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PURPOSE Patients with locally advanced grade 2-3 extremity/truncal soft tissue sarcomas (STS) are at high risk of recurrence. The objective of this study was to assess the efficacy and feasibility of neoadjuvant concurrent chemoradiotherapy (cCRT) in selected grade 2-3 patients with limb or trunk wall STS, and to compare this schedule to a sequential approach combining neoadjuvant chemotherapy and adjuvant radiotherapy. METHODS We retrospectively included patients who underwent neoadjuvant cCRT at two comprehensive cancer centers from 1992-2016. We then compared these results to those of patients treated with preoperative chemotherapy and postoperative radiotherapy from a third comprehensive cancer center with a propensity score matched analysis. RESULTS A total of 53 patients were treated by neoadjuvant cCRT; 58 patients could be matched with 29 patients in each treatment group after propensity score matching. Disease-free survival and overall survival at 5 years were 54.9 and 63.5%, respectively with neoadjuvant cCRT, with no significant difference when compared to the sequential treatment group. R0 resection rate was higher (90.9 vs 44.8%, p

Riassunto Il dolore neuropatico e difficile da alleviare. I trattamenti farmacologici di prima o di seconda intenzione per questo dolore comprendono gli antidepressivi triciclici (in particolare, amitriptilina), gli antidepressivi inibitori del reuptake della serotonina e della noradrenalina (in particolare, duloxetina), gli antiepilettici (gabapentin e pregabalina), il tramadolo, trattamenti topici (cerotti alla lidocaina, capsaicina ad alta concentrazione e tossina botulinica A per il dolore neuropatico periferico). Questi trattamenti possono essere associati tra di loro in caso di risposta parziale alla monoterapia. Gli oppiacei forti costituiscono un trattamento di ripiego, da soli o in associazione con uno dei trattamenti precedenti. Gli studi recenti e una migliore metodologia degli studi clinici, che ora tengono maggiormente conto della natura dei sintomi neuropatici, dovrebbero permettere di prevedere meglio i profili dei responder ai trattamenti. I nuovi trattamenti in fase di sviluppo includono in particolare gli antagonisti dei recettori di alcuni canali del sodio.

Objective To assess the contribution of large and small nerve fiber alteration in erythromelalgia (EM). Methods Thirty-three EM patients were included and underwent clinical evaluation based on EM severity score, DN4, and Utah Early Neuropathy Scale (UENS) score. Neurophysiological evaluation consisted in nerve conduction studies (NCS) for large nerve fibers and specific tests for small nerve fibers: electrochemical skin conductance, cold and warm detection thresholds, and laser evoked potentials. Finally, the evaluation of vascular changes was based on the presence of clinical feature of microvascular disorders and the measurement of the Toe Pressure Index (TPI). Results While 28 patients (85%) had vascular alteration on TPI or clinical features, 23 patients (70%) had small-fiber neuropathy on neurophysiological tests, and only 10 patients (30%) had large fiber neuropathy on NCS. Regarding clinical scores, there was no difference between groups (presence or absence of large- or small-fiber neuropathy or microvascular disorder) except for a higher UENS score in patients with large fiber neuropathy. Conclusion Peripheral neuropathy, mostly involving small nerve fibers, is almost as common as microvascular changes in EM, but remains inconstant and not related to a specific neuropathic pattern or higher clinical severity. Significance The association of neuropathic and vascular factors is not systematic in EM, this syndrome being characterized by different pathophysiological mechanisms leading to a common clinical phenotype.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18–75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: −0.048 ± 0.02; 95% CI: −0.09 to −0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: −0.003 ± 0.01; 95% CI: −0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.

International audience; Neuropathic pain highly affects quality of life, well-being, and function. It has recently been shown based on cluster analysis studies that most patients with neuropathic pain may be categorized into 1 of 3 sensory phenotypes: sensory loss, mechanical hyperalgesia, and thermal hyperalgesia. If these phenotypes reflect underlying pathophysiological mechanisms, they may be more relevant for patient management than underlying neurological diagnosis or pain intensity. The aim of this study was thus to examine the impact of these sensory phenotypes on mental health, functionality, and quality of life. Data of 433 patients from the IMI/EuroPain network database were analyzed, and results of HADS-D/A, Pain Catastrophizing Scale, Euro Quality of Life 5D/-VAS, Brief Pain Inventory, and Graded Chronic Pain Scale between the sensory phenotypes were compared using multiple regression analysis. There was no difference in chronic pain grade, pain intensity, depression, or anxiety scores between phenotypes. Pain interference (Brief Pain Inventory) was higher (P = 0.002); self-reported health state lower (Euro Quality of Life 5D VAS, P = 0.02); and problems regarding mobility (P = 0.008), usual activities (P = 0.004), and self-care (P = 0.039) more prominent (EQ5-D) in the sensory loss compared with the thermal hyperalgesia phenotype. Patients with sensory loss also showed higher pain catastrophizing scores (P = 0.006 and 0.022, respectively) compared with the 2 other groups. Sensory phenotype is associated with the impact of neuropathic pain conditions on well-being, daily functionality, and quality of life but is less associated with pain intensity. These results suggest that the somatosensory phenotype should be considered for personalized pain management. Copyright

Spinal cord injury pain encompasses musculoskeletal and neuropathic pain. Its management is often multidisciplinary and involves specific drugs such as antidepressants and antiepileptics, and nonpharmacological treatment including psychotherapy, physical therapy and neuromodulation techniques. Recent progress in the diagnosis, assessment, and understanding of its mechanisms offers the perspective of a more rational therapeutic management, which should result in better therapeutic outcome.

Bortezomib, lenalidomide, and dexamethasone plus transplant is a standard of care for eligible patients with multiple myeloma. Because responses can deepen with time, regimens with longer and more potent induction/consolidation phases are needed. In this phase 2 study, patients received eight 28-day cycles of carfilzomib (K) 20/36 mg/m2 (days 1-2, 8-9, 15-16), lenalidomide (R) 25 mg (days 1–21), and dexamethasone (d) 20 mg (days 1-2, 8-9, 15-16, 22-23). All patients proceeded to transplant after 4 cycles and received 1 year of lenalidomide maintenance (10 mg, days 1-21). The primary objective was stringent complete response at the completion of consolidation. Overall, 48 patients were screened and 46 enrolled; 21% had adverse cytogenetics. Among 42 evaluable patients after consolidation, 26 were in stringent complete response (CR; 61.9%), 27 were at least in CR (64.3%): 92.6% had undetectable minimal residual disease according to flow cytometry (≥2.5 × 10−5) and 63.0% according to next-generation sequencing (10−6). Median time to CR was 10.6 months. According to multiparametric flow cytometry and next-generation sequencing, 69.0% and 66.7% of patients, respectively, had undetectable minimal residual disease at some point. With a median follow-up of 60.5 months, 21 patients progressed, and 10 died (7 of multiple myeloma). Median progression-free survival was 56.4 months. There were no KRd-related deaths. Four patients discontinued the program due to toxicities; 56 serious adverse events were reported in 31 patients, including 8 cardiovascular events (2 heart failures, 5 pulmonary embolisms or deep vein thrombosis). Common grade 3/4 adverse events were hematologic (74%) and infectious (22%). In summary, 8 cycles of KRd produce fast and deep responses in transplant-eligible patients with newly diagnosed multiple myeloma. The safety profile is acceptable, but cardiovascular adverse events should be closely monitored. This clinical trial is registered at www.clinicaltrials.gov as #NCT02405364.

