Timeliness metrics for screening and preventing TB in household contacts of pulmonary TB patients in Kenya.

BACKGROUND: The study assessed whether a "7-1-7" timeliness metric for screening and TB preventive therapy (TPT) could be implemented for household contacts (HHCs) of index patients with bacteriologically confirmed pulmonary TB under routine programmatic settings in Kenya. METHODS: A longitudinal cohort study conducted among index patients and their HHCs in 12 health facilities, Kiambu County, Kenya. RESULTS: Between January and June 2023, 95% of 508 index patients had their HHCs line-listed within 7 days of initiating anti-TB treatment ("First 7"). In 68% of 1,115 HHCs, screening outcomes were ascertained within 1 day of line-listing ("Next 1"). In 65% of 1,105 HHCs eligible for further evaluation, anti-TB treatment, TPT or a decision for no drugs was made within 7 days of screening ("Second 7"). Altogether, 62% of screened HHCs started TPT during the "7-1-7" period compared with 58% in a historical cohort. Main barriers to TPT uptake were HHCs not consulting clinicians, HHCs being unwilling to initiate TPT and drug shortages. Healthcare workers felt that a timeliness metric was valuable for streamlining HHC management and proposed "3-5-7" as a workable alternative. CONCLUSIONS: The national TB programme must generate awareness about TPT, ensure uninterrupted drug supplies and assess whether the "3-5-7" metric can be operationalised.

CONTEXTE: L'étude a évalué si une mesure de rapidité "7-1-7" pour le dépistage et le traitement préventif de la TB (TPT) pouvait être mise en œuvre pour les contacts familiaux des patients index atteints de TB pulmonaire confirmée bactériologiquement dans le cadre d'un programme de routine au Kenya. MÉTHODES: Étude de cohorte longitudinale menée auprès de patients index et de leurs contacts familiaux dans 12 établissements de santé du comté de Kiambu, au Kenya. RÉSULTATS: Entre janvier et juin 2023, 95% des 508 patients index ont eu leur centre de santé inscrit sur la liste dans les 7 jours suivant le début du traitement antituberculeux (« First 7 ¼ ). Dans 68% des 1 115 centres de santé, les résultats du dépistage ont été vérifiés dans le jour suivant l'inscription sur la liste (« Next 1 ¼). Dans 65% des 1 105 centres de santé éligibles pour une évaluation plus approfondie, le traitement antituberculeux, le TPT ou la décision de ne pas prendre de médicaments a été prise dans les 7 jours suivant le dépistage (« Second 7 ¼). Au total, 62% des patients dépistés ont commencé un traitement antituberculeux au cours de la période « 7-1-7 ¼, contre 58% dans une cohorte historique. Les principaux obstacles à l'adoption du TPT étaient les suivants : les centres de santé ne consultaient pas les cliniciens, les centres de santé n'étaient pas disposés à commencer le TPT et les pénuries de médicaments. Les professionnels de la santé ont estimé qu'une mesure de la rapidité d'exécution était utile pour rationaliser la gestion des centres de santé et ont proposé le « 3-5-7 ¼ comme solution de rechange viable. CONCLUSION: Le programme national de lutte contre la TB doit sensibiliser au TPT, garantir un approvisionnement ininterrompu en médicaments et évaluer si la mesure « 3-5-7 ¼ peut être mise en œuvre.

Using timeliness metrics for household contact tracing and TB preventive therapy in the private sector, India.

Although screening of household contacts (HHCs) of TB patients and provision of TB preventive therapy (TPT) is a key intervention to end the TB epidemic, their implementation globally is dismal. We assessed whether introducing a '7-1-7' timeliness metric was workable for implementing HHC screening among index patients with pulmonary TB diagnosed by private providers in Chennai, India, between November 2022 and March 2023.This was an explanatory mixed-methods study (quantitative-cohort and qualitative-descriptive).There were 263 index patients with 556 HHCs. In 90% of index patients, HHCs were line-listed within 7 days of anti-TB treatment initiation. Screening outcomes were ascertained in 48% of HHCs within 1 day of line-listing. Start of anti-TB treatment, TPT or a decision to receive neither was achieved in 57% of HHC within 7 days of screening. Overall, 24% of screened HHCs in the '7-1-7' period started TPT compared with 16% in a historical control (P < 0.01). Barriers to achieving '7-1-7' included HHC reluctance for evaluation or TPT, refusal of private providers to prescribe TPT and reliance on facility-based screening of HHCs instead of home visits by health workers for screening.Introduction of a timeliness metric is a workable intervention that adds structure to HHC screening and timely management..

