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The transition from a comorbidity-based to a multimorbidity-focused to ultimately a network medicine approach in people with rheumatic diseases might mark a significant shift in how we understand and manage these complex conditions. Multimorbidity expands on the concept of comorbidity by encompassing the presence of multiple diseases, which results in further individual and societal impacts. This approach, while valuable, often leads to fragmented care focused on individual diseases rather than the patient as a whole.Network medicine, on the other hand, offers a more integrated perspective. It is an emerging concept that leverages the understanding of biologic networks and their interactions within the human body to gain insights into disease mechanisms. In the context of rheumatic diseases, network medicine involves examining how different diseases interconnect and influence each other through shared pathways, genetic factors, and molecular mechanisms.This paradigm shift allows for a more holistic understanding in how we manage rheumatic diseases. For instance, rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus are not just a collection of symptoms affecting various organs but are also interconnected through underlying systemic inflammatory processes, immune system dysregulation, and genetic predispositions., Competing Interests: Declarations. Conflict of Interest: Winston Gilcrease, Luca Manfredi, Savino Sciascia, and Fulvio Ricceri have nothing to disclose. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors., (© 2024. The Author(s).)

Inflammatory bowel disease (IBD) causes chronic inflammation of the colon and digestive tract, and it can be classified as Crohn's disease (CD) and Ulcerative colitis (UC). IBD is more prevalent in Europe and North America, however, since the beginning of the 21st century it has been increasing in South America, Asia, and Africa, leading to its consideration as a worldwide problem. Optical colonoscopy is one of the crucial tests in diagnosing and assessing the progression and prognosis of IBD, as it allows a real-time optical visualization of the colonic wall and ileum and allows for the collection of tissue samples. The accuracy of colonoscopy procedures depends on the expertise and ability of the endoscopists. Therefore, algorithms based on Deep Learning (DL) and Convolutional Neural Networks (CNN) for colonoscopy images and videos are growing in popularity, especially for the detection and classification of colorectal polyps. The performance of this system is dependent on the quality and quantity of the data used for training. There are several datasets publicly available for endoscopy images and videos, but most of them are solely specialized in polyps. The use of DL algorithms to detect IBD is still in its inception, most studies are based on assessing the severity of UC. As artificial intelligence (AI) grows in popularity there is a growing interest in the use of these algorithms for diagnosing and classifying the IBDs and managing their progression. To tackle this, more annotated colonoscopy images and videos will be required for the training of new and more reliable AI algorithms. This article discusses the current challenges in the early detection of IBD, focusing on the available AI algorithms, and databases, and the challenges ahead to improve the detection rate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Braverman-Jaiven and Manfredi.)

Background: It is unknown whether the association between ultra-processed food (UPF) intake and type 2 diabetes mellitus differs from other degrees of food processing. We examined the association between degree of food processing and incident type 2 diabetes mellitus., Methods: This was a prospective cohort analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC). Dietary intake was assessed at baseline using dietary questionnaires and classified according to the Nova classification into unprocessed/minimally processed food (MPF), processed culinary ingredients (PCI), processed food (PF) and UPF. Type 2 diabetes mellitus cases were verified through multiple methods. Cox regression and statistical substitution analysis was used to estimate associations between MPF + PCI, PF and UPF intake and incident type 2 diabetes mellitus. To investigate heterogeneity in the association between UPF and incident type 2 diabetes mellitus, UPF sub-group analysis was conducted. Different reference groups were used in each analysis., Findings: Over an average 10.9 years follow-up of 311,892 individuals, 14,236 type 2 diabetes mellitus cases were identified. Each 10% increment of total daily food intake from UPF (%g/day) was associated with 17% (95% confidence interval (95%CI): 1.14-1.19) higher incident type 2 diabetes mellitus. Each 10% increment in MPF + PCI or PF intake was associated with lower incident type 2 diabetes mellitus (MPF + PCI hazard ratio: 0.94 (95%CI: 0.92-0.96); PF hazard ratio: 0.92 (95%CI: 0.89-0.95)). Replacing UPF with MPF + PCI or PF was associated with lower incident type 2 diabetes mellitus. However, heterogeneity was observed across UPF sub-groups, with breads, biscuits and breakfast cereals, sweets and desserts, and plant-based alternatives associated with lower incident type 2 diabetes mellitus., Interpretation: These findings support recommendations to focus on reducing intake of specific UPF for lowering type 2 diabetes mellitus risk., Funding: International Agency for Research on Cancer., Competing Interests: SJD receives royalties from Amazon for a self-published book that mentions ultra-processed food, and payments from Red Pen Reviews. RLB is an employee of Eli Lilly and Company and reports honoraria from Novo Nordisk, Eli Lilly, Medscape, ViiV Healthcare Ltd and International Medical P and advisory board and consultancy work for Novo Nordisk, Eli Lilly, Pfizer, Gila Therapeutics Ltd, Epitomee Medical Ltd and ViiV Healthcare Ltd. All other authors declare no conflicts of interest., (© 2024 The Author(s).)

Objectives: Our study aimed to investigate how physical activity (PA) changes over an 11-year follow-up among adults from different socioeconomic positions (SEP) near retirement age. Moreover, an analysis of different PA types is considered., Methods: We used data from the EPIC-Italy cohort. We evaluated PA using the Cambridge Physical Activity Index (CPAI) and the metabolic equivalent of tasks (MET) per hour of activity for recreational PA and household PA. Educational level was assessed using the Relative Index of Inequality (RII). Occupational classes were classified according to LIFEPATH Consortium knowledge. Logistic regression was used to analyse PA among SEP and changes during follow-up. Analyses were also conducted separately for sex., Results: The higher educated were more prevalent in the higher quartile of recreational PA than the lower educated both at baseline and follow-up (37% vs 28% and 37% vs 27%, respectively). At the baseline, the lower educated had a higher risk of being physically inactive than the higher educated based on recreational PA (overall OR: 1.50, 95% CI 1.40 to 1.60). Manual workers did not show a higher risk of less PA than professionals/managers (overall OR: 1.03, 95% CI 0.91 to 1.16).At follow-up, the lower educated and manual workers showed a higher risk of being physically inactive (lower educated OR: 1.46, 95% CI 1.37 to 1.56; manual worker OR: 1.33, 95% CI 1.18 to 1.50). The analyses of changes in PA showed that those who were less educated or manual workers had a higher risk of worsening their PA during the follow-up period, particularly women in recreational PA and men in CPAI measurement., Conclusion: Individuals who had a disadvantaged SEP showed a higher risk of performing less PA over time., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Circulating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk., Methods: We analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics., Results: Circulating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade., Conclusions: Estimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk., (© 2024. The Author(s).)