International audience; The study of complex reactive flows met in aeronautical engines is an experimental challenge that requires the development of noninvasive and precise measurement techniques. Coherent anti-Stokes Raman scattering (CARS) is a standard spectroscopic technique used for temperature measurements, which provides unmatched reliability and accuracy at high repetition rate thanks to its recent adaptation to femtosecond temporal regime. This paper reports the first demonstration of hybrid fs/ps-CARS thermometry in a representative aeronautical combustor (ONERA MICADO test bench, Reynolds number ≈105). Single-shot N2 CARS spectra have been recorded at 1 kHz, allowing temperature follow up, statistical and frequency (0.1–500 Hz) analysis of CH4/air flame at 0.34-MPa total pressure. The achieved results demonstrate the ability of the technique to be applied in representative engines conditions and its maturity for semi-industrial applications.

Endowing a companion robot with cognitive abilities to recognize human daily activities, in particular from body skeletons information, is a significant challenge, which needs complex and novel approaches. Recently, most of the proposed approaches exploit the hand-crafted features or the predefined traversal rules techniques to recognize human daily activities from skeleton information, which often lead to the deficit of robustness and generalization. In this work, a novel hybrid framework for human activity-aware robotic system is proposed. In the low-level, a novel Spatio-Temporal Joint based Convolutional Neural Network (STJ-CNN) is proposed to recognize human daily activities in the ambient environments. In the high-level, novel representation and inference services based on Narrative Knowledge Representation Language (NKRL) are proposed to represent and combine the detected human activities with the ambient events, and to infer the semantic context of the detected activity. Empirical experiments on real-world datasets have been conducted, besides an online demonstration created to validate the proposed approach. The final results show that the proposed approach outperforms the baseline models with a significant improvement up to 24% in terms of $F$ -score on DAHLIA dataset.

Pulmonary hypertension is associated with stiffening of pulmonary arteries which increases right ventricular pulsatile loading. High pulmonary artery wedge pressure (PAWP) in postcapillary pulmonary hypertension (Pc-PH) further decreases pulmonary arterial compliance (PAC) at a given pulmonary vascular resistance (PVR) compared with precapillary pulmonary hypertension, thus responsible for a higher total arterial load. In all other vascular beds, arterial compliance is considered as mainly determined by the distending pressure, due to non-linear stress-strain behaviour of arteries. We tested the applicability, advantages and drawbacks of two comparison methods of PAC depending on the level of mean pulmonary arterial pressure (mPAP; isobaric PAC) or PVR. Right heart catheterisation data including PAC (stroke volume/pulse pressure) were obtained in 112 Pc-PH (of whom 61 had combined postcapillary and precapillary pulmonary hypertension) and 719 idiopathic pulmonary arterial hypertension (iPAH). PAC could be compared over the same mPAP range (25–66 mmHg) in 792 (95.3%) out of 831 patients and over the same PVR range (3–10.7 WU) in only 520 (62.6%) out of 831 patients. The main assumption underlying comparisons at a given PVR was not verified as the PVR×PAC product (RC-time) was not constant but on the contrary more variable than mPAP. In the 788/831 (94.8%) patients studied over the same PAC range (0.62–6.5 mL·mmHg−1), PVR and thus total arterial load tended to be higher in iPAH. Our study favours comparing PAC at fixed mPAP level (isobaric PAC) rather than at fixed PVR. A reappraisal of the effects of PAWP on the pulsatile and total arterial load put on the right heart is needed, and this point deserves further studies., In postcapillary and precapillary pulmonary hypertension patients, this study favours comparing pulmonary arterial compliance (PAC) at fixed mean pulmonary artery pressure level (isobaric PAC) rather than at fixed pulmonary vascular resistance level https://bit.ly/3aTLYdS

Summary Background Shortening the duration of antibiotic therapy for patients admitted to hospital with community-acquired pneumonia should help reduce antibiotic consumption and thus bacterial resistance, adverse events, and related costs. We aimed to assess the need for an additional 5-day course of β-lactam therapy among patients with community-acquired pneumonia who were stable after 3 days of treatment. Methods We did this double-blind, randomised, placebo-controlled, non-inferiority trial (the Pneumonia Short Treatment [PTC]) in 16 centres in France. Adult patients (aged ≥18 years) admitted to hospital with moderately severe community-acquired pneumonia (defined as patients admitted to a non-critical care unit) and who met prespecified clinical stability criteria after 3 days of treatment with β-lactam therapy were randomly assigned (1:1) to receive β-lactam therapy (oral amoxicillin 1 g plus clavulanate 125 mg three times a day) or matched placebo for 5 extra days. Randomisation was done using a web-based system with permuted blocks with random sizes and stratified by randomisation site and Pneumonia Severity Index score. Participants, clinicians, and study staff were masked to treatment allocation. The primary outcome was cure 15 days after first antibiotic intake, defined by apyrexia (temperature ≤37·8°C), resolution or improvement of respiratory symptoms, and no additional antibiotic treatment for any cause. A non-inferiority margin of 10 percentage points was chosen. The primary outcome was assessed in all patients who were randomly assigned and received any treatment (intention-to-treat [ITT] population) and in all patients who received their assigned treatment (per-protocol population). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT01963442, and is now complete. Findings Between Dec 19, 2013, and Feb 1, 2018, 706 patients were assessed for eligibility, and after 3 days of β-lactam treatment, 310 eligible patients were randomly assigned to receive either placebo (n=157) or β-lactam treatment (n=153). Seven patients withdrew consent before taking any study drug, five in the placebo group and two in the β-lactam group. In the ITT population, median age was 73·0 years (IQR 57·0–84·0) and 123 (41%) of 303 participants were female. In the ITT analysis, cure at day 15 occurred in 117 (77%) of 152 participants in the placebo group and 102 (68%) of 151 participants in the β-lactam group (between-group difference of 9·42%, 95% CI −0·38 to 20·04), indicating non-inferiority. In the per-protocol analysis, 113 (78%) of 145 participants in the placebo treatment group and 100 (68%) of 146 participants in the β-lactam treatment group were cured at day 15 (difference of 9·44% [95% CI −0·15 to 20·34]), indicating non-inferiority. Incidence of adverse events was similar between the treatment groups (22 [14%] of 152 in the placebo group and 29 [19%] of 151 in the β-lactam group). The most common adverse events were digestive disorders, reported in 17 (11%) of 152 patients in the placebo group and 28 (19%) of 151 patients in the β-lactam group. By day 30, three (2%) patients had died in the placebo group (one due to bacteraemia due to Staphylococcus aureus, one due to cardiogenic shock after acute pulmonary oedema, and one due to heart failure associated with acute renal failure) and two (1%) in the β-lactam group (due to pneumonia recurrence and possible acute pulmonary oedema). Interpretation Among patients admitted to hospital with community-acquired pneumonia who met clinical stability criteria, discontinuing β-lactam treatment after 3 days was non-inferior to 8 days of treatment. These findings could allow substantial reduction of antibiotic consumption. Funding French Ministry of Health.

