This article presents the testimonies and data obtained for the "Overseas and French-speaking countries" sub-working group made up of 45 volunteer correspondents, located in 20 regions of the world. In view of the delayed spread of the SARS-CoV-2 virus, the overseas regions and the French-speaking regions have benefited from feedback from the first territories confronted with COVID-19. Thus, the entry of the virus or its spread in epidemic form could be avoided, thanks to the rapid closure of borders. The overseas territories depend very strongly on air and/or sea links with the metropolis or with the neighboring continent. The isolation of these countries is responsible for reagent supply difficulties and has necessitated emergency orders and the establishment of stocks lasting several months, in order to avoid shortages and maintain adequate patient care. In addition, in countries located in tropical or intertropical zones, the diagnosis of COVID-19 is complicated by the presence of various zoonoses (dengue, Zika, malaria, leptospirosis, etc.).

[SFBC working group "Biochemical markers of COVID-19"]. / Groupe de travail SFBC « Marqueurs biochimiques de COVID-19 ¼.

The SARS-CoV-2 virus is responsible for an epidemic disease called COVID-19, which was initially evidenced in Wuhan, China, and spread very rapidly in China and around the world. In France, the first isolated case seems now to be reported in December 2019, stage 3 of the COVID-19 epidemic was triggered on March 14th, the start of the planned containment exit from May 11th. Healthcare services have faced a large influx of patients who may be beyond their capacity to receive and care, particularly in the Large-East and Ile-de-France regions. Some patients show an evolution of the disease never observed before with other coronaviruses and develop in a few days a very important inflammatory reaction, which can lead to death of patients. A working group of the French Society of Clinical Biology (SFBC) was set up with the objective of providing updated information on the current status of the biological prescriptions (focusing on biochemistry ones) and their evolution during the epidemic, and of analyzing the biological parameters associated with comorbidities and patient evolution in order to link biological results with medical events. The expanded working group covers all sectors of medical biology in France and extends to the French-speaking world: hospital sectors (CHU and CH, Army Training Hospitals) and the private sector opening a field of view on the biological situation in establishments for dependent elderly, social establishments and clinical medical institutions. The purpose of this article is the presentation of this working group and its immediate and future actions.

[Urinary exploration of metabolism: nutrition assessment, urolithiasis and tubulopathy]. / Exploration urinaire du métabolisme : bilan nutritionnel, lithiase urinaire et tubulopathie.

The SFBC working group aimed to deal with biological tests outside the french nomenclature that may be useful in the context of urinary exploration of metabolism. This section will be divides into three parts: 1) nutritional assessment using urinary urea; 2) metabolic assessment of urolithiasis; 3) exploration of tubulopathies. National and international recommendations support the evaluation of nutritional status from urea measurements in urine and dialysate with the following indications: primary metabolic evaluation of urolithiasis patients, monitoring of protein intake in chronic renal failure stage 3 or stage 5D with residual diuresis. For the management of the urolithiasis disease, biomedical tests recommended by the national and international guidelines are the measurement of the urinary density using refractometry in the primary metabolic evaluation as well as the determination of oxalemia in the diagnosis (patients with GFR< 30 mL/min/1.73 m2) and follow-up (patients with GFR< 60 mL/min/1.73 m2) of primary hyperoxaluria. The determination of the bicarbonaturia is retained for the in depth exploration of urolithiasis and tubular acidosis. The measure of chlore in urine is used to evaluate the volume status during metabolic alkalosis and to calculate the urinary anionic gap during metabolic acidosis.

[Estimation of glomerular filtration rate using cystatin C]. / Estimation du débit de filtration glomérulaire par la cystatine C.

