Bacterial Lipopolysaccharides Exacerbate Neurogenic Heterotopic Ossification Development.

Neurogenic heterotopic ossifications (NHO) are heterotopic bones that develop in periarticular muscles after severe central nervous system (CNS) injuries. Several retrospective studies have shown that NHO prevalence is higher in patients who suffer concomitant infections. However, it is unclear whether these infections directly contribute to NHO development or reflect the immunodepression observed in patients with CNS injury. Using our mouse model of NHO induced by spinal cord injury (SCI) between vertebrae T11 to T13 , we demonstrate that lipopolysaccharides (LPS) from gram-negative bacteria exacerbate NHO development in a toll-like receptor-4 (TLR4)-dependent manner, signaling through the TIR-domain-containing adapter-inducing interferon-ß (TRIF/TICAM1) adaptor rather than the myeloid differentiation primary response-88 (MYD88) adaptor. We find that T11 to T13 SCI did not significantly alter intestinal integrity nor cause intestinal bacteria translocation or endotoxemia, suggesting that NHO development is not driven by endotoxins from the gut in this model of SCI-induced NHO. Relevant to the human pathology, LPS increased expression of osteoblast markers in cultures of human fibro-adipogenic progenitors isolated from muscles surrounding NHO biopsies. In a case-control retrospective study in patients with traumatic brain injuries, infections with gram-negative Pseudomonas species were significantly associated with NHO development. Together these data suggest a functional association between gram-negative bacterial infections and NHO development and highlights infection management as a key consideration to avoid NHO development in patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Impact of Early Out-of-Bed Mobilization on Functional Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study.

BACKGROUND: Effects of early mobilization are not well documented in patients with aneurysmal subarachnoid hemorrhage (aSAH). Only a few studies have investigated it through progressive mobilization protocols and suggested that it is safe and feasible. This study aimed to determine the impact of early out-of-bed mobilization (EOM) on 3-month functional outcome and cerebral vasospasm (CVS) occurrence in patients with aSAH. METHODS: A retrospective review of consecutive patients admitted to the intensive care unit with a diagnosis of aSAH was performed. EOM was defined as out-of-bed (OOB) mobilization performed before or on day 4 after aSAH onset. The primary outcome was 3-month functional independence (i.e., a modified Rankin Scale below 3) and the occurrence of CVS. RESULTS: A total of 179 patients with aSAH met the inclusion criteria. Thirty-one patients constituted the EOM group, and 148 patients were in the delayed out-of-bed mobilization group. Functional independence was more frequent in the EOM group than in the delayed out-of-bed mobilization group (n = 26 [84%] vs. n = 83 [56%], P = 0.004). In a multivariable analysis, EOM was an independent predictor of functional independence (adjusted odds ratio = 3.11; 95% confidence interval, 1.11-10.36; P < 0.05). The delay between bleeding and first OOB mobilization was also identified as an independent risk factor for the occurrence of CVS (adjusted odds ratio = 1.12; 95% confidence interval = 1.06-1.18, P < 0.001). CONCLUSIONS: EOM was independently associated with favorable functional outcome after aSAH. The delay between bleeding and OOB mobilization was an independent risk factor for reduced functional independence and CVS occurrence. Prospective randomized trials are necessary to confirm these results and improve clinical practice.

Therapeutic drug monitoring guides the management of patients with chronic non-infectious uveitis treated with adalimumab: a retrospective study.

