Systematic review of the patient burden of generalised myasthenia gravis in Europe, the Middle East, and Africa.

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disease characterised by muscle weakness, and progression from ocular (oMG) to generalised (gMG) symptoms results in a substantial negative impact on quality of life (QoL). This systematic review aimed to provide an overview of the patient burden experienced by people living with gMG. METHODS: Electronic database searches (conducted March 2022), supplemented by interrogation of grey literature, were conducted to identify studies reporting patient burden outcomes in patients with gMG in Europe, the Middle East and Africa. Results were synthesised narratively due to the heterogeneity across trials. RESULTS: In total, 39 patient burden publications (representing 38 unique studies) were identified as relevant for inclusion in the systematic review, consisting of 37 publications reporting formal patient-reported outcome measures (PROMs), and two publications describing alternative qualitative assessments of patient experience. The studies included a variety of measures including generic and disease-specific PROMs, as well as symptom-specific PROMs focusing on key comorbidities including depression, anxiety, fatigue and sleep disturbance. The findings showed some variation across studies and PROMs; however, in general there was evidence for worse QoL in patients with gMG than in healthy controls or in patients with oMG, and a trend for worsening QoL with increasing MG severity. CONCLUSIONS: This review highlights the importance of considering patient QoL when developing and assessing treatment and management plans for patients with gMG. However, the heterogeneity identified across studies illustrates the need for further representative and well-powered studies in large cohorts administering consistent, validated questionnaires. TRIAL REGISTRATION: The protocol for this systematic review was registered in PROSPERO: CRD42022328444.

Pharmacokinetic characterisation of a valproate Autism Spectrum Disorder rat model in a context of co-exposure to α-Hexabromocyclododecane.

Assessing the role of α-hexabromocyclododecane α-HBCDD as a factor of susceptibility for Autism Spectrum disorders by using valproic acid-exposed rat model (VPA) required characterizing VPA pharmacokinetic in the context of α-HBCDD-co-exposure in non-pregnant and pregnant rats. The animals were exposed to α-HBCDD by gavage (100 ng/kg/day) for 12 days. This was followed by a single intraperitoneal dose of VPA (500 mg/kg) or a daily oral dose of VPA (500 mg/kg) for 3 days. Exposure to α-HBCDD did not affect the pharmacokinetics of VPA in pregnant or non-pregnant rats. Surprisingly, VPA administration altered the pharmacokinetics of α-HBCDD. VPA also triggered higher foetal toxicity and lethality with the PO than IP route. α-HBCDD did not aggravate the embryotoxicity observed with VPA, regardless of the route of exposure. Based on this evidence, a single administration of 500 mg/kg IP is the most suitable VPA model to investigate α-HBCDD co-exposure.

Loss of muscle mass in the immediate post-operative period is associated with inadequate dietary protein and energy intake.

Despite the implementation of 'Enhanced Recovery After Surgery' (ERAS) protocols, major abdominal surgery is still associated with significant and detrimental losses of muscle mass and function in the post-operative period. Although ERAS protocols advocate both early mobility and dietary intake, dietary composition in the immediate post-operative period is poorly characterised, despite muscle losses being greatest in this period. Herein, we show in 15 patients (66 ± 6 y, 12:3 M:F) who lost ~10% m. vastus lateralis muscle mass in the 5 days after open colorectal resective surgery, mean energy intake was only ~25% of the minimum ESPEN recommendation of 25 kcal/kg/d and daily dietary protein intake was only ~12% of the ESPEN recommended guidelines of 1.5 g/kg/d. Given the known importance of nutrition for muscle mass maintenance, innovative dietary interventions are needed in the immediate post-operative period, accounting for specific patient dietary preference to maximise compliance (e.g., soft-textured foods).

Comparing coordination uranyl(vi) complexes with 2-(1H-imidazo[4,5-b]phenazin-2-yl)phenol and derivatives.

Four derivatives of 2-(1H-imidazo[4,5-b]phenazin-2-yl)phenol have been synthesized and characterized structurally using X-ray crystallography. Coordination complexes with uranyl (UO22+) and copper (Cu2+) were prepared and absorption/emission spectra detailed. We observed increased fluorescence upon uranyl binding, in stark contrast to rapid quenching observed with the addition of copper. These phenomena have been further examined by DFT computational methods.