Introduction: Existing research highlights the significance of prosocial behavior (voluntary, intentional behavior that results in benefits for another) to people's well-being. Yet, the extent to which this expected positive relation operates at the within-person level (e.g., is more prosocial behavior than usual related to a higher than usual level of well-being?) while taking into account stable interindividual differences, remains a research question that deserves further investigation. In this study, we aimed to explore the relations between prosocial behavior and hedonic (HWB; subjective assessment of life satisfaction and happiness) and eudaimonic (EWB; actualization of human potential in alignment with personal goals, including concepts like meaning in life and closeness to others) well-being in daily life., Method: Using ecological momentary assessment for 4 weeks, data were collected from two British samples, comprising 82 adolescents and 166 adults., Results: Dynamic Structural Equation Modeling revealed a positive relations between prosocial behavior and HWB/EWB at both between and within-person levels across the samples., Conclusion: In summary, these findings further support the positive link between prosocial behavior and well-being in everyday life. Notably, this association was consistent across different age groups (adolescent and adults) at both between and within-person levels., (© 2024 Wiley Periodicals LLC.)

Introduction: Dietary intake of (poly)phenols has been linked to reduced adiposity and body weight (BW) in several epidemiological studies. However, epidemiological evidence on (poly)phenol biomarkers, particularly plasma concentrations, is scarce. We aimed to investigate the associations between plasma (poly)phenols and prospective BW change in participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort., Methods: This study included 761 participants with data on BW at baseline and after 5 years of follow-up. Plasma concentrations of 36 (poly)phenols were measured at baseline using liquid chromatography-tandem mass spectrometry. Associations were assessed through general linear mixed models and multinomial logistic regression models, using change in BW as a continuous or as a categorical variable (BW loss, maintenance, gain), respectively. Plasma (poly)phenols were assessed as log2-transformed continuous variables. The false discovery rate (FDR) was used to control for multiple comparisons., Results: Doubling plasma (poly)phenol concentrations showed a borderline trend towards a positive association with BW loss. Plasma vanillic acid showed the strongest association (-0.53 kg/5 years; 95% confidence interval [CI]: -0.99, -0.07). Similar results were observed for plasma naringenin comparing BW loss versus BW maintenance (odds ratio: 1.1; 95% CI: 1.0, 1.2). These results did not remain significant after FDR correction., Conclusion: Higher concentrations of plasma (poly)phenols suggested a tendency towards 5-year BW maintenance or loss. While certain associations seemed promising, they did not withstand FDR correction, indicating the need for caution in interpreting these results. Further studies using (poly)phenol biomarkers are needed to confirm these suggestive protective trends., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Colorectal cancer (CRC) is the third most common cancer worldwide and responsible for approximately 1 million deaths annually. Early screening is essential to increase the chances of survival, and it can also reduce the cost of treatments for healthcare centres. Colonoscopy is the gold standard for CRC screening and treatment, but it has several drawbacks, including difficulty in manoeuvring the device, patient discomfort, and high cost. Soft endorobots, small and compliant devices thatcan reduce the force exerted on the colonic wall, offer a potential solution to these issues. However, controlling these soft robots is challenging due to their deformable materials and the limitations of mathematical models. In this Review, we discuss model-free and model-based approaches for controlling soft robots that can potentially be applied to endorobots for colonoscopy. We highlight the importance of selecting appropriate control methods based on various parameters, such as sensor and actuator solutions. This review aims to contribute to the development of smart control strategies for soft endorobots that can enhance the effectiveness and safety of robotics in colonoscopy. These strategies can be defined based on the available information about the robot and surrounding environment, control demands, mechanical design impact and characterization data based on calibration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Asgari, Magerand and Manfredi.)

Background: Healthcare agencies and perioperative professional organizations recommend avoiding preoperative screening tests for low-risk surgical procedures. However, low-value preoperative tests are still commonly ordered even for generally healthy patients and active strategies to reduce this testing have not been adequately described., Objective: We sought to learn from hospitals with either high levels of testing or that had recently reduced use of low-value screening tests (aka "delta sites") about reasons for testing and active deimplementation strategies they used to effectively improve practice., Design: Qualitative study of semi-structured telephone interviews., Participants: We identified facilities in the US Veterans Health Administration (VHA) with high or recently improved burden of potentially low-value preoperative testing for carpal tunnel release and cataract surgery. We recruited perioperative clinicians to participate., Approach: Questions focused on reasons to order preoperative screening tests for patients undergoing low-risk surgery and, more importantly, what strategies had been successfully used to reduce testing. A framework method was used to identify common improvement strategies and specific care delivery innovations., Key Results: Thirty-five perioperative clinicians (e.g., hand surgeons, ophthalmologists, anesthesiologists, primary care providers, directors of preoperative clinics, nurses) from 29 VHA facilities participated. Facilities that successfully reduced the burden of low-value testing shared many improvement strategies (e.g., building consensus among stakeholders; using evidence/norm-based education and persuasion; clarifying responsibility for ordering tests) to implement different care delivery innovations (e.g., pre-screening to decide if a preop clinic evaluation is necessary; establishing a dedicated preop clinic for low-risk procedures)., Conclusions: We identified a menu of common improvement strategies and specific care delivery innovations that might be helpful for institutions trying to design their own quality improvement programs to reduce low-value preoperative testing given their unique structure, resources, and constraints., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Existing epidemiological evidence regarding the potential role of (poly)phenol intake in prostate cancer (PCa) risk is scarce and, in the case of flavonoids, it has been suggested that their intake may increase PCa risk. We investigated the associations between the intake of the total and individual classes and subclasses of (poly)phenols and the risk of PCa, including clinically relevant subtypes. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort included 131,425 adult men from seven European countries. (Poly)phenol intake at baseline was assessed by combining validated center/country-specific dietary questionnaires and the Phenol-Explorer database. Multivariable-adjusted Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). In total, 6939 incident PCa cases (including 3501 low-grade and 710 high-grade, 2446 localized and 1268 advanced, and 914 fatal Pca cases) were identified during a mean follow-up of 14 years. No associations were observed between the total intake of (poly)phenols and the risk of PCa, either overall (HR log2 = 0.99, 95% CI 0.94-1.04) or according to PCa subtype. Null associations were also found between all classes (phenolic acids, flavonoids, lignans, and stilbenes) and subclasses of (poly)phenol intake and the risk of PCa, overall and according to PCa subtype. The results of the current large prospective cohort study do not support any association between (poly)phenol intake and PCa incidence.