AIM: To assess the relevance of therapeutic drug monitoring (TDM) of adalimumab (ADA) treatment for the control of intraocular inflammation and treatment adjustment in chronic non-infectious uveitis (CNIU). METHODS: Retrospective study of CNIU patients treated with ADA and for whom at least one dosage of serum ADA level and an antibodies against ADA (AAA) serology were performed, between June 2003 and July 2019. RESULTS: A total of 44 ADA-treated patients benefited from a TDM. A total of 48/79 (61%) TDM were performed in responders, 11/79 (14%) in primary non-responders, and 20/79 (25%) in secondary non-responders. Responders had significantly higher ADA levels than non-responders (p=0.0004). AAA were detectable in six patients, they were primary non-responders (n=2), secondary non-responders (n=3) or responders (n=1). In the five non-responders and immunised patients, ADA was switched (to golimumab or methotrexate). Among non-responders, TDM led to an increased frequency of injections 12/31 (38%), increased dose 1/31 (3%) and switch of treatment 10/31 (32%) (one missing data). No modification of biotherapy was performed 7/31 (22%) and only local or oral corticotherapy was adjusted. In 24/31 cases of therapeutic adjustment in non-responders, an improvement was observed in 87% of cases. Among responders for whom the ADA level was above the efficacy threshold, the frequency of injections was decreased for 15/31 (48.4%) cases and no relapse was observed in 12/15 (80%) cases. CONCLUSION: TDM of ADA treatment proved relevant to provide CNIU patients with a personalised and optimised treatment course (in terms of frequency and type of drug).

Aflibercept in real-life for the treatment of age-related macular degeneration using a treat and extend protocol: The Armada study.

PURPOSE: To report the visual and anatomic outcomes in treatment-naïve neovascular age-related macular degeneration (nAMD) patients treated with aflibercept under a standardized Treat and Extend (T&E) protocol for up to 3 years of follow-up in "real-life" practice. METHODS: This retrospective, observational, multicenter study included patients with treatment-naïve nAMD and at least 12 months of follow-up. T&E regimen adjustment was initiated after loading phase. At each visit best-corrected visual acuity (BCVA) and optical coherence tomography parameters were performed. RESULTS: One hundred and thirty-six eyes of 115patients had at least 1 year of follow-up with 114 and 82 eyes completing at least 2 and 3 years of follow-up, respectively (mean follow-up duration: 2.7 ± 1.3 years). Mean age was 78.6 ± 8.6 years old and 52% were women. Mean BCVA increased from 60.6 ± 18.7 letters at diagnosis to 66.9 ± 16.2 letters at 1 year (+6.3 letters, p = 0.003) and remained stable throughout the follow-up period (63.1 ± 20.3 letters (+2.5, p = 0.1) and 64.0 ± 20.1 letters (+3.4, p = 0.27) at 2 and 3 years, respectively). The mean central retinal thickness decreased significantly from 358.2 ± 87.9 µm at baseline to 302 ± 71.7 µm at 12 months and maintained stable after 36 months of follow-up (297.1 ± 76 µm, p < 0.0001). Mean number of injections was 6.6 ± 2.2, 4.8 ± 1.9, and 5.6 ± 1.7 at 1, 2, and 3 years, respectively. Mean cumulative number of 16.4 ± 5.6 injections after 3 years. Mean treatment interval was 6.8 ± 2.5 weeks at 1 year. Eight-week and 12-week treatment interval were achieved in 59.5% and 19.1%, 65.8%, and 36.8% and 69.5% and 41.5% at 1, 2, and 3 years, respectively. CONCLUSIONS: Our study demonstrated that intravitreal injections of aflibercept initiated under a standardized T&E for patients with treatment-naïve nAMD allow for significant visual improvement at 12 months, which was maintained over a 3-year follow-up period.

Prevalence and risk factors of dermatoporosis in older adults in a rehabilitation hospital.

BACKGROUND: The term dermatoporosis (DP) is used to describe the clinical signs and functional consequences of age-related extreme skin fragility. It is associated with potentially severe complications, including deep dissecting hematomas and extended skin lacerations. No studies have evaluated the prevalence and risk factors of DP in adults aged 75 and older. METHODS: The aim of our study was to assess the prevalence, complications, and risk factors of DP in a cohort of older patients hospitalized in a rehabilitation center. A case-control, single-center study was conducted between September and October 2020 in our rehabilitation ward, Rothschild Hospital, Paris, France. A senior dermatologist and a resident in geriatric medicine performed a systematic dermatological examination. The presence of DP, its stage, its location, and complications were collected, as were demographical data, comorbidities, past sun exposure, skin phototype, treatments, and biological data. RESULTS: A total of 101 patients (62 women, median age 86 years [extreme values 75-104]) were included. The overall prevalence of DP was 27%. Stage 1 was the most frequent. DP was mainly located on the upper limbs. Ten (37%) patients had a DP complication: eight (30%) skin lacerations and two (7%) deep dissecting hematomas. Multivariate analysis revealed a significant association between DP and age (odds ratio [OR] 5.82, 95% confidence interval [CI] 1.67-24.92, p = 0.009), smoking (OR 8.67, 95% CI 2.59-34.85, p = 0.001), recreational sun exposure (OR 4.23, 95% CI 1.30-15.21, p = 0.02), and anticoagulant therapy (OR 4.53, 95% CI 1.32-17.26, p = 0.02). CONCLUSION: Our study is the first to analyze the prevalence and risk factors of DP in older adults in rehabilitation. Frequency of DP makes it relevant for the geriatrician and should be described more to prevent potential severe complications. A multicentric study, with inpatients and outpatients, could evaluate the prevalence of DP in a more representative older adult population.