The relationship of peritubular capillary density with glomerular volume and kidney function in living kidney donors.

BACKGROUND: Peritubular capillary rarefaction plays an important role in the progression of chronic kidney disease. Little is known about the relation between peritubular capillary density, glomerular volume and filtration rate in the healthy kidney. METHODS: In this single-center study, we included 69 living kidney donors who donated between 2005 and 2008 and had representative renal biopsies available. In all donors, glomerular filtration rate was measured using 125I-Iothalamate before donation and at five years after donation. Before donation, the increase in glomerular filtration rate after dopamine stimulation was measured. Glomerular volume and peritubular capillary density were determined in biopsies taken at the time of transplantation. Pearson's correlation coefficient and linear regression were used to assess relations between parameters. RESULTS: Mean donor age was 52 ± 11 years and mean measured glomerular filtration rate was 119 ± 22 mL/min before donation and 82 ± 15 mL/min at five years after donation. While peritubular capillary density (measured by either number of peritubular capillaries/50,000 µm2 or number of peritubular capillaries/tubule) was not associated with measured glomerular filtration rate before or after donation, number of peritubular capillaries/tubule was associated with the increase in measured glomerular filtration rate after dopamine stimulation (St.ß = 0.33, p = 0.004), and correlated positively with glomerular volume (R = 0.24, p = 0.047). Glomerular volume was associated with unstimulated measured glomerular filtration rate before donation (St.ß = 0.31, p = 0.01) and at five years (St.ß = 0.30, p = 0.01) after donation, independent of age. CONCLUSIONS: In summary, peritubular capillary density was not related to unstimulated kidney function before or after kidney donation, in contrast to glomerular volume. However, number of peritubular capillaries/tubule correlated with the increase in glomerular filtration rate after dopamine stimulation in healthy kidneys, and with glomerular volume. These findings suggest that peritubular capillary density and glomerular volume differentially affect kidney function in healthy living kidney donors.

Eculizumab Rescue Therapy in Patients With Recurrent Atypical Hemolytic Uremic Syndrome After Kidney Transplantation.

Introduction: Since 2016, kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) in the Netherlands is performed without eculizumab prophylaxis. Eculizumab is given in case of posttransplant aHUS recurrence. Eculizumab therapy is monitored in the CUREiHUS study. Methods: All participating kidney transplant patients who received eculizumab therapy for a suspected posttransplant aHUS recurrence were evaluated. Overall recurrence rate was monitored prospectively at Radboud University Medical Center. Results: In the period from January 2016 until October 2020, we included 15 (12 females, 3 males; median age 42 years, range 24-66 years) patients with suspected aHUS recurrence after kidney transplantation in this study. The time interval to recurrence showed a bimodal distribution. Seven patients presented early after transplantation (median 3 months, range 0.3-8.8 months), with typical aHUS features: rapid loss of estimated glomerular filtration rate (eGFR) and laboratory signs of thrombotic microangiopathy (TMA). Eight patients presented late (median 46 months, range 18-69 months) after transplantation. Of these, only 3 patients had systemic TMA, whereas 5 patients presented with slowly deteriorating eGFR without systemic TMA. Treatment with eculizumab resulted in improvement or stabilization of eGFR in 14 patients. Eculizumab discontinuation was tried in 7 patients; however, it was successful only in 3. At the end of the follow-up (median 29 months, range 3-54 months after start of eculizumab), 6 patients had eGFR <30 ml/min per 1.73 m2. Graft loss had occurred in 3 of them. Overall, aHUS recurrence rate without eculizumab prophylaxis was 23%. Conclusions: Rescue treatment of posttransplant aHUS recurrence is effective; however, some patients suffer from irreversible loss of kidney function, likely caused by delayed diagnosis and treatment and/or too aggressive discontinuation of eculizumab. Physicians should be aware that recurrence of aHUS can present without evidence of systemic TMA.