Optical colonoscopy is the gold standard procedure to detect colorectal cancer, the fourth most common cancer in the United Kingdom. Up to 22%-28% of polyps can be missed during the procedure that is associated with interval cancer. A vision-based autonomous soft endorobot for colonoscopy can drastically improve the accuracy of the procedure by inspecting the colon more systematically with reduced discomfort. A three-dimensional understanding of the environment is essential for robot navigation and can also improve the adenoma detection rate. Monocular depth estimation with deep learning methods has progressed substantially, but collecting ground-truth depth maps remains a challenge as no 3D camera can be fitted to a standard colonoscope. This work addresses this issue by using a self-supervised monocular depth estimation model that directly learns depth from video sequences with view synthesis. In addition, our model accommodates wide field-of-view cameras typically used in colonoscopy and specific challenges such as deformable surfaces, specular lighting, non-Lambertian surfaces, and high occlusion. We performed qualitative analysis on a synthetic data set, a quantitative examination of the colonoscopy training model, and real colonoscopy videos in near real-time., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mathew, Magerand, Trucco and Manfredi.)

Breast cancer (BC) is a multifactorial disease caused by an interaction between genetic predisposition and environmental exposures. MicroRNAs are a group of small non-coding RNA molecules, which seem to have a role either as tumor suppressor genes or oncogenes and seem to be related to cancer risk factors. We conducted a systematic review and meta-analysis to identify circulating microRNAs related to BC diagnosis, paying special attention to methodological problems in this research field. A meta-analysis was performed for microRNAs analyzed in at least three independent studies where sufficient data to make analysis were presented. Seventy-five studies were included in the systematic review. A meta-analysis was performed for microRNAs analyzed in at least three independent studies where sufficient data to make analysis were presented. Seven studies were included in the MIR21 and MIR155 meta-analysis, while four studies were included in the MIR10b metanalysis. The pooled sensitivity and specificity of MIR21 for BC diagnosis were 0.86 (95%CI 0.76-0.93) and 0.84 (95%CI 0.71-0.92), 0.83 (95%CI 0.72-0.91) and 0.90 (95%CI 0.69-0.97) for MIR155, and 0.56 (95%CI 0.32-0.71) and 0.95 (95%CI 0.88-0.98) for MIR10b, respectively. Several other microRNAs were found to be dysregulated, distinguishing BC patients from healthy controls. However, there was little consistency between included studies, making it difficult to identify specific microRNAs useful for diagnosis.

Background: Since the outbreak of the COVID-19 pandemic, identifying the main risk factors has been imperative to properly manage the public health challenges that the pandemic exposes, such as organizing effective vaccination campaigns. In addition to gender and age, multimorbidity seems to be 1 of the predisposing factors coming out of many studies investigating the possible causes of increased susceptibility to SARS-CoV-2 infection and adverse outcomes. However, only a few studies conducted have used large samples., Objective: The objective is to evaluate the association between multimorbidity, the probability to be tested, susceptibility, and the severity of SARS-CoV-2 infection in the Piedmont population (Northern Italy, about 4 million inhabitants). For this purpose, we considered 5 main outcomes: access to the swab, positivity to SARS-CoV-2, hospitalization, intensive care unit (ICU) admission, and death within 30 days from the first positive swab., Methods: Data were obtained from different Piedmont health administrative databases. Subjects aged from 45 to 74 years and infections diagnosed from February to May 2020 were considered. Multimorbidity was defined both with the Charlson Comorbidity Index (CCI) and by identifying patients with previous comorbidities, such as diabetes and oncological, cardiovascular, and respiratory diseases. Multivariable logistic regression models (adjusted for age and month of infection and stratified by gender) were performed for each outcome. Analyses were also conducted by separating 2 age groups (45-59 and 60-74 years)., Results: Of 1,918,549 subjects, 85,348 (4.4%) performed at least 1 swab, of whom 12,793 (14.9%) tested positive for SARS-CoV-2. Of these 12,793 subjects, 4644 (36.3%) were hospitalized, 1508 (11.8%) were admitted to the ICU, and 749 (5.9%) died within 30 days from the first positive swab. Individuals with a higher CCI had a higher probability of being swabbed but a lower probability of testing positive. We observed the same results when analyzing subjects with previous oncological and cardiovascular diseases. Moreover, especially in the youngest group, we identified a greater risk of being hospitalized and dying. Among comorbidities considered in the study, respiratory diseases seemed to be the most likely to increase the risk of having a positive swab and worse disease outcomes., Conclusions: Our study shows that patients with multimorbidity, although swabbed more frequently, are less likely to get infected with SARS-CoV-2, probably due to greater attention on protective methods. Moreover, a history of respiratory diseases is a risk factor for a worse prognosis of COVID-19. Nonetheless, whatever comorbidities affect the patients, a strong dose-response effect was observed between an increased CCI score and COVID-19 hospitalization, ICU admission, and death. These results are important in terms of public health because they help in identifying a group of subjects who are more prone to worse SARS-CoV-2 outcomes. This information is important for promoting targeted prevention and developing policies for the prioritization of public health interventions., (©Alberto Catalano, Lucia Dansero, Winston Gilcrease, Alessandra Macciotta, Carlo Saugo, Luca Manfredi, Roberto Gnavi, Elena Strippoli, Nicolás Zengarini, Valeria Caramello, Giuseppe Costa, Carlotta Sacerdote, Fulvio Ricceri. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 09.02.2023.)