Cardiovascular severe maternal morbidity in pregnant and postpartum women: development and internal validation of risk prediction models.

OBJECTIVES: To develop and internally validate risk prediction models identifying women at risk for cardiovascular severe maternal morbidity (CSMM). DESIGN: A retrospective cohort study. SETTING: An obstetric teaching hospital between 2007 and 2017. POPULATION: A total of 89 681 delivery hospitalisations. METHODS: We created and evaluated two models, one predicting CSMM at delivery (delivery model) and the other predicting CSMM postpartum following discharge from delivery hospitalisation (postpartum CSMM). We assessed model discrimination and calibration and used bootstrapping for internal validation. MAIN OUTCOME MEASURES: Cardiovascular severe maternal morbidity comprised the following confirmed conditions: pulmonary oedema/acute heart failure, myocardial infarction, aneurysm, cardiac arrest/ventricular fibrillation, heart failure/arrest during surgery or procedure, cerebrovascular disorders, cardiogenic shock, conversion of cardiac rhythm and difficult-to-control severe hypertension. RESULTS: The delivery model contained 11 variables and 3 interaction terms. The strongest predictors were gestational hypertension, chronic hypertension, multiple gestation, cardiac lesions or valvular heart disease, maternal age ≥40 years and history of poor pregnancy outcome. The postpartum model comprised eight variables. The strongest predictors were severe pre-eclampsia, non-Hispanic Black race/ethnicity, chronic hypertension, gestational hypertension, non-severe pre-eclampsia and maternal age ≥40 years at delivery. The delivery and postpartum models had an area under the receiver operating characteristic curve of 0.87 (95% CI 0.85-0.89) and 0.85 (95% CI 0.80-0.90), respectively. Both models were adequately calibrated and performed well on internal validation. CONCLUSIONS: These tools may help providers to identify women at highest risk of CSMM and enable future prevention measures. TWEETABLE ABSTRACT: Risk assessment tools for cardiovascular severe maternal morbidity were developed and internally validated.

[Epidemiological specificities of COVID-19 in Africa: Current or future public health concern?] / Spécificités épidémiologiques de la COVID-19 en Afrique : préoccupation de santé publique actuelle ou future ?

OBJECTIVES: Africa is the continent which is the least equipped to fight the COVID-19 epidemic. However, Africa, which represents 17 % of the world's population, is estimated to have only 5 % of global cases (source: WHO on 2020/08/04). In this work, the authors try to identify and understand the reasons for these epidemiological data. METHOD: Some follow-up indicators have been carried out, mainly through WHO reports. These data were compared with the literature and the field expertise of the association "Biologie sans frontières" in Africa. RESULTS: The following points mark the particularity of COVID-19 in Africa: (1) insufficient diagnostic capacity (linked to gross national product), (2) a younger population limiting the population at risk and the number of deaths, (3) a favourable climate (hot and humid) which is decreasing viral transmission, (4) some socio-cultural factors that can reduce cases reporting. CONCLUSION: Today, this health crisis is omnipresent while the number of deaths remains limited in Africa. Simultaneously, actions concerning African public health priorities (malaria, diarrhoea, AIDS…) are interrupted or slowed down.

Is there an optimal sampling time and number of samples for assessing exposure to fast elimination endocrine disruptors with urinary biomarkers?

In studies investigating the effects of endocrine disruptors (ED) such as phthalates, bisphenols and some pesticides on human health, exposure is usually characterized with urinary metabolites. The variability of biomarkers concentration, due to rapid elimination from the body combined with frequent exposure is however pointed out as a major limitation to exposure assessment. This study was conducted to assess variability of urinary metabolites of ED, and to investigate how sampling time and number of samples analyzed impacts exposure assessment. Urine samples were collected over 6 months from 16 volunteers according to a random sampling design, and analyzed for 16 phthalate metabolites, 9 pesticide metabolites and 4 bisphenols. The amount of biomarkers excreted in urine at different times of the day were compared. In parallel, 2 algorithms were developed to investigate the effect of the number of urine samples analyzed per subject on exposure assessment reliability. In the 805 urine samples collected from the participants, all the biomarkers tested were detected, and 18 were present in >90% of the samples. Biomarkers variability was highlighted by the low intraclass correlation coefficients (ICC) ranging from 0.09 to 0.51. Comparing the amount of biomarkers excreted in urine at different time did not allow to identify a preferred moment for urine collection between first day urine, morning, afternoon and evening. Algorithms demonstrated that between 10 (for monobenzyl (MBzP) phthalate) and 31 (for bisphenol S) samples were necessary to correctly classify 87.5% of the subjects into quartiles according to their level of exposure. The results illustrate the high variability of urinary biomarkers of ED over time and the impossibility to reliably classify subjects based on a single urine sample (or a limited number). Results showed that classifying individuals based on urinary biomarkers requires several samples per subject, and this number is highly different for different biomarkers.