Dieticians' practices in intensive care: A national survey.

BACKGROUND & AIMS: A real public health problem, namely, malnutrition in the hospital, also concerns intensive care patients. The diagnosis and prevention of malnutrition are major issues in the multidisciplinary management of patients hospitalized in the intensive care unit (ICU). To our knowledge, few data describe dietary management in French ICUs, and few international scientific publications mention professional practices or how dieticians are integrated in this type of specialized and technical sector. The objective of this study is to identify the practices of dieticians in the ICU at a national level. METHODS: This study is based on the use of an electronic questionnaire distributed to registered dietician nutritionists practising in intensive care. RESULTS: A total of 185 dieticians participated in this survey, which allowed us to describe the practices of 174 ICUs. Among the respondents (n = 185), 95% were women with a median age of 37 [31; 52]. The respondents graduated a median of 14 years ago [8.5; 30] and have been practising in intensive care for 5 years [2; 10]. With a median number of 12 beds [10; 18] (n = 174), the ICU has a median of 0.1 [0.05; 0.25] (n = 185) full-time equivalent dieticians. The solicitation of the dietitian is variable in different ICUs. Nevertheless, information from dietitians is frequently sought. Dietary initiatives mainly concern acts relating to oral nutrition and enteral nutrition. A nutrition protocol was present in 38% of the ICUs (n = 174). The integration felt by dieticians in the service is heterogeneous. Statistical analysis reveals that a dietitian who spends more than 4 h a week in the ICU, has a nutrition protocol in his or her department and does not encounter any obstacles, such as the absence of a doctor's prescription, is more likely to be integrated into an ICU. CONCLUSIONS: This research work has made it possible to describe and make visible the role and involvement of dieticians working in ICUs in France and oversea departments and territories. Proposals to increase the involvement of dieticians in these sectors were reported at the end of this analysis.

Effect of implementing a regional referral network on surgical referral rate of benign polyps found during a colorectal cancer screening program: A population-based study.

INTRODUCTION: Surgical management is too often performed as the first-line treatment for large, benign colorectal polyps. We report the management of benign lesions detected by organised colorectal cancer (CRC) screening. METHODS: Population-based study in 2012, 2016, and 2017, analyzing the evolution of surgical management of benign polyps of≥2cm diameter discovered in the context of organised CRC screening after the implementation of a regional referral network for the management of superficial colorectal lesions. RESULTS: A total of 1571 patients underwent colonoscopy following a positive test during the study period, among which 981 colonoscopies yielded at least one lesion. The adenoma detection rate was lower in 2012 (Guaiac test) than in 2016 and 2017 (fecal immunochemical test) (40% vs. 60% vs. 57%, P<0.0001). The surgery rate for benign lesions decreased from 14.6% in 2012 to 7.7% in 2016 and 5% in 2017 (P=0.017). The risk factors for surgery for benign lesions were year 2012 (odds ratio [OR]=3.35, P=0.022), high-grade dysplasia (OR=2.49, P=0.04), in situ carcinoma (OR=5, P=0.003), size≥20mm (OR=17.39, P<0.0001), and private sector (OR=6.6, P=0.0002). The morbidity rate of surgery for benign polyp≥2cm was 20.4% at 1month and its cost was sixfold higher than that of endoscopy. CONCLUSION: The establishment of a regional referral network for the management of large colorectal polyps reduces the rate of surgical management of such lesions.