[Equine anaplasmosis and equine piroplasmosis in Germany, Austria and Switzerland - previously anecdotal, now relevant?] / Equine Anaplasmose und equine Piroplasmose in Deutschland, Österreich und der Schweiz ­ früher anekdotisch, heute relevant?

INTRODUCTION: Equine granulocytic anaplasmosis (EGA) and equine piroplasmosis (EP) are triggered by tick-borne pathogens - the intracellular bacterium Anaplasma phagocytophilum and the intracellular protozoa Babesia caballi and Theileria equi. These pathogens attack cells in the blood stream and cause similar clinical symptoms and changes in laboratory values. Although the treatment principles are naturally different, similarities in prophylaxis exists due to the transmission route. Tick transmitted pathogens can play a greater role in equine medicine in the future due to various factors, such as the tendency of relevant tick species to spread, but also the increasing import and travel activities of and with pets (both in the context of sporting events and as a leisure activity). While EGA is endemic in Central Europe, EP is a sporadic disease in Switzerland, Austria and Germany. However, EP must be viewed as underdiagnosed, as horses persistently infected with T. equi are also repeatedly detected in Central Europe. These diseases should be considered in horses with a fever and corresponding laboratory changes. Available diagnostic tests are direct pathogen detection by blood smear or PCR, and, indirect antibody detection, which is considered to be highly sensitive and (as a competitive ELISA) also very specific. Acute infections can be detected with PCR, serology is more suitable for chronic infections. A pathogen-free condition after treatment can be demonstrated with decreasing antibody titers in combination with repeated PCR tests. In addition, clinically healthy horses infected with T. equi should be identified by antibody detection and appropriate preventative transmission measures must be initiated. The prophylaxis of tick bites in horses is difficult due to the high exposure, and long-term tick bite prevention can hardly be guaranteed. Monitoring of tick activity and strict measures to prevent the spread of the pathogen within the tick population are therefore of great importance.

INTRODUCTION: L'anaplasmose granulocytaire équine (EGA) et la piroplasmose équine (EP) sont causées par des agents pathogènes transmis par les tiques ­ la bactérie intracellulaire Anaplasma phagocytophilum et les protozoaires intracellulaires Babesia caballi et Theileria equi. Ces agents pathogènes attaquent les cellules sanguines et provoquent des symptômes cliniques similaires et des modifications des valeurs de laboratoire. Bien que les principes de traitement soient naturellement différents, des similitudes dans la prophylaxie existent en raison de la voie de transmission. Les agents pathogènes transmis par les tiques pourraient jouer un rôle plus important en médecine équine à l>avenir en raison de divers facteurs, tels que la tendance des espèces de tiques concernées à se propager, mais aussi l>augmentation des activités d>importation et de voyage d>animaux de compagnie avec eux (à la fois dans le contexte d>événements sportifs et comme activité de loisir). Alors que l>EGA est endémique en Europe centrale, l>EP est une maladie sporadique en Suisse, en Autriche et en Allemagne. Cependant, l'EP doit être considérée comme sous-diagnostiquée, car des chevaux infectés de manière persistante par T. equi ont également été détectés à plusieurs reprises en Europe centrale. Ces maladies doivent être envisagées chez les chevaux présentant de la fièvre et des modifications biologiques correspondantes. Les tests de diagnostic disponibles sont la détection directe des agents pathogènes par frottis sanguin ou par PCR et la détection indirecte des anticorps, qui est considérée comme très sensible et, en tant qu'ELISA compétitif, également très spécifique. Les infections aiguës peuvent être détectées par PCR, la sérologie est plus adaptée aux infections chroniques. Une condition sans agent pathogène après le traitement peut être démontrée avec des titres d'anticorps décroissants en combinaison avec des tests PCR répétés. De plus, les chevaux cliniquement sains infectés par T. equi doivent être identifiés par détection d'anticorps et des mesures appropriées pour prévenir la transmission doivent être initiées. La prophylaxie des morsures de tiques chez les chevaux est difficile en raison de la forte exposition et la prévention des morsures de tiques à long terme peut difficilement être garantie. La surveillance de l'activité des tiques et des mesures strictes pour empêcher la propagation de l'agent pathogène au sein de la population de tiques sont donc d'une grande importance.