Women’s sexual health and wellbeing with cervical or vaginal cancer may be largely affected by complications from external beam radiotherapy (EBRT) and utero-vaginal brachytherapy (BT), of which vaginal stenosis is the main complication. The objective of this study was to assess the impact of support by a nurse sexologist on sexuality, vaginal side-effects, and the quality of clinical follow-up in patients treated with brachytherapy for cervical or vaginal cancer. We performed a retrospective study of the sexuality of women treated for cervical or vaginal cancer. Data from patients with cervical or vaginal cancer who underwent brachytherapy between 2013 and 2017 were collected at Institut Universitaire de Cancer de Toulouse-Oncopole (IUCT-Oncopole). Patients were divided into two groups: group A (intervention group) received support from a nurse sexologist and group B (control group) did not. The chi-square test and a logistic multivariate model were used for data analysis. A total of 156 patients were included in this study, including 57.7% who were followed by a nurse sexologist. We observed low compliance in using vaginal dilators after brachytherapy and/or radiotherapy over time regardless of the group, and patients’ sexual activity was inadequately addressed. Information regarding the resumption of sexuality 2 months after treatment was missing in 1.1% of patients in group A and in 36.4% of patients in group B. Multivariate analysis showed that patients in group A had a lower risk of developing vaginal stenosis with OR crude = 0.5 (95% CI = 0.25–0.92) and OR adj. = 0.5 (95% CI = 0.26–1.09) compared with those in group B. This retrospective study highlights the lack of information collected by physicians during follow-up concerning the sexuality of patients with cervical or vaginal cancer treated by EBRT and BT. The support offered by nurse sexologists in improving patients’ sexual activity and reducing their physical side-effects such as vaginal stenosis is likely to be beneficial. A prospective study is currently being conducted to validate the present findings.

Die Patellaluxation ist ein haufiges Krankheitsbild und bei vielen Patienten mit Rezidivereignissen, patellofemoralen Schmerzen, Knorpelschaden, Einschrankungen der sportlichen Aktivitat und des sozialen Lebens sowie langfristig mit dem Risiko einer Femoropatellararthrose verbunden. Obwohl viele Studien die Ergebnisse unterschiedlicher Behandlungsmodalitaten nach erstmaliger Patellaluxation untersuchten, gibt es bislang kein Konsensmanagement hoherer Evidenz. Ein pragmatischer Ansatz besteht darin, die Risikofaktoren der Patellainstabilitat zu erfassen sowie den Patienten einer individuellen Risikostratifizierung zu unterziehen und dadurch die Entscheidungsfindung hinsichtlich einer konservativen oder operativen Therapie treffen zu konnen. In diesem Ubersichtsartikel wird, basierend auf spezifischen Risikofaktoren und veroffentlichten Scores, ein Algorithmus zur Behandlung von Erst- und Rezidivluxationen der Patella vorgestellt.

With human population growth, rapid urbanisation, increasing globalisation, and climate change, the interdependency of human health and animal health is mounting. Therefore, the importance of national emergency management plans (NEMPs) for the mitigation of, and preparedness for, all hazards, including disease epidemics, both zoonotic and zootic, is ever increasing. The authors decided to take a One Health approach by assessing the inclusion of Veterinary Services and animal health in NEMPs, based on geographical region, the date of the NEMP, national income status, and the proportion of the agricultural sector in national gross domestic product (GDP). To carry out the assessment, the authors analysed the publicly available NEMPs of 86 Members of the World Organisation for Animal Health. Of the 86 NEMPs reviewed, only a third expressly mentioned Veterinary Services, almost 60% mentioned zoonotic and/or zootic diseases, and about two-thirds mentioned animals to some extent. The highest correlating factor to the inclusion of animal health in NEMPs was the level of the agricultural sector's contributions to the national GDP. Fisheries and aquaculture were not a major consideration in any of the reviewed NEMPs, especially not in relation to diseases. Based on region, Latin America and the Caribbean exhibited the lowest inclusion rate of animal health in NEMPs. The results demonstrate that the omission of animal health is still a problem. A multi-disciplinary approach that includes veterinary medicine as well as human medicine is vital in the construction and/or revision of NEMPs. Future studies should consider whether or not there is a connection between countries' veterinary capacities and the inclusion of Veterinary Services in their NEMPs and whether or not they have the infrastructure and human resources to put into operation the roles of Veterinary Services as identified in their NEMPs.

Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.

One of the main objectives of Ambient Assisted Living (AAL) systems is to proactively provide intelligent services to improve the quality of people's lives in terms of autonomy, safety, and well-being. Designing AAL systems that can autonomously monitor human's activities and provide assistance services poses several challenges of which Human Activity Recognition (HAR) which is critically important to adapt the assistance services to the user. In this letter, a robust multi-label HAR framework is proposed. The proposed framework is composed of two main modules: (i) activity classification module and (ii) classification error detection and correction module. In the first module, machine-learning models are used to predict human activities. Since these models may produce predictions with errors, there is a requirement to detect and correct these errors. The classification error detection and correction module is based on two acyclic directed graphical models and operates in two phases: (i) classification error detection and (ii) classification error correction. The proposed framework is evaluated on the Opportunity dataset , a benchmark and a unique dataset for multi-label human daily living activity recognition. The obtained results demonstrate the ability of the proposed framework to improve the performances of HAR.