Ultra performance liquid chromatography - tandem mass spectrometer method applied to the analysis of both thyroid and steroid hormones in human hair.

Hair is increasingly used as a biological matrix of interest for the assessment of hormone secretion over extended periods of time. This study described the development and the validation of a sensitive UPLC-MS/MS method for simultaneous analysis of steroid and thyroid hormones in human hair. The gradient designed in this method enables to obtain a satisfactory separation of 9 hormones of interest: cortisol, cortisone, THE, THF, α-THF, triiodothyronine (T3) and thyroxine (T4), estradiol, and testosterone. Several methodological parameters of extraction (such as the used of "cut hair" versus "pulverized hair", the extraction time, the incubation solvent purification on SPE column and hydrolysis) that may influence the determination of hormones levels in human hair, have thus been tested here. Therefore, the results obtained highlighted the necessity of using a C18 SPE purification method for the determination of both steroid and thyroid hormones in hair. This method allows reaching suitable levels of sensitivity for cortisol and cortisone since the results obtained pointed out concentration levels of cortisol in hair of volunteers similar to those observed in the literature. This method could also offer an important impact in the field of hormone analysis since it allows, for the first time, the quantification of both T3 and T4 in human hair.

The effects of foam sclerotherapy on ulcer healing: a single-centre prospective study.

INTRODUCTION: This prospective study of foam sclerotherapy for varicose veins aimed to determine the outcomes of treatment including ulcer healing and complication rates in our unit. Data were collected prospectively over a 10-year period and maintained on a database by our vascular sciences unit, which performed the planning and post-treatment venous duplex scans. Patients undergoing treatment due to venous ulceration were identified from this database. An initial cohort of patients underwent a follow-up scan and assessment at one year. MATERIALS AND METHODS: Patients were treated with foam sclerotherapy, in multiple sessions if required, to occlude all incompetent superficial veins greater than 3 mm in size. We used 3% sodium tetradecyl sulphate as our sclerosing agent, according to our departmental protocol, followed by a period of compression therapy. Patients underwent pre- and post-treatment scans to assess venous competence, the effects of treatment and any complications that arose. RESULTS: We identified 336 patients treated for clinical, aetiological, anatomical and pathophysiological stage 5/6 venous ulceration. At six weeks post-treatment, 21% had fully healed ulcers and a further 46.1% were clinically improving with no further venous incompetence. The remainder continued treatment. An initial cohort of 162 patients was assessed at one year and 77.1% ulcers remained healed. The remainder demonstrated some venous incompetence and ultimately 12.5% required further treatment. Our complication rates were similar to those quoted in published meta-analyses including a deep vein thrombosis rate of 1.16%. CONCLUSIONS: Foam sclerotherapy remains a useful treatment option for venous ulceration with a low morbidity rate.

Fibrin glue is a quick and effective treatment for primary and recurrent pilonidal sinus disease.