A growing amount of research suggests that inflammatory responses have a crucial role in the complex pathophysiology of Major Depressive Disorder (MDD), a disabling medical condition. The present review has two primary goals. Firstly, to highlight and summarize results from studies that investigated the changes of IL-6 in MDD patients before and after combined treatment. The second aim is to enlighten the need for further research on the difference in the concentration of the pro-inflammatory cytokines between MDD and Treatment-Resistant MDD. The protocol of this study was written using PRISMA, and it is registered at PROSPERO (identification: CRD42021289233). We searched the following bibliographic databases to identify potentially eligible articles without any time limit until September 2021: Pubmed, Web of Science, Scopus, PsycINFO. As they met the eligibility criteria, 14 articles were included in this systematic review. The selected studies assessed twelve different elements as an adjunction to the standard pharmacotherapy (ECT, Ketamine, CBT, NCT, Ketoprofene, Lithium, Celecoxib, Metformin tDCS, Pentoxifylline, ethyl-EPA, Zinc). Significant results were found in the studies that analyzed the impact of combined treatment with the adjunction of the following elements: ECT, Ketamine, CBT, NCT, Celecoxib, Metformin, and Pentoxifylline. Overall, this systematic review identifies several potentially beneficial combined treatments for MDD patients. Further evidence is needed to confirm the efficacy of reducing IL-6 levels in patients with Treatment-Resistant MDD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

It is currently unknown which genetic polymorphisms are involved in substance use disorder (SUD) comorbid with bipolar disorder (BD). The research on polymorphisms in BD comorbid with SUD (BD + SUD) is summarized in this systematic review. We looked for case-control studies that genetically compared adults and adolescents with BD and SUD, healthy controls, and BD without SUD. PRISMA was used to create our protocol, which is PROSPERO-registered (identification: CRD4221270818). The following bibliographic databases were searched indefinitely until December 2021 to identify potentially relevant articles: PubMed, PsycINFO, Scopus, and Web of Science. This systematic review, after the qualitative analysis of the study selection, included 17 eligible articles. In the selected studies, 66 polymorphisms in 29 genes were investigated. The present work delivers a group of potentially valuable genetic polymorphisms associated with BD + SUD: rs11600996 ( ARNTL ), rs228642/rs228682/rs2640909 ( PER3 ), PONQ192R ( PON1 ), rs945032 ( BDKRB2 ), rs1131339 ( NR4A3 ), and rs6971 ( TSPO ). It is important to note that none of those findings have been confirmed by two or more studies; thus, we believe that all the polymorphisms identified in this review require additional evidence to be confirmed.

Background: Since 2011 Italy has faced an extraordinary increase in migrants arrivals, mainly from the Mediterranean route, one of the world's most dangerous journeys. The purpose of the present article is to provide a comprehensive picture of the migrants' health status in the "T. Fenoglio" centre, Settimo Torinese (Turin, Italy)., Methods: A retrospective cross-sectional study was conducted using data collected from June 2016 to May 2018 on adult migrants (over 18 years old) from Africa, Middle East and South East Asia (Bangladesh, Cambodia, India, Nepal). Data was collected through the migrants' medical records. Descriptive statistics were performed on socio-demographic variables. The diagnosed diseases were anonymously registered and classified according to the International Classification of Primary Care (ICPC-2). Conditional Inference Trees were used to perform a descriptive analysis of the sample and to detect the covariates with the strongest association with the variables Disease on arrival, Disease after arrival, ICPC on arrival and ICPC after arrival., Results: Analyzed observations were 9 857. 81.8% were men, median age was 23 (Interquartile range: 20.0-27.4). 70.3% of the sample came from Sub-Saharan Africa. 2 365 individuals (24%) arrived at the centre with at least one disease. On arrival, skin (27.71%), respiratory (14.46%), digestive (14.73%) and generic diseases (20.88%) were the most frequent. During the stay respiratory diseases were the most common (25.70%). The highest probability of arriving with a disease occurred in 2018 and during the period September-November 2016, in particular for people from the Horn of Africa. During this period and also in the first half of 2017, skin diseases were the most reported. In seasons with lower prevalence of diseases on arrival the most common disease code was generic for both men and women (usually fever or trauma)., Conclusions: This study provides information on the diverse diseases that affect the asylum seekers population. In our sample, the Horn of Africa was the most troubled area of arrival, with severe conditions frequently reported regarding skin diseases, in particular scabies. 2018 was the most critical year, especially for migrants from the Horn of Africa and Sub-Saharan Africa. During the stay at the camp, the prevalence of respiratory diseases increased. However, skin diseases remained the main issue for people from the Horn of Africa. Overall, the most reported diseases in the sample were dermatological, respiratory, digestive and generic diseases, both on arrival and during the stay. A better understanding of the health status of asylum seekers is an important factor to determine a more efficient reception and integration process and a better allocation of economic resources in the context of migrants' health care., (© 2022. The Author(s).)

Introduction: Puerperium is a critical period for patients affected by autoimmune rheumatic diseases for the risk of disease's flares and difficulties in treating lactating mothers. We want to summarize the literature data about psychological and pharmacological management of these patients and possible risk factors of disease's flares., Areas Covered: We made a narrative review on recent studies about puerperium in rheumatic autoimmune diseases patients., Expert Opinion: The physicians involved in management of patients during puerperium and in the follow-up of babies need to agree on maternal treatment because they need to reassure mothers about the safety of the prescribed medications. Furthermore, women with rheumatic diseases could present some musculoskeletal limitations and psychological problems, such as postpartum depression, which can lead to a sense of inadequacy to the mother's task. Families and physicians should be aware of these possible complications and support the new mothers providing correct counseling and practical help.

Colorectal cancer (CRC) is the second most common cause of cancer death worldwide, after lung cancer (Sung et al., 2021). Early stage detection is key to increase the survival rate. Colonoscopy remains to be the gold standard procedure due to its dual capability to optically inspect the entire colonic mucosa and to perform interventional procedures at the same time. However, this causes pain and discomfort, whereby it requires sedation or anaesthesia of the patient. It is a difficult procedure to perform that can cause damage to the colonic wall in some cases. Development of new technologies aims to overcome the current limitations on colonoscopy by using advancements in endorobotics research. The design of these advanced medical devices is challenging because of the limited space of the lumen, the contorted shape, and the long tract of the large bowel. The force applied to the colonic wall needs to be controlled to avoid collateral effects such as injuries to the colonic mucosa and pain during the procedure. This article discusses the current challenges in the colonoscopy procedure, the available locomotion technologies for endorobots used in colonoscopy at a prototype level and the commercial products available., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Manfredi.)