International audience; Background: ECT is the most effective treatment of major depressive episode (MDE) but remains a neglected treatment. The French Society for Biological Psychiatry and Neuropsychopharmacology aimed to determine whether prescribing practice of ECT followed guidelines recommendations. Methods: This multicenter, retrospective study included adult patients with major depressive disorder (MDD) or bipolar disorder (BD), who have been treated with ECT for MDE. Duration of MDE and number of lines of treatment received before ECT were collected. The reasons for using ECT, specifically first-line indications (suicidality, urgency, presence of catatonic and psychotic features, previous ECT response, patient preference) were recorded. Statistical comparisons between groups used standard statistical tests. Results: Seven hundred and forty-five individuals were included. The mean duration of MDE before ECT was 10.1 months and the mean number of lines of treatment before ECT was 3.4. It was significantly longer for MDD single episode than recurrent MDD and BD. The presence of first-line indications for using ECT was significantly associated to shorter duration of MDE (9.1 vs 13.1 months, p

The Intergroupe Francophone du Myelome 2009 trial (NCT01191060) assessed health-related quality of life (HRQoL) in patients with newly diagnosed multiple myeloma (NDMM) receiving lenalidomide/bortezomib/dexamethasone (RVd) induction therapy followed by consolidation therapy with either autologous stem cell transplantation (ASCT) plus RVd (RVd-ASCT) or RVd-alone; both groups then received lenalidomide maintenance therapy for 1 year. Global HRQoL, physical functioning, and role functioning scores significantly improved for both cohorts from baseline to the end of consolidation and were sustained during maintenance and follow-up, with clinically meaningful changes (RVd-alone

The esophageal atresia (EA) with distal fistula is the most common type of EA and is easily diagnosed by frothy discharge from mouth and nose, respiratory distress and coiling of nasogastric tube in the upper esophagus. The EA with double fistula (proximal and distal) is the least common type of EA which can easily be ignored preoperatively and intraoperatively. So it offers diagnostic challenge. Herein, we present a case of EA with double fistula in which the proximal fistula was not preoperatively appreciated by us, but identified during dissection.

Background Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation., Karolinska Institute, Open access funding provided by Karolinska Institute.

Background. Sleep disturbance is particularly common among medical students worldwide and affects their wellbeing and academic performance. However, little is known about this issue in Yemen. This study looks at sleep quality and its association with personal and life-style factors and self-reported academic performance among medical students at the largest Yemeni university. Methods. A cross-sectional survey was conducted at Sana’a University, Yemen, in 2017. The Pittsburgh Sleep Quality Index (PSQI), consisting of 19 items and 7 components ( score range = 0 ‐ 3 ), was used to assess sleep quality. The summation of the components’ scores yields the global PSQI score ( range = 0 ‐ 21 ). A global PSQI value higher than 5 indicates poor quality of sleep. Logistic regression was applied to look at relationships. Results. 240 male (41%) and female (59%) medical students took part in the study with 54% being preclinical and 46% clinical with an average age of 23.3 years ( SD = 1.7 ). The mean global score (SD) was 6.85 (2.8), and 68% of the students ( N = 163 ) were identified as poor sleepers. The mean global PSQI score (SD) and proportion of poor sleepers were higher among males (7.7 (2.8) and 81%, respectively) than females (6.27 (2.42) and 59.2%, respectively), p ≤ 0.001 . Good sleep quality was more likely (OR (95% CI)) among females (3.4 (1.3-8.8)), the unmarried (2.8 (1-7.8)), those in good health (2.3 (1.1-4.5)), and nonkhat chewers (4.9 (1.4-17.1)). Nonsmokers were less likely to have good quality sleep compared to occasional smokers (0.185 (0.071-.485)). Stress (30%) and academic workload (21%) were the most commonly reported causes of poor sleep quality. Almost two-thirds of the students (65%) mentioned that disturbed sleep undermined their academic performance. Conclusions. Poor sleep quality is common among Sana’a medical students and impacts their academic performance. Specific stress management and sleep hygiene promoting programs should be incorporated early on in medical education.

Simple Summary Brain metastases are one of the most frequent complications for cancer patients. Stereotactic radiosurgery is considered a cornerstone treatment for patients with limited brain metastases and the ideal dose and fractionation schedule still remain unknown. The aim of this literature review is to discuss the dose-effect relation in brain metastases treated by stereotactic radiosurgery, accounting for fractionation and technical considerations. Abstract For more than two decades, stereotactic radiosurgery has been considered a cornerstone treatment for patients with limited brain metastases. Historically, radiosurgery in a single fraction has been the standard of care but recent technical advances have also enabled the delivery of hypofractionated stereotactic radiotherapy for dedicated situations. Only few studies have investigated the efficacy and toxicity profile of different hypofractionated schedules but, to date, the ideal dose and fractionation schedule still remains unknown. Moreover, the linear-quadratic model is being debated regarding high dose per fraction. Recent studies shown the radiation schedule is a critical factor in the immunomodulatory responses. The aim of this literature review was to discuss the dose–effect relation in brain metastases treated by stereotactic radiosurgery accounting for fractionation and technical considerations. Efficacy and toxicity data were analyzed in the light of recent published data. Only retrospective and heterogeneous data were available. We attempted to present the relevant data with caution. A BED10 of 40 to 50 Gy seems associated with a 12-month local control rate >70%. A BED10 of 50 to 60 Gy seems to achieve a 12-month local control rate at least of 80% at 12 months. In the brain metastases radiosurgery series, for single-fraction schedule, a V12 Gy < 5 to 10 cc was associated to 7.1–22.5% radionecrosis rate. For three-fractions schedule, V18 Gy < 26–30 cc, V21 Gy < 21 cc and V23 Gy < 5–7 cc were associated with about 0–14% radionecrosis rate. For five-fractions schedule, V30 Gy < 10–30 cc, V 28.8 Gy < 3–7 cc and V25 Gy < 16 cc were associated with about 2–14% symptomatic radionecrosis rate. There are still no prospective trials comparing radiosurgery to fractionated stereotactic irradiation.

The neuromodulation induced by neurofeedback training (NFT) remains a matter of debate. Investigating the modulation of brain activity specifically associated with NF requires controlling for multiple factors, such as reward, performance, congruency between task and targeted brain activity. This can be achieved using sham feedback (FB) control condition, equating all aspects of the experiment but the link between brain activity and FB. We aimed at investigating the modulation of individual alpha EEG activity induced by NFT in a double-blind, randomized, sham-controlled study. Forty-eight healthy participants were assigned to either NF (n = 25) or control (n = 23) group and performed alpha upregulation training (over 12 weeks) with a wearable EEG device. Participants of the NF group received FB based on their individual alpha activity. The control group received the auditory FB of participants of the NF group. An increase of alpha activity across training sessions was observed in the NF group only (p 0.001). This neuromodulation was selective in that there was no evidence for similar effects in the theta (4–8 Hz) and low beta (13–18 Hz) bands. While alpha upregulation was found in the NF group only, psychological outcome variables showed overall increased feeling of control, decreased anxiety level and increased relaxation feeling, without any significant difference between the NF and the control groups. This is interpreted in terms of learning context and placebo effects. Our results pave the way to self-learnt, NF-based neuromodulation with light-weighted, wearable EEG systems.

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39.