BACKGROUND: Pilonidal sinus disease (PSD) is a common, chronic inflammatory condition involving hair follicles within the natal cleft. It mainly affects young males and creates a significant health, social and economic burden. Traditional surgery is often radical resulting in pain, wound complications, long recovery times and poor cosmesis. The aim of our study was to evaluate fibrin glue as a primary treatment for PSD. METHODS: Fibrin glue procedures for a single surgeon at our institution were identified from operative coding databases and the logbook from January 2011 to January 2016. Patients had curettage of the sinus with fibrin glue obliteration. Recurrence data was collected retrospectively. RESULTS: One hundred and forty-six patients were identified; (115 (79%) males, mean age 30 (range 16-78 years). One hundred and forty-four (99%) were discharged the same day. Four (2.7%) were treated conservatively for wound discharge. Median operating time was 9 (range 4-28) min. There were 40 (27%) recurrences after one glue application. Median time to recurrence was 4 (range 0.25-36) months. Twenty-four (60%) of the recurrences had repeat glue treatment with 4 (16.6%) recurrences. After 2 rounds of treatment with glue alone, 126 out of 130 (96.9%) patients had healed. CONCLUSIONS: Fibrin glue application following curettage of the sinus is a quick and effective procedure for first and second line treatment of PSD.

Tunable ligand emission of napthylsalophen triple-decker dinuclear lanthanide(iii) sandwich complexes.

The fluorescent ligand 1,1'-((1E,1'E)-(1,2-phenylenebis(azanylylidene))bis(methanylylidene)) bis(naphthalen-2-ol) (H2L) was used to prepare lanthanide(iii) metal complexes. These were found to self-assemble as triple decker sandwich complexes of the type (Ln2L3), where Ln = Pr(iii), Nd(iii), Sm(iii), Eu(iii), Gd(iii), Tb(iii), Dy(iii), Ho(iii), Er(iii), Yb(iii), or Lu(iii). The structures of the complexes Nd2L3, Gd2L3, Tb2L3, Dy2L3, Ho2L3, Yb2L3, and Lu2L3 are structurally characterized by single crystal X-ray diffraction. In the Nd2L3 complex, both metals are 8 coordinate. Yb2L3, Tb2L3, Dy2L3, and Lu2L3 are isostructural. In these, as in the Gd2L3 and Ho2L3 complexes, one metal is 8 coordinate, one 7 coordinate. The ligand was found to have tunable emission in the solid state across the lanthanide series with a maximum at 556 nm for the Sm2L3 complex to 617 nm for Er2L3. Of these, most demonstrate only ligand-centered fluorescence at room temperature. The ligand was found to have much greater fluorescence in the complex Lu2L3. Here, we describe these distinctive triple decker complexes and their absorption and emission properties as both solids and solutions.

Th(iv) and Ce(iv) napthylsalophen sandwich complexes: characterization of unusual thorium fluorescence in solution and solid-state.

The synthesis, characterization, and electronic spectroscopy of two ML2 sandwich complexes, where M = Ce(iv) or Th(iv) and L = napthylsalophen2- are described. The ThL2 complex, unlike the isovalent CeL2, complex possesses unusual fluorescence properties in both solution and solid-state. These observations are explained with TD-DFT.

Genetic and epigenetic alterations in normal and sensitive COPD-diseased human bronchial epithelial cells repeatedly exposed to air pollution-derived PM2.5.

Even though clinical, epidemiological and toxicological studies have progressively provided a better knowledge of the underlying mechanisms by which air pollution-derived particulate matter (PM) exerts its harmful health effects, further in vitro studies on relevant cell systems are still needed. Hence, aiming of getting closer to the human in vivo conditions, primary human bronchial epithelial cells derived from normal subjects (NHBE) or sensitive chronic obstructive pulmonary disease (COPD)-diseased patients (DHBE) were differentiated at the air-liquid interface. Thereafter, they were repeatedly exposed to air pollution-derived PM2.5 to study the occurrence of some relevant genetic and/or epigenetic endpoints. Concentration-, exposure- and season-dependent increases of OH-B[a]P metabolites in NHBE, and to a lesser extent, COPD-DHBE cells were reported; however, there were more tetra-OH-B[a]P and 8-OHdG DNA adducts in COPD-DHBE cells. No increase in primary DNA strand break nor chromosomal aberration was observed in repeatedly exposed cells. Telomere length and telomerase activity were modified in a concentration- and exposure-dependent manner in NHBE and particularly COPD-DHBE cells. There were a global DNA hypomethylation, a P16 gene promoter hypermethylation, and a decreasing DNA methyltransferase activity in NHBE and notably COPD-DHBE cells repeatedly exposed. Changes in site-specific methylation, acetylation, and phosphorylation of histone H3 (i.e., H3K4me3, H3K9ac, H3K27ac, and H3S10ph) and related enzyme activities occurred in a concentration- and exposure-dependent manner in all the repeatedly exposed cells. Collectively, these results highlighted the key role played by genetic and even epigenetic events in NHBE and particularly sensitive COPD-DHBE cells repeatedly exposed to air pollution-derived PM2.5 and their different responsiveness. While these specific epigenetic changes have been already described in COPD and even lung cancer phenotypes, our findings supported that, together with genetic events, these epigenetic events could dramatically contribute to the shift from healthy to diseased phenotypes following repeated exposure to relatively low doses of air pollution-derived PM2.5.