One-year results of gastric peroral endoscopic myotomy for refractory gastroparesis: a French multicenter study.

BACKGROUND: Data on the long-term outcomes of gastric peroral endoscopic myotomy (G-POEM) for refractory gastroparesis are lacking. We report the results of a large multicenter long-term follow-up study of G-POEM for refractory gastroparesis. METHODS: This was a retrospective multicenter study of all G-POEM operations performed in seven expert French centers for refractory gastroparesis with at least 1 year of follow-up. The primary endpoint was the 1-year clinical success rate, defined as at least a 1-point improvement in the Gastroparesis Cardinal Symptom Index (GCSI). RESULTS: 76 patients were included (60.5 % women; age 56 years). The median symptom duration was 48 months. The median gastric retention at 4 hours (H4) before G-POEM was 45 % (interquartile range [IQR] 29 % - 67 %). The median GCSI before G-POEM was 3.6 (IQR 2.8 - 4.0). Clinical success was achieved in 65.8 % of the patients at 1 year, with a median rate of reduction in the GCSI score of 41 %. In logistic regression analysis, only a high preoperative GCSI satiety subscale score was predictive of clinical success (odds ratio [OR] 3.41, 95 % confidence interval [CI] 1.01 - 11.54; P = 0.048), while a high rate of gastric retention at H4 was significantly associated with clinical failure (OR 0.97, 95 %CI 0.95 - 1.00; P = 0.03). CONCLUSIONS: The results confirm the efficacy of G-POEM for the treatment of refractory gastroparesis, as evidenced by a 65.8 % clinical success rate at 1 year. Although G-POEM is promising, prospective sham-controlled trials are urgently needed to confirm its efficacy and identify the patient populations who will benefit most from this procedure.

Benzodiazepine and Z drug cessation in elderly patients: A qualitative study on the perception of healthcare providers and the place of advanced practice nurses.

Sedative-use disorder can occur in elderly individuals, but remains a taboo subject. France is the second top-consuming country of benzodiazepines (BZDs) and Z drugs in Europe, with 38% of women >80 years old using these drugs. Despite the recommendations of the French National Authority for Health (HAS) to general practitioners, deprescription remains rare. The aim of this study was to understand the perception of healthcare providers towards BZD or Z drug withdrawal within a psychogeriatric unit and to provide insights from advanced practice nurses (APRNs) on this topic. Eight healthcare providers from different professions in a psychogeriatric unit were interviewed. The interviews were recorded and transcribed verbatim, and the data were analysed following the interpretive phenomenological approach. The COREQ statement was used as a guide in the reporting of the study. Four themes were identified in the interview transcripts: (i) problems specific to the elderly; (ii) problems specific to BZD or Z drug consumption; (iii) present care; and (iv) envisioned practice. While the healthcare providers interviewed appeared to have knowledge on the adverse effects of BZDs, it appears difficult to taper the use of BZDs outside crisis periods of behaviour disorders in elderly patients. Caregivers recommend an evolution of practices, such as introducing BDZ and Z drug withdrawal programs that could involve the emerging profession of APRNs in general practice in France. APRNs could be a valuable resource to screen for BZD-related disorders and to manage withdrawal strategies in complex cases.

Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients.

Familial Mediterranean fever (FMF) is the most frequent hereditary systemic autoinflammatory syndrome. FMF is usually caused by biallelic mutations in the MEFV gene, encoding Pyrin. Conclusive genetic evidence lacks for about 30% of patients diagnosed with clinical FMF. Pyrin is an inflammasome sensor maintained inactive by two kinases (PKN1/2). The consequences of MEFV mutations on inflammasome activation are still poorly understood. Here, we demonstrate that PKC superfamily inhibitors trigger inflammasome activation in monocytes from FMF patients while they trigger a delayed apoptosis in monocytes from healthy donors. The expression of the pathogenic p.M694V MEFV allele is necessary and sufficient for PKC inhibitors (or mutations precluding Pyrin phosphorylation) to trigger caspase-1- and gasdermin D-mediated pyroptosis. In line with colchicine efficacy in patients, colchicine fully blocks this response in FMF patients' monocytes. These results indicate that Pyrin inflammasome activation is solely controlled by Pyrin (de)phosphorylation in FMF patients while a second control mechanism restricts its activation in healthy donors/non-FMF patients. This study paves the way toward a functional characterization of MEFV variants and a functional test to diagnose FMF.