Purpose of review Neuropathic pain remains difficult to treat. This review provides an update regarding recent advances in therapeutic management, particularly with regards to newer drugs, neurostimulation techniques and original study designs. Recent findings Although the mainstay of neuropathic pain management is still represented by drug therapy, particularly antidepressants and antiepileptics, the place of nonpharmacological therapy including in particular brain neuromodulation techniques has substantially increased in recent years. Newer study designs are also increasingly implemented, based on in depth phenotypic profiling to achieve more individualized therapy, or on screening strategies to decrease placebo effect and contribute to increase assay sensitivity. These approaches are now considered the most promising to decrease therapeutic failures in neuropathic pain. Summary Neuropathic pain management should not be restricted to pharmacotherapy but now encompasses multiple approaches including particularly neuromodulation techniques. Multimodal assessment can also help identify predictors of the response in clinical trials in order to ensure appropriate management.

ObjectiveTo test whether contralateral sensory abnormalities in the clinically unaffected area of patients with unilateral neuropathic pain are due to the neuropathy or pain mechanisms.MethodsWe analyzed the contralateral clinically unaffected side of patients with unilateral painful or painless neuropathy (peripheral nerve injury [PNI], postherpetic neuropathy [PHN], radiculopathy) by standardized quantitative sensory testing following a validated protocol. Primary outcome was the independent contribution of the following variables on the contralateral sensory function using generalized linear regression models: pain intensity, disease duration, etiology, body area, and sensory patterns in the most painful area.ResultsAmong 424 patients (PNI n = 256, PHN n = 78, radiculopathy n = 90), contralateral sensory abnormalities were frequent in both painful (n = 383) and painless (n = 41) unilateral neuropathy, demonstrating sensory loss for thermal and mechanical nonpainful stimuli and both sensory loss and gain for painful test stimuli. Analysis by etiology revealed contralateral pinprick hyperalgesia in PHN and PNI. Analysis by ipsilateral sensory phenotype demonstrated mirror-image pinprick hyperalgesia in both mechanical and thermal hyperalgesia phenotypes. Pain intensity, etiology, and affected body region predicted changes in only single contralateral somatosensory parameters. Disease duration had no impact on the contralateral sensory function.ConclusionMechanisms of sensory loss seem to spread to the contralateral side in both painful and painless neuropathies. Contralateral spread of pinprick hyperalgesia was restricted to the 2 ipsilateral phenotypes that suggest sensitization; this suggest a contribution of descending net facilitation from supraspinal areas, which was reported in rodent models of neuropathic pain but not yet in human patients.

INTRODUCTION Acute supraglottitis is a potentially life-threatening condition that often necessitates intensive care unit (ICU) admission for airway monitoring. The objective of this study was to identify clinical criteria that predict a benign course for patients with acute supraglottitis. METHODS A prospective observational study was performed. Adult patients hospitalized in the ICU between 2007 and 2019 diagnosed with acute supraglottitis were included. All patients were treated with antibiotics and corticosteroids. Fiber optic laryngoscopy (FOL) was performed every 12 h, with each exam defined as "improving", "no change" or "deteriorating" based on the presence of airway edema. Need for airway intervention was correlated to changes in the FOL exam. RESULTS Of 146 patients included, 14 (10%) required intubation, ten on admission, and four during the first 6 h of ICU admission. FOL follow-up was performed on 528 occasions-427 (81%) exams showed improvement, 16 (3%) deterioration, and 85 (16%) with no change. On no occasions was improvement in FOL followed by deterioration. The median ICU length of stay was 3 (IQR 2-3.5) vs. 1 (IQR 1.0-1.25) day for patients who did or did not require intubation (p

Background To understand the implications of switching from paliperidone palmitate 1-monthly (PP1M) to paliperidone palmitate 3-monthly (PP3M) treatment of schizophrenia from the perspective of four key stakeholders: patients, physicians, nurses and carers. Methods This was a cross-sectional, retrospective, non-interventional study comprising a one-time questionnaire (PINC-Q) for adult patients (aged ≥18 years) with schizophrenia (International Classification of Diseases; ICD-10) and their physician, nurse and carer. Questionnaires were developed in association with patient and carer advocacy groups (GAMIAN and EUFAMI) and following an advisory board formed of psychiatrists and nurses. The degree of alignment between stakeholders was also examined. Results Responses were received from a total of 224 evaluable patients. For most patients (88.4%), responses were received from at least two other stakeholders. Patients were moderately ill with mild-to-moderate lack of insight and had received PP1M for a mean (standard deviation [SD]) of 23.9 (21.28) months before switching to PP3M (duration mean [SD] 12.8 [3.72] months). The most frequently reported reasons to switch from PP1M to PP3M were ‘to live life as normally as possible’ and ‘patient convenience’. Over 79% of responses within each stakeholder group stated that PP3M helped the patients, with increased patient activity and social involvement, improved frequency and quality of physician–patient and nurse–patient communication and decreased perceived stigma. Conclusions The results of this study add to the increasing body of evidence supporting the benefits of PP3M in a population of patients with schizophrenia representative of real-world clinical practice.

Background Chronic pain affects approximately 30% of the general population, severely degrades quality of life (especially in older adults) and professional life (inability or reduction in the ability to work and loss of employment), and leads to billions in additional health care costs. Moreover, available painkillers are old, with limited efficacy and can cause significant adverse effects. Thus, there is a need for innovation in the management of chronic pain. Better characterization of patients could help to identify the predictors of successful treatments, and thus, guide physicians in the initial choice of treatment and in the follow-up of their patients. Nevertheless, current assessments of patients with chronic pain provide only fragmentary data on painful daily experiences. Real-life monitoring of subjective and objective markers of chronic pain using mobile health (mHealth) programs can address this issue. Objective We hypothesized that regular patient self-monitoring using an mHealth app would lead physicians to obtain deeper understanding and new insight into patients with chronic pain and that, for patients, regular self-monitoring using an mHealth app would play a positive therapeutic role and improve adherence to treatment. We aimed to evaluate the feasibility and acceptability of a new mHealth app called eDOL. Methods We conducted an observational study to assess the feasibility and acceptability of the eDOL tool. Patients completed several questionnaires using the tool over a period of 2 weeks and repeated assessments weekly over a period of 3 months. Physicians saw their patients at a follow-up visit that took place at least 3 months after the inclusion visit. A composite criterion of the acceptability and feasibility of the eDOL tool was calculated after the completion of study using satisfaction surveys from both patients and physicians. Results Data from 105 patients (of 133 who were included) were analyzed. The rate of adherence was 61.9% (65/105) after 3 months. The median acceptability score was 7 (out of 10) for both patients and physicians. There was a high rate of completion of the baseline questionnaires and assessments (mean 89.3%), and a low rate of completion of the follow-up questionnaires and assessments (63.8% (67/105) and 61.9% (65/105) respectively). We were also able to characterize subgroups of patients and determine a profile of those who adhered to eDOL. We obtained 4 clusters that differ from each other in their biopsychosocial characteristics. Cluster 4 corresponds to patients with more disabling chronic pain (daily impact and comorbidities) and vice versa for cluster 1. Conclusions This work demonstrates that eDOL is highly feasible and acceptable for both patients with chronic pain and their physicians. It also shows that such a tool can integrate many parameters to ensure the detailed characterization of patients for future research works and pain management. Trial Registration ClinicalTrial.gov NCT03931694; http://clinicaltrials.gov/ct2/show/NCT03931694

Dental erosions and molar-incisor hypomineralization are two common dental pathologies requiring minimally invasive restorations such as overlays. The currently used restorative materials are diver...