The genetic polymorphisms involved in the physiopathology of binge eating disorder (BED) are currently unclear. This systematic review aims to highlight and summarize the research on polymorphisms that is conducted in the BED. We looked for observational studies where there was a genetic comparison between adults with BED, in some cases also with obesity or overweight, and healthy controls or obesity/overweight without BED. Our protocol was written using PRISMA. It is registered at PROSPERO (identification: CRD42020198645). To identify potentially relevant documents, the following bibliographic databases were searched without a time limit, but until September 2020: PubMed, PsycINFO, Scopus, and Web of Science. In total, 21 articles were included in the qualitative analysis of the systematic review, as they met the eligibility criteria. Within the selected studies, 41 polymorphisms of 17 genes were assessed. Overall, this systematic review provides a list of potentially useful genetic polymorphisms involved in BED: 5-HTTLPR (5-HTT), Taq1A (ANKK1/DRD2), A118G (OPRM1), C957T (DRD2), rs2283265 (DRD2), Val158Met (COMT), rs6198 (GR), Val103Ile (MC4R), Ile251Leu (MC4R), rs6265 (BNDF), and Leu72Met (GHRL). It is important to emphasize that Taq1A is the polymorphism that showed, in two different research groups, the most significant association with BED. The remaining polymorphisms need further evidence to be confirmed.

Background: Approximately 15%-20% of total knee arthroplasty (TKA) patients do not experience clinically meaningful improvements. We sought to compare the accuracy and parsimony of several machine learning strategies for developing predictive models of failing to experience minimal clinically important differences in patient-reported outcome measures (PROMs) 1 year after TKA., Methods: Patients (N = 587) in 3 large Veteran Health Administration facilities completed PROMs before and 1 year after TKA (92% follow-up). Preoperative PROMs and electronic health record data were used to develop and validate models to predict failing to experience at least a minimal clinically important difference in Knee Injury and Osteoarthritis Outcome Score (KOOS) Total, KOOS JR, and KOOS subscales (Pain, Symptoms, Activities of Daily Living, Quality of Life, and recreation). Several machine learning strategies were used for model development. Ten-fold cross-validation and bootstrapping were used to produce measures of overall accuracy (C-statistic, Brier Score). The sensitivity and specificity of various predicted probability cut-points were examined., Results: The most accurate models produced were for the Activities of Daily Living, Pain, Symptoms, and Quality of Life subscales of the KOOS (C-statistics 0.76, 0.72, 0.72, and 0.71, respectively). Strategies varied substantially in terms of the numbers of inputs required to achieve similar accuracy, with none being superior for all outcomes., Conclusion: Models produced in this project provide estimates of patient-specific improvements in major outcomes 1 year after TKA. Integrating these models into clinical decision support, informed consent and shared decision making could improve patient selection, education, and satisfaction., Level of Evidence: Level III, diagnostic study., (Published by Elsevier Inc.)

Aims: Cardiac involvement in patients with systemic sclerosis (SSc) is frequent and represents a negative prognostic factor. Recent studies have described subclinical heart involvement of both the right ventricle (RV) and left ventricle (LV) via speckle-tracking-derived global longitudinal strain (GLS). It is currently unknown if SSc-related cardiomyopathy progresses through time. Our aim was to assess the progression of subclinical cardiac involvement in patients with SSc via speckle-tracking-derived GLS., Methods: This was a prospective longitudinal study enrolling 72 consecutive patients with a diagnosis of SSc and no structural heart disease nor pulmonary hypertension. A standard echocardiographic exam and GLS calculations were performed at baseline and at follow-up., Results: Traditional echocardiographic parameters did not differ from baseline to 20-month follow-up. LV GLS, despite being already impaired at baseline, worsened significantly during follow-up (from -19.8 ± 3.5% to -18.7 ± 3.5%, p  = .034). RV GLS impairment progressed through the follow-up period (from -20.9 ± 6.1% to -18.7 ± 5.4%, p  = .013). The impairment was more pronounced for the endocardial layers of both LV (from -22.5 ± 3.9% to -21.4 ± 3.9%, p  = .041) and RV (-24.2 ± 6.2% to -20.6 ± 5.9%, p  = .001). A 1% worsening in RV GLS was associated with an 18% increased risk of all-cause death or major cardiovascular event ( p  = .03) and with a 55% increased risk of pulmonary hypertension ( p  = .043)., Conclusion: SSC-related cardiomyopathy progresses over time and can be detected by speckle-tracking GLS. The highest progression towards reduced deformation was registered for the endocardial layers, which supports the hypothesis that microvascular dysfunction is the main determinant of heart involvement in SSc patients and starts well before overt pulmonary hypertension.

Systemic sclerosis (scleroderma, SSc) is a systemic disease characterized by vascular lesions, fibrosis, and circulating autoantibodies. A complex interplay between innate and adaptive immunity, and with regard to the latter, between humoral and cellular immunity, is believed to be involved in SSc pathogenesis. Lately, close attention has been paid to the role of B cells which, once activated, release profibrotic cytokines, promote profibrotic Th2 differentiation, and produce autoantibodies. Several novel interesting autoantibodies, targeting antigens within the extracellular matrix or on the cell surface, rather than the nuclear antigens of canonical SSc-autoantibodies, have been recently described in patients with SSc. As they show stimulatory or inhibitory activity or react with structures involved in the pathogenesis of SSc lesions, they can be considered as potentially pathogenic. In this paper, we will review those which have been better characterized.