Blood concentration of cystatin C is independent of muscle mass and tubular secretion. It can be used, in the absence of a reference method, as an alternative marker to creatinine for the evaluation of renal function and the estimation of glomerular filtration rate (GFR). Both particle-enhanced immunonephelemetry (PENIA) or immunoturbidimetry (PETIA) methods are available to determine cystatin C. From an analytical point of view, it is recommended to use methods whose calibration is traceable to the reference material (ERM-DA471/IFCC) and to report an estimated GFR based on cystatin C. The main equations used are those developed in 2012 by the group "Chronic kidney disease epidemiology collaboration (CKD-EPI)" for adults and those published by Schwartz in 2012 for children. National and international recommendations suggest using a cystatin C-based GFR estimate as a confirmatory test in the clinical settings where the relationship between creatinine production and muscular mass impairs the clinical performance of creatinine. The indications retained by the working group were graded according to the level of recommendations. The essential indications are the estimation and/or the monitoring of renal function in children and adolescents due to rapid changes in muscle mass; in patients with impaired muscle mass and in patients with an alteration of tubular secretion of creatinine (essentially iatrogenic effects).

[Dialysis monitoring: peritoneal equilibrium test, regional citrate anticoagulation and residual renal function]. / Suivi de la dialyse : test d'équilibration péritonéale, anticoagulation régionale au citrate, et fonction rénales résiduelle.

The SFBC working group aimed to deal with biological tests outside the French nomenclature that may be useful for the follow-up of dialysis patients. Our discussion was divided into 3 parts: 1) evaluation of peritoneal membrane characteristics; 2) monitoring of renal replacement therapy using regional citrate anticoagulation; 3) estimation of residual renal function (RRF). International recommendations underline the importance of assessing peritoneal membrane characteristics for peritoneal dialysis prescription. This peritoneal equilibrium test requires the measurement in dialysate of the following parameters: glucose, urea, creatinine and sodium. As part of the monitoring of continuous renal replacement therapy using regional citrate anticoagulation, the determination of ionized calcium assay is essential according to national and international guidelines to ensure a balance between effective anticoagulation and appropriate calcium levels. Finally, the RRF plays a key role in the dialysis adequacy and patient survival. European and international recommendations highlight the potential interest of RRF in peritoneal dialysis and hemodialysis. The RRF corresponds to the mean of urinary urea and creatinine clearance, assessed from a urine collection with measurement of urinary urea.

Nickel and associated metals in New Caledonia: Exposure levels and their determinants.

The ultramafic massifs of the New Caledonian archipelago contain about 10% of the world's nickel reserves, which also contain significant but lower amounts of cobalt, chromium, and manganese. Natural erosion of these massifs and mining activities may contribute to the exposure of local populations to these metals through contamination of air, food, and water resources. We conducted a biomonitoring survey to evaluate exposure to these four metals and its main determinants by constructing a stratified sample of 732 adults and children (>3 years old) from visitors to 22 health centers across the archipelago. Urine was collected and analyzed by inductively-coupled plasma mass spectrometry to determine metal concentrations. A face-to-face interview was conducted to document sociodemographic characteristics, lifestyle and dietary habits, and residence-mine distance. Environmental samples (soil, house dust, water, and foodstuffs) were collected from two areas (one with and one without mining activity) to delineate determinants of exposure in more detail. Nickel and chromium were metals with the highest concentrations found in urine, especially in children, at levels exceeding reference values derived from representative national surveys elsewhere throughout the world (for children: 4.7 µg/g creatinine for nickel and 0.50 µg/g creatinine for chromium): 13% of children exceeded the reference value for nickel and 90% for chromium. Large variations were observed by region, age, and sex. In this geological setting, urinary and environmental nickel concentrations appear to be driven mainly by soil content. This is the first archipelago-wide survey of metal exposure in New Caledonia. The potential health consequences of this chronic high exposure need to be assessed.

Rapid screening and multi-toxin profile confirmation of tetrodotoxins and analogues in human body fluids derived from a puffer fish poisoning incident in New Caledonia.