New insights into urine-based assessment of polycyclic aromatic hydrocarbon-exposure from a rat model: Identification of relevant metabolites and influence of elimination kinetics.

A gas chromatography tandem mass-spectrometry method dedicated to the analysis of 50 metabolites of polycyclic aromatic hydrocarbons (OH-PAHs) was applied to urine specimens collected from female Long Evans rats under controlled exposure to a mixture of PAHs (at 7 doses ranging from 0.01 to 0.8 mg/kg, by gavage, 3 times per week for 90 days). On four occasions (day 1, 28, 60 and 90), urine samples were collected over a 24 h period. Among these 50 OH-PAHs, 41 were detected in urine samples. Seven additional OH-PAHs were identified for the first time: 1 corresponding to metabolite of pyrene and 3 of anthracene. Strong linear dose versus urinary concentration relationships were observed for 25 of the 41 OH-PAHs detected in rat urine, confirming their suitability for assessing exposure to their respective parent compound. In addition, some isomers (e.g. 1-OH-pyrene, 3-OH-/4-OH-chrysene, 10-OH-benz[a]anthracene, 8-OH-benzo[k]fluoranthene, 11-OH-benzo[b]fluoranthene and 3-OH-benzo[a]pyrene) that were detected starting from the lowest levels of exposure or even in controls were considered particularly relevant biomarkers compared to metabolites only detected at higher levels of exposure. Finally, on the basis of the excretion profiles (on days 1, 28, 60 and 90) and urinary elimination kinetics of each OH-PAH detected at days 1 and 60, this study highlighted the fact that sampling time may influence the measurement of metabolites in urine. Taken together, these results provide interesting information on the suitability of the analysis of OH-PAHs in urine for the assessment of PAH exposure, which could be taken into consideration for the design of epidemiological studies in the future.

An example of unusual pyridine donor Schiff base uranyl (UO22+) complexes.

The pentadentate coordination environment of a 2,6-bis[1-[(2-hydroxyphenyl)imino]ethyl] pyridine ligand scaffold was designed to accommodate the larger atomic radius of uranium as the uranyl dioxo cation, while fully occupying its equatorial plane. Here, two new uranyl (UO22+) complexes utilizing this scaffold have been synthesized from successive condensation reactions and subsequent metal complexation. Surprising Zn fluorescence is also discussed.

Differential responses of healthy and chronic obstructive pulmonary diseased human bronchial epithelial cells repeatedly exposed to air pollution-derived PM4.

While the knowledge of the underlying mechanisms by which air pollution-derived particulate matter (PM) exerts its harmful health effects is still incomplete, detailed in vitro studies are highly needed. With the aim of getting closer to the human in vivo conditions and better integrating a number of factors related to pre-existing chronic pulmonary inflammatory, we sought to develop primary cultures of normal human bronchial epithelial (NHBE) cells and chronic obstructive pulmonary disease (COPD)-diseased human bronchial epithelial (DHBE) cells, grown at the air-liquid interface. Pan-cytokeratin and MUC5AC immunostaining confirmed the specific cell-types of both these healthy and diseased cell models and showed they are closed to human bronchial epithelia. Thereafter, healthy and diseased cells were repeatedly exposed to air pollution-derived PM4 at the non-cytotoxic concentration of 5 µg/cm2. The differences between the oxidative and inflammatory states in non-exposed NHBE and COPD-DHBE cells indicated that diseased cells conserved their specific physiopathological characteristics. Increases in both oxidative damage and cytokine secretion were reported in repeatedly exposed NHBE cells and particularly in COPD-DHBE cells. Diseased cells repeatedly exposed had lower capacities to metabolize the organic chemicals-coated onto the air-pollution-derived PM4, such as benzo[a]pyrene (B[a]P), but showed higher sensibility to the formation of OH-B[a]P DNA adducts, because their diseased state possibly affected their defenses. Differential profiles of epigenetic hallmarks (i.e., global DNA hypomethylation, P16 promoter hypermethylation, telomere length shortening, telomerase activation, and histone H3 modifications) occurred in repeatedly exposed NHBE and particularly in COPD-DHBE cells. Taken together, these results closely supported the highest responsiveness of COPD-DHBE cells to a repeated exposure to air pollution-derived PM4. The use of these innovative in vitro exposure systems such as NHBE and COPD-DHBE cells could therefore be consider as a very useful and powerful promising tool in the field of the respiratory toxicology, taking into account sensitive individuals.