Purpose The purpose of this study was to report the clinical evaluation of a 3D-printed protective face shield designed to protect interventional radiologists from droplet transmission of the SARS-Cov-2. Materials and methods A protective face shield consisting in a standard transparent polymerizing vinyl chloride (PVC) sheet was built using commercially available 3D printers. The 3D-printed face shield was evaluated in 31 interventional procedures in terms of ability to perform the assigned intervention as usual, quality of visual comfort and tolerance using a Likert scale (from 1, as very good to 5, as extremely poor). Results The mean rating for ability to perform the assigned intervention as usual was 1.7 ± 0.8 (SD) (range: 1–4). The mean visual tolerance rating was 1.6 ± 0.7 (SD) (range: 1–4). The mean tolerability rating was 1.4 ± 0.7 (SD) (range: 1–3). Conclusion The 3D-printed protective face shield is well accepted in various interventions. It may become an additional option for protection of interventional radiologists.

The aim of this study was to investigate the association of femoral (FT), tibial (TT), and knee torsion (KT) on the patella tilt (PT), the axial engagement index (AEI), and the tibial tuberosity–trochlear groove distance (TTTG). Femoral torsion, tibial torsion, knee torsion, patella tilt, the axial engagement index, the TTTG, and trochlear dysplasia were retrospectively evaluated on 59 patients suffering from recurrent patella instability or anterior knee pain with 118 torsional lower limb magnetic resonance imaging studies. FT and TT did not show any significant associations with TTTG, PT, and AEI (n.s.). KT was significantly associated with a higher TTTG, higher PT, and lower AEI (all, p

Introduction: Antimicrobial-resistant HAI (Healthcare associated infection) are a global challenge due to their impact on patient outcome. Implementation of antimicrobial stewardship programmes (AMSP) is needed at institutional and national levels. Assessment of core capacities for AMSP is an important starting point to initiate nationwide AMSP. We conducted an assessment of the core capacities for AMSP in a network of Indian hospitals, which are part of the Global Health Security Agenda-funded work on capacity building for AMR-HAIs. Subjects and Methods: The Centers for Disease Control and Prevention's core assessment checklist was modified as per inputs received from the Indian network. The assessment tool was filled by twenty hospitals as a self-administered questionnaire. The results were entered into a database. The cumulative score for each question was generated as average percentage. The scores generated by the database were then used for analysis. Results and Conclusion: The hospitals included a mix of public and private sector hospitals. The network average of positive responses for leadership support was 45%, for accountability; the score was 53% and for key support for AMSP, 58%. Policies to support optimal antibiotic use were present in 59% of respondents, policies for procurement were present in 79% and broad interventions to improve antibiotic use were scored as 33%. A score of 52% was generated for prescription-specific interventions to improve antibiotic use. Written policies for antibiotic use for hospitalised patients and outpatients were present on an average in 72% and 48% conditions, respectively. Presence of process measures and outcome measures was scored at 40% and 49%, respectively, and feedback and education got a score of 53% and 40%, respectively. Thus, Indian hospitals can start with low-hanging fruits such as developing prescription policies, restricting the usage of high antibiotics, enforcing education and ultimately providing the much-needed leadership support.

Resume Introduction La retinopathie diabetique est la resultante d’interactions entre facteurs genetiques et environnementaux. Notre interet a porte sur le gene de la synthase du monoxyde d’azote endotheliale ou l’eNOS compte tenu de l’implication de cette enzyme dans les alterations fonctionnelles des microvaisseaux retiniens au cours du diabete. L’objectif est donc d’evaluer l’association du polymorphisme T786C de l’eNOS avec la retinopathie diabetique chez la population algerienne. Patients et methodes Notre etude a porte sur 110 patients diabetiques de type 1 avec et sans RD. L’analyse genetique du polymorphisme eNOS T786C a ete realisee par la technique PCR-RFLP. Nous avons egalement explore l’association entre ce polymorphisme et certaines caracteristiques cliniques et biologiques des patients avec RD. Resultats Une augmentation significative de la frequence du genotype CC est notee chez les individus sans RD (p = 0,03). Egalement une augmentation significative de la somme des frequences genotypiques TT+TC est retrouvee chez les individus avec RD (p = 0,03) et l’association entre les differents genotypes et les profils cliniques ou biologiques rapportent des taux bas du NO chez les sujets porteurs du genotype TT (p = 0,039). Conclusion Nos resultats preliminaires suggerent que le genotype CC pourrait conferer une protection a la retinopathie diabetique chez la population algerienne tandis que l’allele T serait de susceptibilite.

BACKGROUND: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.METHODS: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.RESULTS: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; PCONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).

The traditional translational approach in neuropathic pain research has mainly consisted to date in translating basic findings from animal models of nerve injury to the clinic. Because of the difficulty to extrapolate mechanisms from animals to humans, an inverse translational approach ("top-down") has been advocated and contributed to the development of therapy. In particular, a number of treatments such as neurostimulation techniques have been initially assessed in patients and then translated to animal models for further investigation of their mechanisms. Therapeutic approaches based on an in-depth assessment of sensory phenotypes, suggestive of mechanisms, have also been implemented. The biggest trend in recent translational research is to investigate mechanisms or predict therapeutic response in patients by integrating multimodal approaches. The present narrative review emphasizes these various aspects of translational research in neuropathic pain.