In August 2014, a puffer fish poisoning incidence resulting in one fatality was reported in New Caledonia. Although tetrodotoxin (TTX) intoxication was established from the patients' signs and symptoms, the determination of TTX in the patient's urine, serum or plasma is essential to confirm the clinical diagnosis. To provide a simple cost-effective rapid screening tool for clinical analysis, a maleimide-based enzyme-linked immunosorbent assay (mELISA) adapted for the determination of TTX contents in human body fluids was assessed. The mELISA was applied to the analysis of urine samples from two patients and a response for the presence of TTX and/or structurally similar analogues was detected in all samples. The analysis by LC-MS/MS confirmed the presence of TTX but also TTX analogues (4-epiTTX, 4,9-anhydroTTX and 5,6,11-trideoxyTTX) in the urine. A change in the multi-toxin profile in the urine based on time following consumption was observed. LC-MS/MS analysis of serum and plasma samples also revealed the presence of TTX (32.9 ng/mL) and 5,6,11-trideoxyTTX (374.6 ng/mL) in the post-mortem plasma. The results provide for the first time the TTX multi-toxin profile of human samples from a puffer fish intoxication and clearly demonstrate the implication of TTX as the causative agent of the reported intoxication case.

Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives.

22 Flavokawain derivatives (FKd) were obtained by one step syntheses in order to conduct a SAR study to understand the structural requirements for optimum and selective cytotoxicity. FKd and natural flavokawains A and B found into kava, a South Pacific traditional beverage, were evaluated against nine cancer and one healthy cell lines. The targeted cell cycle phases as well as the effects on the induction of apoptosis and cell cycle protein levels were investigated. Therapeutic improvements (more activity and selectivity) were achieved with FKd compared to natural flavokawains and notably with the 2',3,4',6'-tetramethoxychalcone (FKd 19). FKd induced a G1/S arrest on p53 wild-type cells and an M arrest on p53 mutant-type, via the up-regulation of p21 and cyclin B1 proteins, followed by apoptosis. Moreover, FKd exhibited a 24h-effect on Akt/mTor normal cells versus a 48h-effect on Akt/mTor up-regulated cells. The SAR study resulted in the conclusion that trimethoxy A-ring allowed the best compromise between cytotoxicity and selectivity, as well as the substitution of the meta position on the B-ring and the use of halogens substituents.

Changes in cardiovascular disease risk factors over 30 years in Polynesians in the French Pacific Territory of Wallis Island.

BACKGROUND: Wallis Island is part of a French Territory in the South Pacific. In 1980 the prevalence of hypertension and type 2 diabetes mellitus (T2DM) was low, consistent with a subsistence economy. Considerable social and economic changes have occurred over the last 30 years. METHODS: Survey data from 1980 and 2009 were analysed by sex in 10-year age groups, and 25-64 years age-standardised to the 2008 Census. Means and prevalences were calculated for blood pressure, fasting plasma glucose, body mass index (BMI), blood cholesterol and triglycerides as risk factors contributing to cardiovascular disease. RESULTS: During 1980-2009 there were significant increases (p < 0.05) in age-standardised means and prevalences of blood pressure and hypertension, fasting plasma glucose and T2DM, BMI and obesity, blood cholesterol (men) and triglycerides; and non-significant increases in mean diastolic blood pressure and fasting plasma glucose in women. Mean cholesterol and the prevalence of elevated cholesterol declined in women. Hypertension prevalence increased from 12% to 43% in men and from 15% to 30% in women, with 42% of the increase in men and 33% of the increase in women statistically explained by increases in BMI. T2DM increased from 2.3% to 12.2% in men and from 4.0% to 15.8% in women, with 35% of the increase in men and 26% of the increase in women statistically explained by increases in BMI. CONCLUSIONS: Risk factors for cardiovascular disease have increased considerably in Wallis Island over the past 30 years, consistent with modernisation in way of life.

Newly diagnosed rheumatic heart disease among indigenous populations in the Pacific.