Importance: The minimal clinically important difference (MCID) in a patient-reported outcome measure (PROM) is the smallest change that patients perceive as beneficial. Accurate MCIDs are required when PROMs are used to evaluate the value of surgical interventions., Objective: To use well-defined distribution-based and anchor-based methods to calculate MCIDs in the Hip Disability and Osteoarthritis Outcome Score (HOOS) and in the Knee Injury and Osteoarthritis Outcome Score (KOOS) for veterans undergoing primary total hip arthroplasty or total knee arthroplasty., Design, Setting, and Participants: A prospective cohort study was conducted of 858 patients undergoing total joint replacement between March 16, 2015, and March 9, 2017, at 3 high-complexity Veterans Affairs Medical Centers., Interventions: Patients undergoing total hip arthroplasty or total knee arthroplasty were administered HOOS or KOOS PROMs prior to and 1 year after surgery. The Self-Administered Patient Satisfaction Scale (SAPS) for primary hip or knee arthroplasty was administered at 1-year follow-up as an anchor PROM., Main Outcomes and Measures: The HOOS and KOOS before and 1 year after surgery, change scores (difference between postoperative and preoperative PROM scores), and MCIDs for each measure. For anchor-based methods, receiver operating characteristic curve analysis was performed, including calculation of the area under the curve., Results: The mean (SD) age of the 271 patients who underwent hip arthroplasty was 65.6 (8.3) years, and the mean (SD) age of the 587 patients who underwent knee arthroplasty was 66.1 (8.2) years. There were 547 men in the knee arthroplasty cohort and 256 men in the hip arthroplasty cohort (total, 803 men). There were significant improvements in the mean values of every PROM, with mean (SD) differences greater than 39 for HOOS Joint Replacement (JR) and every hip subscale (HOOS JR, 39.7 [20.2]; pain, 47.6 [20.5]; symptoms, 45.1 [21.5]; activities of daily living, 43.7 [22.1]; recreation, 49.2 [33.5]; quality of life, 50.3 [27.8]) and mean (SD) differences greater than 29 for KOOS JR and every knee subscale (KOOS JR, 30.4 [17.5]; pain, 38.0 [20.4]; symptoms, 29.5 [22.1]; activities of daily living, 34.8 [20.5]; recreation, 34.6 [31.1]; quality of life, 35.2 [26.8]). Different calculation methods yielded a wide range of MCIDs. Distribution-based approaches tended to give lower values than the anchor-based approaches, which gave similar values for most PROMs. Area under the curve values demonstrated good to excellent discrimination for SAPS for nearly all PROMs., Conclusions and Relevance: Minimal clinically important difference estimates can be highly variable depending on the method used. Patient satisfaction measured by SAPS is a suitable anchor for the HOOS and KOOS. This study suggests that the SAPS-anchored MCID values presented here be used in future studies of total hip arthroplasty and total knee arthroplasty for veterans.

The design of a smart robot for colonoscopy is challenging because of the limited available space, slippery internal surfaces, and tortuous 3D shape of the human colon. Locomotion forces applied by an endoscopic robot may damage the colonic wall and/or cause pain and discomfort to patients. This study reports a Soft Pneumatic Inchworm Double balloon (SPID) mini-robot for colonoscopy consisting of two balloons connected by a 3 degrees of freedom soft pneumatic actuator. SPID has an external diameter of 18 mm, a total length of 60 mm, and weighs 10 g. The balloons provide anchorage into the colonic wall for a bio-inspired inchworm locomotion. The proposed design reduces the pressure applied to the colonic wall and consequently pain and discomfort during the procedure. The mini-robot has been tested in a deformable plastic colon phantom of similar shape and dimensions to the human anatomy, exhibiting efficient locomotion by its ability to deform and negotiate flexures and bends. The mini-robot is made of elastomer and constructed from 3D printed components, hence with low production costs essential for a disposable device.

Objectives: The aim of our study was to assess the role of videofluorography (VFG) in the evaluation of swallowing and oesophageal peristalsis in patients with systemic sclerosis (SSc)., Methods: From June 2014 to September 2017, 55 consecutive SSc patients, defined according to the 2013 ACR/EULAR classification criteria, underwent VFG study using a remote-controlled digital device. In order to evaluate possible abnormalities, 18 dynamic parameters were chosen, dividing the act of swallowing into three phases: oral, pharyngeal and oesophageal phases. The following dynamic radiological findings were considered: veil motility in phonation, leakage, drooling, salivation and presence of residues in the oral cavity, pharyngeal residues, penetration, aspiration, altered motility of the upper oesophageal sphincter, efficacy of primary peristaltic contractions, oesophageal clearance capacity, reflux, oesophagitis and motility of the lower oesophageal sphincter., Results: The VFG study was well tolerated in all patients. Dysfunctions of oesophageal motility were common and included abnormal motility of UES (12.7%) and LES (76.4%), inadequate primary peristalsis (52.7%), abnormal secondary peristalsis (29.1%) and non-peristaltic contractions (40%). A defective oesophageal clearance was observed in 69.4% of patients. Moreover, most patients presented signs of oesophageal reflux (63.6%), oesophagitis (81.8%) and hiatal hernia (80%). Pharyngeal abnormalities were less common and involved up to 50% of patients. Oesophageal dysfunction and defective clearance were associated with dcSSc and pulmonary involvement., Conclusions: The VFG study is a useful technique for the morphological and functional evaluation of swallowing in SSc patients.

Objective: Arthritis is the most frequent extra-intestinal manifestation in patients with inflammatory bowel diseases (IBD). The coexistence of intestinal and articular inflammation advocates the need for a multidisciplinary management of patients with IBD-associated spondyloarthritis., Methods: Consecutive IBD patients were evaluated jointly by the gastroenterologist and the rheumatologist in a combined clinic. All the patients were assessed and screened for articular involvement, disease activity and health related quality of life. After the prescription of a shared treatment, patients with spondyloarthritis were followed up for 24 months., Results: Two hundred sixty-two IBD patients, including 80 who were classified as affected by spondyloarthritis according to the ASAS criteria, were included in the study. At baseline, patients with both IBD and spondyloarthritis showed worse quality of life in both the physical and mental domains. The multidisciplinary management provided a significant improvement of gastrointestinal and articular manifestations, as well as the health-related quality of life. Moreover, global and gastrointestinal-specific quality of life significantly correlated with articular disease activity., Conclusion: The multidisciplinary management significantly improves both articular and gastrointestinal disease activities and the quality of life of patients with IBD-associated spondyloarthritis. An appropriate screening strategy and the integrated management of these patients should be encouraged and employed in clinical practice., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Natural history and outcomes of patients with pulmonary embolism (PE) without typical symptoms (atypical PE) remain unclear. The aim of the study is to compare the clinical characteristics and the prognosis between typical PE and atypical PE., Methods: We retrospectively analyzed data from consecutive patients admitted to the Emergency Department (ED) because of a diagnosis of PE and classified them in two groups: typical PE and atypical PE. We defined PE to be typical in presence of almost one of the following symptoms or signs: dyspnea, chest pain, hemoptysis or signs of deep vein thrombosis., Results: Of the 191 patients with PE, 154 (81%) had typical PE and 37 (19%) had atypical PE. Patients with atypical and typical PE seemed to had similar prognostic factor such as high risk sPESI (73% vs 65%, p=0.3), right ventricular dysfunction (30% vs 26%, p=0.6) and central PE at chest CT scan (38% vs 36%, p=0.8). The rate of 30 day mortality was 7% in the typical group and 8% in the atypical group (p=0.8). The length of stay in hospital was the same in the two groups (6 days; p=0.2)., Conclusions: We found that atypical and typical PE seem to be related diseases with a similar short term prognosis. Therefore, we could speculate that a missed diagnosis of PE in ED could expose the patients to a worsen prognosis. Further perspective studies are required for better investigate this diagnostic challenge.