Solid state π-π stacking and higher order dimensional crystal packing, reactivity, and electrochemical behaviour of salphenazine actinide and transition metal complexes.

Condensation of a 2,3-diaminophenazine or 2,3-diamino-2-quinoxalinol with two equivalents of 3,5-ditertbutylsalicylaldehyde affords new Schiff base ligands. Here, we describe and compare the synthesis, UV-Vis, electrochemical, solution, and solid state behaviour of the free base, salphenazine ligand [L(I)], and M[L(I)] complexes, where M = UO2(vi), Cu(ii), VO(iv), Zn(ii), Co(ii), and Ni(ii). The change in π-overlap and π-stacking between molecules and long-range ordering of the solid-state structure is vastly different depending on the size and electronic character of the metal. A sterically constrained µ-oxo Fe(iii) dimer complex is also reported.

Efficacy and tolerability of saxagliptin compared with glimepiride in elderly patients with type 2 diabetes: a randomized, controlled study (GENERATION).

AIMS: To assess the efficacy and safety of adjunctive saxagliptin vs glimepiride in elderly patients with type 2 diabetes (T2D) and inadequate glycaemic control. METHODS: In this multinational, randomized, double-blind, phase IIIb/IV study (GENERATION; NCT01006603), patients aged ≥65 years were randomized (1 : 1) to receive saxagliptin 5 mg/day or glimepiride ≤6 mg/day, added to metformin, during a 52-week treatment period. The primary endpoint was achievement of glycated haemoglobin (HbA1c) <7.0% at week 52 without confirmed/severe hypoglycaemia. The key secondary endpoint was incidence of confirmed/severe hypoglycaemia. Safety and tolerability were also assessed. RESULTS: Of 720 patients randomized (360 in each treatment group; mean age 72.6 years; mean T2D duration 7.6 years), 574 (79.8%) completed the study (saxagliptin 80.3%; glimepiride 79.2%). Similar proportions of patients achieved the primary endpoint with saxagliptin and glimepiride (37.9 vs 38.2%; odds ratio 0.99, 95% confidence interval 0.73, 1.34; p = 0.9415); however, a significant treatment-by-age interaction effect was detected (p = 0.0389): saxagliptin was numerically (but not significantly) superior to glimepiride for patients aged <75 years (39.2 vs 33.3%) and numerically inferior for patients aged ≥75 years (35.9 vs 45.5%). The incidence of confirmed/severe hypoglycaemia was lower with saxagliptin vs glimepiride (1.1 vs 15.3%; nominal p < 0.0001). Saxagliptin was generally well tolerated, with similar incidences of adverse events compared with glimepiride. CONCLUSION: As avoiding hypoglycaemia is a key clinical objective in elderly patients, saxagliptin is a suitable alternative to glimepiride in patients with T2D aged ≥65 years.

Synthesis, structural characterization, electronic spectroscopy, and microfluidic detection of Cu(+2) and UO2(+2) [di-tert-butyl-salphenazine] complexes.

Metal templation by condensation of 2,3-diaminophenazine with 3,5-di-tert-butyl-2-hydroxybenzaldehyde around the metal centers [M = Cu(II), and UO2(VI)] affords a new class of M[di-tert-butyl salphenazine] metal complexes. Reported here is the synthesis, single crystal X-ray structural characterization, electronic spectroscopy, and microfluidic detection of the formation of these M[di-tert-butyl sal-phenazine] complexes.