JAK inhibitors for the treatment of autoimmune and inflammatory diseases.

Cytokines play a central role in the pathophysiology of autoimmune and inflammatory diseases. Several cytokines signal through the JAK-STAT pathway, which is now recognized as a major target to inhibit the effect of a wide array of cytokines. JAK inhibitors are increasingly used in the setting of inflammatory and autoimmune diseases. While the currently approved drugs are panJAK inhibitors, more selective small molecules are being developed and tested in various rheumatic disorders. In this extensive review, we present evidence- or hypothesis-based perspectives for these drugs in various rheumatologic conditions, such as rheumatoid arthritis, systemic lupus erythematosus, giant cell arteritis, and autoinflammatory diseases.

High proficiency of colonic endoscopic submucosal dissection in Europe thanks to countertraction strategy using a double clip and rubber band.

Background and study aims ESD in the colon is more challenging technically than in other locations. Here, we report the first comparative case series of colon ESD using a systematic countertraction strategy using two clips and a rubber band. Patients and methods Retrospective comparative study of classic versus countertraction colon ESD performed in colon ESD cases collected prospectively at Lyon Edouard Herriot Hospital and Limoges University Hospital from January 2016 until December 2017. Results The study included 192 cases (control = 76, countertraction = 116). Countertraction using the double clip and rubber band technique versus the control group resulted in a significant decrease in the procedure time (94.7 vs . 117 min; P  = 0.004) and significant increases in procedure speed (28.2 vs . 16.7 mm 2 /min; P  < 0.0001), en bloc resection rate (95.7 % vs . 76.3 %, P  < 0.0001), and R0 resection rate (78.5 % vs . 64.5 %, P  = 0.04). At an individual operator point of view, results varied between operators but the double clip countertraction strategy significantly increased the en bloc resection rate, R0 resection rate, and speed of dissection for each of the 4 operators. Conclusion Systematic countertraction using a double clip and rubber band facilitates colon ESD. This strategy should become the standard for colon ESD.

Influence of nurse's involvement on practices during end-of-life decisions within stroke units.

OBJECTIVES: Decision-making processes concerning end-of-life decisions are not well understood for patients admitted into stroke units with severe stroke. To assess the influence of nurses on the medical perspectives and approaches that lead to withholding and/or withdrawing treatments related to end-of-life (EOL) decisions. PATIENTS AND METHODS: This secondary analysis nested within the TELOS French national survey was based on a physicians' self-report questionnaire and on a I-Score which was linked to nurses' involvement. Physician's responses were evaluated to assess the potential influence of nurse's involvement on physician's choices during an end-of-life decision. RESULTS: Among the 120 questionnaires analyzed, end-of-life decisions were more often made during a round-table discussion (58% vs. 35%, p = 0.004) when physicians declare to involve nurses in the decision process. Neurologists involved with nurses in decision making were more likely to withhold a treatment (98% vs. 88%, p = 0.04), to withdraw artificial feeding and hydration (59% vs. 39%, p = 0.04), and more frequently prescribed analgesics and hypnotics at a potentially lethal dose (70% vs. 48%, p = 0.03). CONCLUSION: The involvement of nurses during end-of-life decisions for patients with acute stroke in stroke units seemed to influence neurologists' intensivist practices and behaviors. Nurses supported the physicians' decisions related to forgoing life sustaining treatment for patients with acute stroke and may positively impact on the family's choice to participate in end-of-life decisions.

Methodological management of end-of-life decision data in intensive care studies: A systematic review of 178 randomized control trials published in seven major journals.