Introduction: The cognitive reserve (CR) theory has been proposed to account for the mismatch between the degree of neuropathological changes and clinical outcome in dementias. Recently, it has also been applied to Parkinson's disease (PD) with promising results, but mostly just focusing on separate proxy measures of CR, such as education, working and leisure time activities, instead of adopting a more comprehensive approach. Using the Cognitive Reserve Index questionnaire (CRIq), this study examined the association of CR with motor functions and cognition in patients with medium-low (1-9 years) and medium-high (>9 years) PD duration., Methods: Fifty patients with PD underwent a neurological and a neuropsychological assessment, comprised of: Unified Parkinson's Disease Rating Scale- section III, Mini-Mental State Examination, Clock-Drawing Test, Rey auditory verbal learning test (immediate and delayed recall trials), Digit Span Forward, Corsi Span Forward, Frontal Assessment Battery, Raven's Colored Progressive Matrices, WAIS similarities subtest, Phonemic Fluency, Semantic Fluency and CRIq., Results: PD patients with a higher CRIq score showed a reduced motor impairment and a better global cognitive performance when compared to PD patients with a lower CRIq score, with an advantage especially observed on executive functions and short-term memory. The CR effect was even enhanced in the case of longer disease duration, as observed when considering the overall neuropsychological tests performance and non-verbal abstract reasoning in particular. The results obtained when considering education, as a single proxy measure of CR, provided no additional findings, nor did they reveal all the effects yielded by the adoption of the CRI score., Conclusion: Our results support the beneficial role of CR against motor and cognitive dysfunctions in PD and suggest that its protective role may be mostly manifested at the later stages of the disease. A theoretical framework able to explain the different impact of CR on Alzheimer Disease and PD is discussed. Finally, our results stressed the importance of using a comprehensive measure of CR instead of focusing on just one of its proxies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Shape memory alloys (SMAs) are smart materials used in robotics because of its light weight and high force-to-weight ratio. The low energy efficiency, up to 5%, has limited their use for large actuators. However, they have shown advantages in the design of mini-robots because of the limited volume required for the actuation system. The present study reports the design and construction of a mini compliant joint (MCJ) with a 2 degrees of freedom (DOFs) intersecting axis. The MCJ prototype has a 20 mm external diameter surrounding a cavity of 8 mm, weighs 2 g, is 20 mm high and can perform an angle rotation of 30 ∘ in less than 260 ms. It uses SMA NiTi wires in antagonistic configuration and springs to reduce the energy consumption and minimise heat production. The design methods and experimental results of the manufactured prototype are reported and discussed.

Objective: Use of psychiatric emergency services in emergency departments (EDs) and inpatient psychiatry units contributes substantially to the cost of mental health care. Among patients who utilize psychiatric emergency services, a small percentage ("high utilizers") contributes a disproportionate share of the total cost, yet little is known about the context of care for these patients. This study employed qualitative methods to identify barriers to and facilitators of reducing use of psychiatric emergency services among high utilizers., Methods: Semistructured phone interviews were conducted with 31 directors of mental health services and providers of psychiatric emergency services across 22 Veterans Health Administration medical centers. The Consolidated Framework for Implementation Research was used to guide the interviews to evaluate the context of care for high utilizers. Thematic coding was used to identify barriers to and facilitators of reducing utilization., Results: Barriers emerged at the patient level (for example, treatment nonadherence and transiency), provider level (for example, stigma toward high utilizers and lack of expertise and training in the management of psychiatric issues among ED staff), and system level (for example, lack of specialized services to address short- and long-term care needs). Facilitators included recovery-oriented care; interdisciplinary care coordination and case management, with emphasis on the role of psychiatric social workers; and predictive analytics to flag high utilizers., Conclusions: The findings lay the groundwork for the design of novel approaches to care for high utilizers of psychiatric emergency services while limiting provider burnout, managing costs, and optimizing treatment outcomes.

Cognitive-behavioral treatments for criminogenic thinking (i.e., antisocial cognitions, attitudes, and traits) are regarded as best practices for reducing criminal recidivism among justice-involved adults. However, the barriers and facilitators to implementation of these treatments within large health care systems such as the Veterans Health Administration (VHA) are largely unknown. To address this gap, we conducted qualitative interviews with 22 Specialists from the VHA's Veterans Justice Programs who had been trained in a cognitive-behavioral treatment for criminogenic thinking (i.e., Moral Reconation Therapy [MRT], Thinking for a Change [T4C]). The time-intensiveness of these treatments emerged as a barrier to implementation. Potential solutions identified were patient incentives for treatment engagement, streamlining the curriculum, and implementing the treatments within long-term/residential programs. At the program level, providers' stigma/bias toward patients with antisocial tendencies was seen as a barrier to implementation, as were time/resource constraints on providers. To address the latter, use of peer providers to deliver the treatments and partnerships between justice programs and behavioral health services were suggested. At the system level, lack of recognition of criminogenic treatments as evidence based, and uncertainty of sustained funds to support ongoing costs of these treatments emerged as implementation barriers. To address the latter, a train-the-trainers model was suggested. Our findings serve as a guide for implementation of criminogenic treatments for providers and policymakers in VHA and other large health care systems, which are increasingly called upon to provide care to justice-involved adults in the community. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Background: Immune checkpoint inhibitors are a new promising class of antitumor drugs that have been associated with a number of immune-related Adverse Events (AEs), including musculoskeletal and rheumatic disease., Methods: We searched Medline reviewing reports of musculoskeletal and rheumatic AEs induced by immune checkpoint inhibitors., Results: Several musculoskeletal and rheumatic AEs associated with immune checkpoint inhibitors treatment are reported in the literature. In particular, arthralgia and myalgia were the most common reported AEs, whereas the prevalence of arthritis, myositis and vasculitis is less characterized and mainly reported in case series and case reports. Other occasionally described AEs are sicca syndrome, polymyalgia rheumatica, systemic lupus erythematosus and sarcoidosis., Conclusion: Newly induced musculoskeletal and rheumatic diseases are a frequent adverse event associated with immune checkpoint inhibitors treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Frequent utilization of emergency department (ED) services contributes substantially to the cost of healthcare nationally and is often driven by psychiatric factors. Using national-level data from the Veterans Health Administration (VHA), the present study examined patient-level factors associated with ED use among veteran psychiatric patients. Veterans who had at least one ED visit with a psychiatric diagnosis in fiscal years 2011-2012 (n = 226,122) were identified in VHA administrative records. Andersen's behavioral model of healthcare utilization was used to identify need, enabling, and predisposing factors associated with frequency of ED use (primary outcome) in multivariate regression models. Greater ED use was primarily linked with need (psychotic, anxiety, personality, substance use, and bipolar disorders) and enabling (detoxification-related service utilization and homelessness) factors. Chronic medical conditions, receipt of an opioid prescription, and predisposing factors (e.g., younger age) were also linked to greater ED use; however, the effect sizes for these factors were markedly lower than those of most psychiatric and psychosocial factors. The findings suggest that intensive case management programs aimed reducing frequent ED use among psychiatric patients may require greater emphasis on homelessness and other psychosocial deficits that are common among these patients, and future research should explore cost-effective approaches to implementing these programs.