Current production by non-methanotrophic bacteria enriched from an anaerobic methane-oxidizing microbial community.

In recent years, the externalization of electrons as part of respiratory metabolic processes has been discovered in many different bacteria and some archaea. Microbial extracellular electron transfer (EET) plays an important role in many anoxic natural or engineered ecosystems. In this study, an anaerobic methane-converting microbial community was investigated with regard to its potential to perform EET. At this point, it is not well-known if or how EET confers a competitive advantage to certain species in methane-converting communities. EET was investigated in a two-chamber electrochemical system, sparged with methane and with an applied potential of +400 mV versus standard hydrogen electrode. A biofilm developed on the working electrode and stable low-density current was produced, confirming that EET indeed did occur. The appearance and presence of redox centers at -140 to -160 mV and at -230 mV in the biofilm was confirmed by cyclic voltammetry scans. Metagenomic analysis and fluorescence in situ hybridization of the biofilm showed that the anaerobic methanotroph 'Candidatus Methanoperedens BLZ2' was a significant member of the biofilm community, but its relative abundance did not increase compared to the inoculum. On the contrary, the relative abundance of other members of the microbial community significantly increased (up to 720-fold, 7.2% of mapped reads), placing these microorganisms among the dominant species in the bioanode community. This group included Zoogloea sp., Dechloromonas sp., two members of the Bacteroidetes phylum, and the spirochete Leptonema sp. Genes encoding proteins putatively involved in EET were identified in Zoogloea sp., Dechloromonas sp. and one member of the Bacteroidetes phylum. We suggest that instead of methane, alternative carbon sources such as acetate were the substrate for EET. Hence, EET in a methane-driven chemolithoautotrophic microbial community seems a complex process in which interactions within the microbial community are driving extracellular electron transfer to the electrode.

Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients.

BACKGROUND: In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. METHODS: This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is 'successful transplantation', defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. CONCLUSIONS: The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03797196 , registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

Evaluation of Tooth Sensitivity of In-office Bleaching with Different Light Activation Sources: A Systematic Review and a Network Meta-analysis.

OBJECTIVES: A systematic review and network meta-analysis were performed to answer the following research question: Are there differences in the risk and the intensity of tooth sensitivity (TS) among eight light activation systems for in-office bleaching in adults? METHODS: Randomized controlled trials (RCTs) that compared at least two different in-office bleaching light activations were included. The risk of bias (RoB) was evaluated with the RoB tool version 1.0 from the Cochrane Collaboration tool. A random-effects Bayesian mixed treatment comparison (MTC) model was used independently for high- and low-concentration hydrogen peroxide. The certainty of the evidence was evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. A comprehensive search was performed in PubMed, Bridge Base Online (BBO), Latin American and Caribbean Health Sciences Literature database (LILACS), Cochrane Library, Scopus, Web of Science, and grey literature without date and language restrictions on April 23, 2017 (updated on September 26, 2019). Dissertations and theses, unpublished and ongoing trials registries, and IADR (International Association for Dental Research) abstracts (2001-2019) were also searched. RESULTS: After title and abstract screening and the removal of duplicates, 32 studies remained. Six were considered to be at low RoB, three had high RoB, and the remaining had an unclear RoB. The MTC analysis showed no significant differences among the treatments in each network. In general, the certainty of the evidence was graded as low due to unclear RoB and imprecision. CONCLUSION: There is no evidence that the risk and intensity of TS are affected by light activation during in-office bleaching.

Nursing Education Intervention Effects on Pain Intensity of Nursing Home Residents with Different Levels of Cognitive Impairment: A Cluster-Randomized Controlled Trial.