OBJECTIVES: Rheumatic heart disease (RHD) remains the leading acquired heart disease in the young worldwide. We aimed at assessing outcomes and influencing factors in the contemporary era. METHODS: Hospital-based cohort in a high-income island nation where RHD remains endemic and the population is captive. All patients admitted with newly diagnosed RHD according to World Heart Federation echocardiographic criteria were enrolled (2005-2013). The incidence of major cardiovascular events (MACEs) including heart failure, peripheral embolism, stroke, heart valve intervention and cardiovascular death was calculated, and their determinants identified. RESULTS: Of the 396 patients, 43.9% were male with median age 18 years (IQR 10-40)). 127 (32.1%) patients presented with mild, 131 (33.1%) with moderate and 138 (34.8%) with severe heart valve disease. 205 (51.8%) had features of acute rheumatic fever. 106 (26.8%) presented with at least one MACE. Among the remaining 290 patients, after a median follow-up period of 4.08 (95% CI 1.84 to 6.84) years, 7 patients (2.4%) died and 62 (21.4%) had a first MACE. The annual incidence of first MACE and of heart failure were 59.05‰ (95% CI 44.35 to 73.75) and 29.06‰ (95% CI 19.29 to 38.82), respectively. The severity of RHD at diagnosis (moderate vs mild HR 3.39 (0.95 to 12.12); severe vs mild RHD HR 10.81 (3.11 to 37.62), p<0.001) and ongoing secondary prophylaxis at follow-up (HR 0.27 (0.12 to 0.63), p=0.01) were the two most influential factors associated with MACE. CONCLUSIONS: Newly diagnosed RHD is associated with poor outcomes, mainly in patients with moderate or severe valve disease and no secondary prophylaxis.

Severe traumatic brain injuries from motor vehicle-related events in New Caledonia: epidemiology, outcome and public health consequences.

OBJECTIVE: Traumatic brain injuries (TBI), which are mostly due to road traffic crash (RTC), are a major public health concern. This article describes the incidence, severity and outcome of TBI caused by RTC in New Caledonia over a five-year period. METHODS: Data of all individuals admitted in intensive care unit with severe TBI (Glasgow Coma Scale score ≤8 at admission) caused by RTC in New Caledonia from 2008 to 2012 were analysed. Causes and severity of trauma, demographic data, and short-term as well as last available long-term outcome of patients were analysed. Five types of road users were compared (car drivers, car passengers, motorcyclists, bicyclists and pedestrians). Outcome was defined according to the Glasgow Outcome Scale classification. RESULTS: A total of 109 patients were included in the study. The median age of patients was 24 [IQR18-33] years with a sex ratio of 2.8 (80 men/29 women). The rate of 44 among Melanesian males was two times higher that among 16 European males (22/100,000 people vs 11/100,000 people). The total survival at the Intensive Care Unit discharge (short-term outcome) was 84%, being the highest among passengers (88%) and the lowest among motorcyclists (69%). Of the patients tested for psychoactive substances, half tested positive. Lost to follow-up rate was 67%. CONCLUSION: Poor outcome occurs in patients with RTC-related TBI, with young Melanesian men being the most affected. Public health action should focus on this group using culturally appropriate messages.

Relationships Between Clinico-Epidemiological Patterns of Invasive Meningococcal Infections and Complement Deficiencies in French South Pacific Islands (New Caledonia).