BACKGROUND: End-of-life (EOL) decisions are a serious ethical dilemma and are frequently carried out in intensive care units (ICUs). The aim of this systematic review was to investigated the different approaches used in ICUs and reported in randomized controlled trials (RCTs) to address EOL decisions and compare the impact of these different strategies regarding potential bias and mortality estimates. METHODS: We identified relevant RCTs published in the past 15 years via PubMed, EMBASE, and CINAHL. In addition, we searched The Cochrane Library and checked registries, including ClinicalTrials.gov to assess concordance between declared and published outcomes. Among the journals we screened were the 3 ICU specialty journals and the four general medicine journals with the highest impact factor. Only RCTs were selected in which in-ICU mortality was the primary or secondary outcome. The primary outcome was information regarding EOL decisions, and the secondary outcome was how EOL decisions were treated in the study analysis. RESULTS: A total of 178 relevant trials were identified. The details regarding the methodological aspects resulting from EOL decisions were reported in only 62 articles (35%). The manner in which EOL decisions were considered in the study analysis was very heterogeneous, often leading to a high risk of bias. CONCLUSION: There is a heterogeneity regarding the management of data on EOL decisions in randomized control trials with mortality endpoints. Recommendations or rules are required regarding the inclusion of patients with potential EOL decisions in RCT analyses and how to manage such decisions from a methodological point of view. TRIAL REGISTRATION: PROSPERO website (CRD42013005724).

What is the cost of endoscopic submucosal dissection (ESD)? A medico-economic study.

Introduction: Endoscopic submucosal dissection (ESD) is the gold-standard treatment for superficial lesions of the digestive tract. No medico-economic study has been conducted in Europe. Material and methods: A monocentric study was conducted including all patients undergoing ESD between January 2015 and December 2017. The global cost of hospital stays was measured by microcosting, and revenue was based on the diagnosis-related group (DRG) system. The primary objective was to assess the cost/revenue balance. A medico-economic comparison with surgery was performed as a secondary outcome. Results: A total of 193 patients were prospectively included. The cost per procedure was €3463.79, subtracted from a €2726.84 revenue, with a deficit of -€736.96 per stay. Presence of comorbidities/complications increasing DRG value was the only predictive factor for a positive budgetary balance in a multivariate analysis (odds ratio 49.21, 95% confidence interval 11.3-214.25, p < 0.0001). In comparison with surgery, ESD was associated with shorter length of stay (11 vs 2 days; p < 0.0001) and lower morbidity (28% vs 14%; p = 0.061), lower cost (€8960 vs €1770; p < 0.0001). Conclusion: The ESD cost/revenue balance is negative in 80% of cases. Given the benefits of ESD in terms of patient morbidity and financial savings compared with surgery, the implementation of a specific ESD reimbursement is warranted.

Does mechanical morcellation of large glands compromise incidental prostate cancer detection on specimen analysis? A pathological comparison with open simple prostatectomy.

OBJECTIVE: This study sought to compare the incidental prostate cancer (iPCa) detection rate between pathological specimens from green laser enucleation of the prostate (GreenLEP) and open simple prostatectomy (OSP). MATERIALS AND METHODS: In two institutions, the charts of all consecutive patients who underwent OSP between January 2005 and December 2010 were retrospectively reviewed, and the data of all consecutive patients who underwent GreenLEP with tissue morcellation between July 2013 and January 2018 were also collected. Preoperative demographics and pathological findings were recorded. iPCa detection rate was retrospectively compared between the GreenLEP and OSP groups in a propensity score model, including all predetermined variables: Age, preoperative PSA level and prostate volume. RESULTS: Of 738 patients, 402 were included in the propensity-score matching analysis, and they were equally distributed among groups. The overall iPCa detection rates were similar in both groups (9.9% vs. 8.5%; p = 0.73), and there were no statistically significant differences in terms of tumour stage, Gleason score or the rate of clinically significant iPCa, although the number of cassettes analysed was significantly higher in the morcellation group than in the OSP group. No predictive factors for iPCa were identified. CONCLUSIONS: The results of the present study suggest that the mechanical morcellation of large glands had no influence on iPCa detection. Compared with a specimen from standard OSP, a large morcellated tissue sample allows adequate pathological evaluation and does not alter a pathologist's ability to detect iPCa.