PURPOSE: Pain management in nursing homes is challenging and pain prevalence remains high. The objective of this study was to improve the pain situation of nursing home residents following a nursing-related educational intervention within a cluster-randomized controlled trial (2016-2018). PARTICIPANTS: Clusters were nursing homes from one nursing home operator in Bavaria, Germany. Nursing home residents who were permanently registered in the facilities, at least 60 years of age, and who themselves or their legal guardians provided informed consent were included. INTERVENTION: In addition to the implementation of pain nurses and pain care assistants, staff of the intervention group received an educational intervention in pain management, containing classroom (quality circles) and web-based training for nurses. METHODS: Based on the Mini-Mental State Examination (MMSE), residents were either interviewed (MMSE 10-30) using self-report instruments or observed (MMSE 0-9) by proxy assessment. The primary outcome in residents able to self-report was maximum pain intensity according to Brief Pain Inventory (BPI); in those not able to self-report treatment-relevant pain above cut-off (≥2) on the Pain Assessment in Advanced Dementia (PAINAD). RESULTS: Out of 20 randomly selected clusters, 9 nursing homes from the control, and 6 nursing homes from the intervention group participated. Multilevel linear (n=347 residents, MMSE 10-30) and logistic regression (n=222 residents, MMSE 0-9) analyses were conducted. Maximum pain intensity was higher after intervention (B=1.32, p<0.01), decreased with a better quality of life (B=-0.07, p<0.001), and was lower when dementia diagnoses were present (B=-1.12, p<0.01). PAINAD scores before and after intervention did not differ significantly (OR=0.89, p=0.724), but chances to exhibit treatment-related pain were higher with decreasing MMSE (OR=0.94, p<0.05). CONCLUSION: While no significant positive intervention effect was measured, findings suggest nurses' raised awareness towards pain management. Overall results indicate that large-scale educational interventions seem to be less effective in complex nursing home settings without also including specific individual-based intervention measures.

ICH3, a selective alpha7 nicotinic acetylcholine receptor agonist, modulates adipocyte inflammation associated with obesity.

PURPOSE: The alpha7 nicotinic acetylcholine receptor (α7nAChR), involved in the modulation of inflammation and insulin sensitivity, is downregulated in white adipose tissue (WAT) of obese patients. This study aims to test the ability of a selective synthetic α7nAChR agonist, the spirocyclic Δ2-isoxazoline derivative (R)-(-)-ICH3 (ICH3), to counteract acute inflammation and obesity-associated modifications in WAT. METHODS: We employed the LPS-septic shock murine model, human primary adipocytes and diet-induced obese (DIO) mice. Inflammatory factor expression was assessed by ELISA and quantitative real-time PCR. Flow cytometry was employed to define WAT inflammatory infiltrate. Insulin signaling was monitored by quantification of AKT phosphorylation. RESULTS: In the septic shock model, ICH3 revealed antipyretic action and reduced the surge of circulating cytokines. In vitro, ICH3 stimulation (10 µM) preserved viability of human adipocytes, decreased IL-6 mRNA (P < 0.05) and blunted LPS-induced peak of TNFα (P < 0.05) and IL-6 (P < 0.01). Chronic administration of ICH3 to DIO mice was associated with lower numbers of CD8+ T cells (P < 0.05) and to changed WAT expression of inflammatory factors (Hp, P < 0.05; CD301/MGL1, P < 0.01; Arg-1, P < 0.05). As compared to untreated, ICH3 DIO mice exhibited improved insulin signaling in the skeletal muscle (P < 0.01) mirrored by an improved response to glucose load (ipGTT: P < 0.05 at 120 min). CONCLUSIONS: We proved that ICH3 is an anti-inflammatory drug, able to reduce inflammatory cytokines in human adipocytes and to blunt the effects of obesity on WAT inflammatory profile, on glucose tolerance and on tissue insulin sensitivity.

Quality of life in nursing home residents with pain: pain interference, depression and multiple pain-related diseases as important determinants.

AIM: Quality of life is an essential outcome parameter in geriatric research and presents an important indicator for the evaluation of care treatments. The present study analyses potential impact factors on health-related quality of life (HRQOL) of nursing home residents (NHR) who are in pain. METHODS: Data came from the cRCT 'PIASMA'. Statistical analyses of 146 respondents were carried out by multiple linear regressions based on the EQ-5D index (Euroquol Quality of Life) as dependent variable. Potential impact factors were applied and categorised in five blocks: pain intensity and interference (according to the Brief Pain Inventory), intervention effect, sex and age, pain-related diagnoses, and scales regarding depressive symptoms and cognitive impairment (based on the Geriatric Depression Scale and the Mini-Mental State Examination). RESULTS: On average, residents showed a pain intensity of 18.49, a pain interference of 29.61, a MMSE score of 22.84, a GDS score of 5.65 and an EQ-5D index of 0.52. Residents with more diagnoses, more depressive symptoms, and a higher pain interference showed a significantly reduced HRQOL. CONCLUSION: Findings underline the importance of identifying and applying treatment options for both pain (especially interference) and depressive disorders to maintain HRQOL of NHR.