The golden ratio (phi, Φ = 1.618) is a proportion that has been found in many phenomena in nature, including the cardiovascular field. We tested the hypothesis that the systolic over mean pulmonary artery pressure ratio (sPAP/mPAP) and the mean over diastolic pressure ratio (mPAP/dPAP) may match Φ in patients with pulmonary arterial hypertension (PAH) and in control patients.In the first, theoretical part of the study, we discuss why our hypothesis is consistent with three known hemodynamic features of the pulmonary circulation: (1) the 0.61 slope of the mPAP vs sPAP relationship, (2) pulmonary artery pulse pressure and mPAP have an almost 1:1 ratio, and (3) the proportional relationship among sPAP, mPAP, and dPAP. In the second part of the study, fluid-filled pressures were analyzed in 981 incident, untreated PAH and high-fidelity pressures were also analyzed in 44 historical control patients (mPAP range, 9-113 mm Hg).In PAH (non-normal distribution), median values of sPAP/mPAP and mPAP/dPAP were 1.591 (98%Φ) and 1.559 (96%Φ), respectively. In control patients (normal distribution), mean sPAP/mPAP and mPAP/dPAP were 1.572 (97%Φ) and 1.470 (91%Φ), respectively. In both PAH and control patients, this was consistent with the Φ hypothesis, assuming 1 mm Hg error in estimation of sPAP, mPAP, and dPAP on average.In PAH and in control patients, the fluctuations in sPAP and dPAP around mPAP exhibited a constant scaling factor matched to Φ. This remarkable property allows linkage of various empirical observations on pulmonary hemodynamics that were hitherto apparently unrelated. These findings warrant further confirmation in other types of pulmonary hypertension and warrant explanation.

Background Glioblastoma, a high-grade glial infiltrating tumor, is the most frequent malignant brain tumor in adults and carries a dismal prognosis. External beam radiotherapy (EBRT) increases overall survival but this is still low due to local relapses, mostly occurring in the irradiation field. As the ratio of spectra of choline/N acetyl aspartate> 2 (CNR2) on MR spectroscopic imaging has been described as predictive for the site of local relapse, we hypothesized that dose escalation on these regions would increase local control and hence global survival. Methods/design In this multicenter prospective phase III trial for newly diagnosed glioblastoma, 220 patients having undergone biopsy or surgery are planned for randomization to two arms. Arm A is the Stupp protocol (EBRT 60 Gy on contrast enhancement + 2 cm margin with concomitant temozolomide (TMZ) and 6 months of TMZ maintenance); Arm B is the same treatment with an additional simultaneous integrated boost of intensity-modulated radiotherapy (IMRT) of 72Gy/2.4Gy delivered on the MR spectroscopic imaging metabolic volumes of CHO/NAA > 2 and contrast-enhancing lesions or resection cavity. Stratification is performed on surgical and MGMT status. Discussion This is a dose-painting trial, i.e. delivery of heterogeneous dose guided by metabolic imaging. The principal endpoint is overall survival. An online prospective quality control of volumes and dose is performed in the experimental arm. The study will yield a large amount of longitudinal multimodal MR imaging data including planning CT, radiotherapy dosimetry, MR spectroscopic, diffusion and perfusion imaging. Trial registration NCT01507506, registration date December 20, 2011.

ZusammenfassungDie Röntgenuntersuchung ist der Goldstandard für die Frakturdiagnostik. Mit den verschiedenen Projektionen können außerdem Operationsplanung, intraoperative Kontrolle, Verlaufsbeurteilung und Funktionsprüfung durchgeführt werden. Dieser Beitrag beschreibt die gängigsten Röntgenprojektionen am Knie, deren Indikationen samt Einstelltechniken. Weiterführende Schnittbilddiagnostik (CT, MRT) wird ebenso besprochen.

The most recent update to the International Myeloma Working Group consensus criteria places a strong emphasis on the need for more sensitive haematological markers of response driven by the success of novel therapies. One such marker is serum free light chain (sFLC) analysis, which was first incorporated into the definition of stringent complete response in 2006. However, over the past decade there has been some reluctance to extend the role of the sFLC assays to replace 24 h urine electrophoresis for monitoring multiple myeloma (MM). In this review, we lay out the evidence in favour of serum over urine for monoclonal FLC measurements and propose modified criteria for response assignment in myeloma.

IF 15.132 (2017); International audience; The introduction of novel agents has led to major improvements in clinical outcomes for patients with multiple myeloma. To shorten evaluation times for new treatments, health agencies are currently examining minimal residual disease (MRD) as a surrogate end point in clinical trials. We assessed the prognostic value of MRD, measured during maintenance therapy by next-generation sequencing (NGS). MRD negativity was defined as the absence of tumor plasma cell within 1 000 000 bone marrow cells (

International audience; We previously reported the benefit of lomustine addition to conventional chemotherapy in older acute myeloid leukemias with nonadverse chromosomal aberrations in the LAM-SA 2007 randomized clinical trial (NCT00590837). A molecular analysis of 52 genes performed in 330 patients included in this trial, 163 patients being treated with lomustine in combination with idarubicin and cytarabine and 167 without lomustine, identified 1088 mutations with an average of 3.3 mutations per patient. NPM1, FLT3, and DNMT3A were the most frequently mutated genes. A putative therapeutic target was identified in 178 patients (54%). Among five molecular classifications analyzed, the ELN2017 risk classification has the stronger association with the clinical evolution. Patients not treated with lomustine have an expected survival prognosis in agreement with this classification regarding the overall and event-free survivals. In strong contrast, lomustine erased the ELN2017 classification prognosis. The benefit of lomustine in nonadverse chromosomal aberrations was restricted to patients with RUNX1, ASXL1, TP53, and FLT3-ITDhigh/NPM1WT mutations in contrast to the intermediate and favorable ELN2017 patients. This post-hoc analysis identified a subgroup of fit elderly AML patients with intermediate cytogenetics and molecular markers who may benefit from lomustine addition to intensive chemotherapy.

Background Patellar instability has a high incidence and occurs particularly in young and female patients. If the patella dislocates for the first time, treatment is usually conservative. However, this cautious approach carries the risk of recurrence and of secondary pathologies such as osteochondral fractures. Moreover, there is also risk of continuous symptoms apparent, as recurrent patella dislocation is related to patellofemoral osteoarthritis as well. An initial surgical treatment could possibly avoid these consequences of recurrent patella dislocation. Methods A prospective, randomized-controlled trial design is applied. Patients with unilateral first-time patella dislocation will be considered for participation. Study participants will be randomized to either conservative treatment or to a tailored patella stabilizing treatment. In the conservative group, patients will use a knee brace and will be prescribed outpatient physical therapy. The surgical treatment will be performed in a tailored manner, addressing the pathologic anatomy that predisposes to patella dislocation. The Banff Patellofemoral Instability-Instrument 2.0, recurrence rate, apprehension test, joint degeneration, and the Patella Instability Severity Score will serve as outcome parameters. The main analysis will focus on the difference in change of the scores between the two groups within a 2-year follow-up. Statistical analysis will use linear mixed models. Power analysis was done for the comparison of the two study arms at 2-year follow-up with regard to the BPII Score. A sample size of N = 64 per study arm (128 overall) provides 80% power (alpha = 0.05, two-tailed) to detect a difference of 0.5 standard deviations in a t-test for independent samples. Discussion Although several studies have already dealt with this issue, there is still no consensus on the ideal treatment concept for primary patellar dislocation. Moreover, most of these studies show a unified surgical group, which means that all patients were treated with the same surgical procedure. This is regarded as a major limitation as surgical treatment of patella dislocation should depend on the patient’s anatomic pathologies leading to patellar instability. To our knowledge, this is the first study investigating whether patients with primary patella dislocation are better treated conservatively or operatively with tailored surgery to stabilize the patella. Trial registration The study will be prospectively registered in the publicly accessible database www.ClinicalTrials.gov.