PURPOSE: Invasive Meningococcal Disease (IMD) is three fold more common in New Caledonia (NC) than in metropolitan France and many IMD cases (35.7%) are due to Y and W135 serogroups. The purpose of our study was to identify IMD risk factors in NC. METHODS: A retrospective study of all IMD cases that occurred in NC between 2005 and 2011 was conducted. Socio-environmental, clinical and biological data were collected. A search for immune deficiency was proposed to all cases. IMD presentation and outcome were compared according to meningoccal serogroups and the complement deficiency status (C-deficiency). RESULTS: Sixty-six sporadic IMD cases (29 B serogroup, 20 Y or W135, 6 C, 1 A, 10 unknown) occurred in 64 patients often <24 years-old and of Melanesian origin. Five patients died (7.8%). No socio-environmental risk factors were identified. No asplenia, HIV infection or immunoglobulin deficiencies were found. Two patients had diabetes and 28 of 53 (52.8%) patients had C-deficiency including 20 (71.4%) cases of late complement component deficiency. Patients with C-deficiency were mainly Melanesian (92.8%) originating from the Loyalty Islands (62.1%). They were mostly infected with Y/W135 (42.9%) or B serogroups (32.1%). They often developed later and more severe disease than patients without C-deficiency (need for intensive cares in 60% versus 28.0% of cases, p = 0.01). CONCLUSIONS: A high prevalence of C-deficiency in the Melanesian population may explain epidemiological and clinical features of IMD in NC. Our results imply an adaptation of meningococcal vaccine strategies in NC.

[Inventory of the use of natriuretic peptides in France]. / État des lieux de l'utilisation des peptides natriurétiques en France.

Since the introduction of routine assay for natriuretic peptides (NP), there is an increasing number of clinical applications for these assays. Due to the continuously increasing number of prescription of those tests, a reappraisal of the use of natriuretic peptide assays, namely BNP and NT-proBNP in France was necessary. This was achieved through a national survey to obtain a detailed description of NP prescription and realization by French laboratories. A questionnaire was sent in April 2010 to hospital and private clinical chemists. Statistical analysis of results concerned 584 answers. This survey demonstrated an equivalent use of BNP and NT-proBNP both in public or private laboratories together with a huge heterogeneity of tests used within labs. Medical prescription heterogeneity both in public or private sectors confirms the large implication of those tests in clinical diagnosis. These assays are not yet standardized, so clinicians and biologists should be very careful when interpreting the results for diagnostic or therapeutic monitoring.

Testing for atropine and scopolamine in hair by LC-MS-MS after Datura inoxia abuse.

Datura inoxia belongs to the family of Solanaceae. This is a very common plant in New Caledonia that contains two main toxic alkaloids, l-atropine and l-scopolamine. In this study, we report the case of a 20-year-old male admitted to an Emergency Unit after consumption of 6 dried flowers in hot water for hallucinations, mydriasis, and agitation associated with tachycardia and increase of systolic blood pressure to 180. Full recovery was observed after one week. Three weeks later, a lock of about 80 hairs (200 mg) was collected from the subject in vertex posterior with scissors to be tested for both atropine and scopolamine. After decontamination with dichloromethane, a strand of hair was segmented into three parts, cut into small segments (< 1 mm), incubated overnight in 1 mL pH 8.4 phosphate buffer in the presence of 2.5 ng atropine-d(3), the internal standard, then extracted with 5 mL dichloromethane/isopropanol/n-heptane (50:17:33). The residue was reconstituted in 100 microL of methanol, from which 10 microL was injected into an XTerra MS C18 column (100 x 2.1 mm, 3.5 microm) eluted with a gradient of acetonitrile and formate buffer delivered at a flow rate of 0.2 mL/min. A Quattro Micro triple-quadrupole mass spectrometer (MS) was used for analyses. Ionization was achieved using electrospray in the positive ionization mode. For each compound, detection was related to two daughter ions (atropine: m/z 290.2 to 124.0 and 92.9; atropine-d(3): m/z 293.1 to 127.0 and 92.9; scopolamine: m/z 304.1 to 138.0 and 156.0). Although atropine was never detected (limit of detection = 2 pg/mg), scopolamine was identified in the three segments, in the range 14 to 48 pg/mg. The absence of atropine in hair is consistent with its very low dosage in the flower of Datura inoxia. Hair segmentation indicated that the subject was previously exposed on several occasions to the plant. Liquid chromatography-tandem MS appears to be a necessity for testing tropane alkaloids of the Datura group, given the low concentrations to be measured.