Alcohol metabolism contributes to brain histone acetylation.

Emerging evidence suggests that epigenetic regulation is dependent on metabolic state, and implicates specific metabolic factors in neural functions that drive behaviour1. In neurons, acetylation of histones relies on the metabolite acetyl-CoA, which is produced from acetate by chromatin-bound acetyl-CoA synthetase 2 (ACSS2)2. Notably, the breakdown of alcohol in the liver leads to a rapid increase in levels of blood acetate3, and alcohol is therefore a major source of acetate in the body. Histone acetylation in neurons may thus be under the influence of acetate that is derived from alcohol4, with potential effects on alcohol-induced gene expression in the brain, and on behaviour5. Here, using in vivo stable-isotope labelling in mice, we show that the metabolism of alcohol contributes to rapid acetylation of histones in the brain, and that this occurs in part through the direct deposition of acetyl groups that are derived from alcohol onto histones in an ACSS2-dependent manner. A similar direct deposition was observed when mice were injected with heavy-labelled acetate in vivo. In a pregnant mouse, exposure to labelled alcohol resulted in the incorporation of labelled acetyl groups into gestating fetal brains. In isolated primary hippocampal neurons ex vivo, extracellular acetate induced transcriptional programs related to learning and memory, which were sensitive to ACSS2 inhibition. We show that alcohol-related associative learning requires ACSS2 in vivo. These findings suggest that there is a direct link between alcohol metabolism and gene regulation, through the ACSS2-dependent acetylation of histones in the brain.

Rituximab in routine care of severe active rheumatoid arthritis : A prospective, non-interventional study in Germany.

OBJECTIVE: To assess safety, effectiveness and onset of effect of rituximab (RTX) in routine clinical treatment of severe, active rheumatoid arthritis (RA). METHODS: Prospective, multi-centre, non-interventional study in rheumatological outpatient clinics or private practices in Germany. RTX-naïve adult patients were to receive RTX according to marketing authorisation and at their physician's discretion. Also according to their physician's discretion, patients could receive a second cycle of RTX (re-treatment = treatment continuation). Major outcome was the change in Disease Activity Score based on 28-joints count and erythrocyte sedimentation rate (DAS28-ESR) over 24 weeks and during 6 months of re-treatment. RESULTS: Overall, 1653 patients received at least one cycle RTX; 99.2% of these had received disease-modifying antirheumatic drugs (DMARD) pre-treatment and 75.5% anti-tumor necrosis factor(TNF)­α pre-treatment. After a mean interval of 8.0 months, 820 patients received RTX re-treatment. Mean DAS28-ESR decreased from 5.3 at baseline to 3.8 after 24 weeks (-1.5 [95% confidence interval, CI: -1.6; -1.4]), and from 4.1 at start of cycle 2 to 3.5 at study end (change from baseline: -1.8 [95% CI: -2.0; -1.7]). Improvements in DAS28-ESR and Health Assessment Questionnaire (HAQ) score occurred mainly during the first 12 weeks of RTX treatment, with further DAS28-ESR improvement until week 24 or month 6 of re-treatment. Improvements in DAS28-ESR and EULAR responses were more pronounced in seropositive patients. RF was a predictor of DAS28-ESR change to study end. Safety analysis showed the established profile of RTX. CONCLUSION: RTX was safe and effective in a real-life setting with rapid and sustained improvement in RA signs and symptoms.

Transmission of hepatitis E virus by water: An issue still pending in industrialized countries.