Background Myasthenia gravis (MG) is an autoimmune disease with a well-established involvement of genetic factors. Aim this study was to assess the human leukocyte antigens (HLA) genes association with myasthenia gravis and its myasthenic manifestations. Methods We performed a case-control study where twenty eight patients and one hundred and nine healthy subjects were included. A subgroup of generalized and acetylcholine receptor antibodies positive myasthenia gravis was examined for myasthenic manifestations associations. HLA genotyping was performed by polymerase chain reaction- sequence specific oligonucleotide (PCR-SSO) method. Results On one hand, HLA A*30 and DRB1*04 alleles were more frequent among patients with myasthenia gravis whereas A*02 and B*49 were less frequent (p Conclusion Our results suggest the association of various HLA alleles with myasthenia gravis and some of its myasthenic manifestations. However, further studies are required support these findings and clarify the underlying mechanisms.

Background HIV stigma undermines a person’s wellbeing and quality of life and hinders HIV control efforts. This study examined the extent and drivers of HIV stigma in the teaching hospitals in Sana’a City, Yemen. The country has low HIV prevalence (4000 (2000-11,000) per 100,000) and limited HIV control funds, worsened by a long conflict and an economic crisis. Methods We conducted a cross-sectional study of 320 Yemeni health professionals in all the four teaching hospitals in Sana’a City. Data were collected anonymously, using an adapted self-completed Arabic version of the Health Policy Project HIV Stigma tool. The questionnaire covered the respondents’ background, the stigmatising practices, and potential personal and professional drivers of stigma. Results The majority of the participants were: females (68%), 20–39 years old (85%), nurses (84%), and holding a nursing diploma (69%) or a bachelor’s degree (27%). None of the hospitals had institutional policies against HIV stigma, and 93% of the participants believed the current infection control measures were inadequate. Less than half of the participants provided care for people living with HIV (PLHIV) (45%), had received HIV training (33%), and were confident that their HIV knowledge was adequate (23%). The majority indicated a preference to test patients for HIV prior to surgical procedures (77%) and disclose positive HIV results to others (99%) without prior knowledge or consent. All the participants had exhibited a form of HIV-related stigmatization, such as avoiding physical contact with PLHIV (87%) or wearing gloves throughout the consultation (96.5%). These practices were significantly correlated with the fear of infection, high perceived risk of infection, and poor work environment (p Conclusion PLHIV face widespread stigmatizing behaviour in the teaching hospitals in Sana’a City, consistent with the higher level of stigma in low HIV prevalence countries and its links to the fear of infection, poor HIV knowledge, and limited funding for HIV control. Stigma reduction interventions are required at institutional and individual levels. In addition, anti-discrimination policies and structural adjustments are needed, in combination with training on HIV and universal precautions, and action to tackle negative attitudes towards PLHIV and key populations.

Summary Background The Global Fund to Fight AIDS, Tuberculosis and Malaria is a robust vertical global health programme. The extent to which vertical programmes financially support health security has not been investigated. We, therefore, endeavoured to quantify the extent to which the budgets of this vertical programme support health security. We believe this is a crucial area of work as the global community works to combine resources for COVID-19 response and future pandemic preparedness. Methods We examined budgets for work in Kenya, Uganda, Vietnam, Democratic Republic of the Congo, Guatemala, Guinea, India, Indonesia, Nigeria, and Sierra Leone from January, 2014 to December, 2020. These ten countries were selected because of the robustness of investments and the availability of data. Using the International Health Regulations Joint External Evaluation (JEE) tool as a framework, we mapped budget line items to health security capacities. Two researchers independently reviewed each budget and mapped items to the JEE. Budgets were then jointly reviewed until a consensus was reached regarding if an item supported health security directly, indirectly, or not at all. The budgets for the study countries were inputted into a single Microsoft Excel spreadsheet and line items that mapped to JEE indicators were scaled up to their respective JEE capacity. Descriptive analyses were then done to determine the total amount of money budgeted for activities that support health security, how much was budgeted for each JEE capacity, and how much of the support was direct or indirect. Findings The research team reviewed 37 budgets. Budgets totalled US$6 927 284 966, and $2 562 063 054 (37·0%) of this mapped to JEE capacities. $1 330 942 712 (19·2%) mapped directly to JEE capacities and $1 231 120 342 (17·8%) mapped indirectly to JEE capacities. Laboratory systems, antimicrobial resistance, and the deployment of medical countermeasures and personnel received the most overall budgetary support; laboratory systems, antimicrobial resistance, and workforce development received the greatest amount of direct budgetary support. Interpretation Over one-third of the Global Fund's work also supports health security and the organisation has budgeted more than $2 500 000 000 for activities that support health security in ten countries since 2014. Although these funds were not budgeted specifically for health security purposes, recognising how vertical programmes can synergistically support other global health efforts has important implications for policy related to health systems strengthening. Funding Resolve to Save Lives: An Initiative of Vital Strategies.

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for “precision medicine” or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

ObjectivePeripheral neuropathic pain (PNP) represents a major public health issue. Severe or refractory cases warrant tertiary multidisciplinary management, but little information is available about real-life care pathways. The primary objective of this cross-sectional, observational study was to investigate the pathways of patients with PNP consulting for the first time or followed for less than 1 year in French tertiary specialized pain clinics.MethodsPNP was diagnosed with the NeuPSIG algorithm. Data collected included demographics, pain characteristics, and details of management before and after the study visit (e.g., drug and non-drug treatment, nature of medical visits), as well as time to referral to a pain clinic and time to a diagnosis of PNP. Factors associated with delayed referral or diagnosis were analyzed with multivariate analysis.ResultsA total of 404 patients with PNP (age 55.8 ± 15.6 years, 60.3% females, 78.3% retired or unemployed, pain duration 43.4 ± 68.9 months) were enrolled by 84 pain specialists. Pain affected mainly the lower limbs (53.5%) and was predominantly related to surgery or trauma (59.4%). Primary care management was characterized by a high proportion of conventional analgesics (60.7%). Time to referral to a pain clinic was 43.4 ± 68.9 months since pain onset and 20.1 ± 39.4 months since the diagnosis of PNP. Delayed referral to a pain clinic was independently predicted by the clinical specialty of the referring doctor and by male gender.ConclusionsThis study highlights the need for accessible guidance for non–pain specialists to improve their diagnostic and management skills and for faster referral of patients with PNP to tertiary pain clinics.