Hepatitis E virus (HEV) is an enteric virus divided into eight genotypes. Genotype 1 (G1) and G2 are specific to humans; G3, G4 and G7 are zoonotic genotypes infecting humans and animals. Transmission to humans through water has been demonstrated for G1 and G2, mainly in developing countries, but is only suspected for the zoonotic genotypes. Thus, the water-related HEV hazard may be due to human and animal faeces. The high HEV genetic variability allows considering the presence in wastewater of not only different genotypes, but also quasispecies adding even greater diversity. Moreover, recent studies have demonstrated that HEV particles may be either quasi-enveloped or non-enveloped, potentially implying differential viral behaviours in the environment. The presence of HEV has been demonstrated at the different stages of the water cycle all over the world, especially for HEV G3 in Europe and the USA. Concerning HEV survival in water, the virus does not have higher resistance to inactivating factors (heat, UV, chlorine, physical removal), compared to viral indicators (MS2 phage) or other highly resistant enteric viruses (Hepatitis A virus). But the studies did not take into account genetic (genogroups, quasispecies) or structural (quasi- or non-enveloped forms) HEV variability. Viral variability could indeed modify HEV persistence in water by influencing its interaction with the environment, its infectivity and its pathogenicity, and subsequently its transmission by water. The cell culture methods used to study HEV survival still have drawbacks (challenging virus cultivation, time consuming, lack of sensitivity). As explained in the present review, the issue of HEV transmission to humans through water is similar to that of other enteric viruses because of their similar or lower survival. HEV transmission to animals through water and how the virus variability affects its survival and transmission remain to be investigated.

Molecular features of Hepatitis E Virus circulation in environmental and human samples.

BACKGROUND AND OBJECTIVES: Hepatitis E virus (HEV) is emerging but its circulation between humans and the environment remains misunderstood. HEV ORF2 gene encodes the capsid playing a key role in viral interactions with surfaces, ORF3 products are involved in the viral cycle. Our aim was to study the molecular characteristics of ORF2 and ORF3 which could favor HEV fitness in patients and the environment. STUDY DESIGN: Samples from 69 patients with hepatitis (blood/stools), 20 urban wastewaters, 20 effluents of a pig slaughterhouse, 22 farm pigs (stools), 20 wild boars (liver/stools) were collected in North-Eastern France. HEV strains were analyzed by direct sequencing within the ORF2 M region, of ORF2/ORF3, for phylogeny and physicochemical prediction and for ORF2 by ultra-deep sequencing. RESULTS: The results showed frequent HEV-positive samples: 9.1% of the patient bloods, 23.1% of their stools; 25.0% of wastewaters, 75.0% for the slaughterhouse, 10.0% of the boar livers, 5.3% of their stools. The strains were classified as HEV genotype 3. In ORF2, HEV highlighted one homogeneous major viral variant within quasispecies and a decrease in predicted antigenicity for two minor mutations (D442G, V402A). A cysteine signature at position 81 in ORF3 was observed in the boars. CONCLUSIONS: HEV RNA genotype 3 was detected in patients and in animals, in a slaughterhouse effluent and in wastewater. Moreover, the low variability of amino acids in the ORF2 M region and molecular features in ORF2 and ORF3 suggested that HEV strains could be advantageous for key properties.

Renal scintigraphy for post-transplant monitoring after kidney transplantation.

BACKGROUND: Clinicians use several diagnostic modalities to recognize post-transplant complications, such as acute tubular necrosis, acute rejection, urologic and vascular complications. Currently, there is no consensus about the best procedural approach to evaluate post-transplant renal dysfunction. Renal needle-biopsy is often required, however, this is invasive and may lead to sample errors and complications, and most clinicians prefer using one of the noninvasive diagnostic modalities. METHODS: A systematic literature search was performed using PubMed, EMBASE, the Cochrane Library, MEDLINE (OvidSP), Web of Science, and Google Scholar to identify relevant articles. This review provides a literature overview of the technical aspects, new developments and clinical value of renal scintigraphy (RS), after kidney transplantation. Additionally, the advantages and limitations of RS in comparison to other diagnostic modalities are addressed. The study protocol is registered with PROSPERO, protocol number CRD42017078391. RESULTS: A total of 32 studies were included. Studies were categorized in the following groups: tracer pharmacokinetics; acute rejection and acute tubular necrosis; vascular complications; urological complications; postoperative fluid collections; early transplant outcomes; one-year transplant outcomes. CONCLUSIONS: Several studies have described the use of RS for the diagnosis of acute rejection, however, differentiating between rejection and acute tubular necrosis remains difficult. For the diagnosis of vascular complications, RS has been described as an alternative for invasive procedures. For urologic complications, studies support the use of RS in combination with routine ultrasonography (US) surveillance. For the diagnosis of postoperative fluid collections, RS provides information to differentiate lymphoceles and urinomas. Altogether, RS should be considered in case of non-acute complications, and if US provides insufficient results.

Performance of genotypic algorithms for predicting tropism for HIV-1 CRF01_AE recombinant.

OBJECTIVES: There is no consensus about the performances of genotypic rules for predicting HIV-1 non-B subtype tropism. Three genotypic methods were compared for CRF01_AE HIV-1 tropism determination. METHODS: The V3 env region of 207 HIV-1 CRF01_AE and 178 B subtypes from 17 centers in France and 1 center in Switzerland was sequenced. Tropism was determined by Geno2Pheno algorithm with false positive rate (FPR) 5% or 10%, the 11/25 rule or the combined criteria of the 11/25, net charge rule and NXT/S mutations. RESULTS: Overall, 72.5%, 59.4%, 86.0%, 90.8% of the 207 HIV-1 CRF01_AE were R5-tropic viruses determined by Geno2pheno FPR5%, Geno2pheno FPR10%, the combined criteria and the 11/25 rule, respectively. A concordance of 82.6% was observed between Geno2pheno FPR5% and the combined criteria for CRF01_AE. The results were nearly similar for the comparison between Geno2pheno FPR5% and the 11/25 rule. More mismatches were observed when Geno2pheno was used with the FPR10%. Neither HIV viral load, nor current or nadir CD4 was associated with the discordance rate between the different algorithms. CONCLUSION: Geno2pheno predicted more X4-tropic viruses for this set of CRF01_AE sequences than the combined criteria or the 11/25 rule alone. For a conservative approach, Geno2pheno FPR5% seems to be a good compromise to predict CRF01_AE tropism.

Lipodystrophy and obesity are associated with decreased number of T cells with regulatory function and pro-inflammatory macrophage phenotype.

BACKGROUND/OBJECTIVES: In lipodystrophy (LD) adipose tissue function to store lipids is impaired, leading to metabolic syndrome, similar to that found in obesity. Emerging evidence links dysmetabolism with disorders of the immune system. Our aim is to investigate whether T-cell populations with regulatory function and monocyte-derived macrophages (MDMs) are affected by LD and obesity. SUBJECTS/METHODS: Blood was collected from 16 LD, 16 obese (OB, BMI>30 kg m-2) and 16 healthy normal-weight women (CNT). Physical parameters, plasma lipid profile, glucose, HbA1c, leptin levels were determined. Flow cytometry was employed to assess the number of circulating CD4+/CD25hi regulatory T cells (Tregs) and invariant natural killer T (iNKT) cells. Characterization of MDMs included: 1. morphological/oil-Red-O staining analyses to define two morphotypes: lipid laden (LL) and spindle-like (sp) MDM; 2. gene expression studies; 3. use of conditioned medium from MDMs (MDMs CM) on human SGBS cells. RESULTS: As compared to CNT, LD and, to a lesser extent, obesity were associated with reduced Tregs and iNKTs (P<0.001 and P<0.01 for LD and OB, respectively), higher number of LL-MDMs (P<0.001 and P<0.01 for LD and OB, respectively), lower number of sp-MDMs (P<0.001 for both LD and OB), which correlated with increased paracrine stimulation of lipid accumulation in cells (P<0.001 and P<0.01 for LD and OB, respectively). LD MDMs showed decreased and increased expression for anti-inflammatory (IL10 and CD163) and pro-inflammatory (CD68 and CCL20) marker genes, respectively. Analysis of correlation indicated that Tregs are directly related with HDL (P<0.01) and inversely related with LL-MDM (P<0.001) and that LL-MDM are directly related with triglycerides (P<0.01) and oxidized LDL (P<0.01). CONCLUSIONS: LD and obesity are associated with changes in the immune system: a significant reduction in the number of T cells with regulatory function and a shift of MDM towards lipid accumulation. Lipid profile of the patients correlates with these changes.