Myostatin is a novel negative regulator of skeletal muscle mass. Myostatin expression is also found in heart in a much less extent, but it can be upregulated in pathological conditions, such as heart failure. Myostatin may be involved in inhibiting protein synthesis and/or increasing protein degradation in skeletal and cardiac muscles. Herein, we used cell cultures and isolated muscles from rats to determine protein degradation and synthesis. Muscles incubated with myostatin exhibited an increase in proteolysis with an increase of Atrogin-1, MuRF1 and LC3 genes. Extensor digitorum longus muscles and C2C12 myotubes exhibited a reduction in protein turnover. Cardiomyocytes showed an increase in proteolysis by activating autophagy and the ubiquitin proteasome system, and a decrease in protein synthesis by decreasing P70S6K. The effect of myostatin on protein metabolism is related to fiber type composition, which may be associated to the extent of atrophy mediated effect of myostatin on muscle.

The availability and utility of services to address recidivism risk factors among justice-involved veterans is unknown. We explored these issues through qualitative interviews with 63 Specialists from the Department of Veterans Affairs' (VA) Veterans Justice Programs. To guide the interviews, we utilized the Risk-Need-Responsivity (RNR) model of offender rehabilitation. Specialists reported that justice-involved veterans generally have access to services to address most RNR-based risk factors (substance abuse; lack of positive school/work involvement; family/marital dysfunction; lack of prosocial activities/interests), but have less access to services targeting risk factors of antisocial tendencies and associates and empirically-based treatments for recidivism in VA. Peer-based services, motivational interviewing/cognitive-behavioral therapy, and Veterans Treatment Courts were perceived as useful to address multiple risk factors. These findings highlight potential gaps in provision of evidence-based care to address recidivism among justice-involved veterans, as well as promising policy-based solutions that may have widespread impact on reducing recidivism in this population.

Background: In the U.S. Department of Veterans Affairs (VA), residential treatment programs are an important part of the continuum of care for patients with a substance use disorder (SUD). However, a limited number of program-specific measures to identify quality gaps in SUD residential programs exist. This study aimed to: (1) Develop metrics for two pre-admission processes: Wait Time and Engagement While Waiting, and (2) Interview program management and staff about program structures and processes that may contribute to performance on these metrics. The first aim sought to supplement the VA's existing facility-level performance metrics with SUD program-level metrics in order to identify high-value targets for quality improvement. The second aim recognized that not all key processes are reflected in the administrative data, and even when they are, new insight may be gained from viewing these data in the context of day-to-day clinical practice., Methods: VA administrative data from fiscal year 2012 were used to calculate pre-admission metrics for 97 programs (63 SUD Residential Rehabilitation Treatment Programs (SUD RRTPs); 34 Mental Health Residential Rehabilitation Treatment Programs (MH RRTPs) with a SUD track). Interviews were then conducted with management and front-line staff to learn what factors may have contributed to high or low performance, relative to the national average for their program type. We hypothesized that speaking directly to residential program staff may reveal innovative practices, areas for improvement, and factors that may explain system-wide variability in performance., Results: Average wait time for admission was 16 days (SUD RRTPs: 17 days; MH RRTPs with a SUD track: 11 days), with 60% of Veterans waiting longer than 7 days. For these Veterans, engagement while waiting occurred in an average of 54% of the waiting weeks (range 3-100% across programs). Fifty-nine interviews representing 44 programs revealed factors perceived to potentially impact performance in these domains. Efficient screening processes, effective patient flow, and available beds were perceived to facilitate shorter wait times, while lack of beds, poor staffing levels, and lengths of stay of existing patients were thought to lengthen wait times. Accessible outpatient services, strong patient outreach, and strong encouragement of pre-admission outpatient treatment emerged as facilitators of engagement while waiting; poor staffing levels, socioeconomic barriers, and low patient motivation were viewed as barriers., Conclusions: Metrics for pre-admission processes can be helpful for monitoring residential SUD treatment programs. Interviewing program management and staff about drivers of performance metrics can play a complementary role by identifying innovative and other strong practices, as well as high-value targets for quality improvement. Key facilitators of high-performing facilities may offer programs with lower performance useful strategies to improve specific pre-admission processes.

Introduction: Gastrointestinal dysfunction is often described in patients with Parkinson disease (PD), and gastrointestinal symptoms are usually attributed to gastroparesis. The consequent delayed gastric emptying (GE) may be an important pharmacokinetic mechanism underlying some of the response fluctuations that develop after long-term levodopa (L-dopa) therapy.The aim of this prospective study was to assess GE time by a liquid meal scintigraphy, in PD patients, and to correlate them with demographic, clinical, and therapeutic data., Methods: Scintigraphy with radiolabeled albumin nanocolloids added to acidified orange juice was performed in 51 consecutive PD patients 1 hour after their usual dopaminergic therapy first dose and after a 12-hour fast. Demographic, neurologic, gastrointestinal, and pharmacologic data were collected., Results: Fifty-one patients were divided into 2 groups using the cutoff point obtained in normal subjects (40 minutes): group 1 included 29 patients with GE T½ of 27.60 ± 7.30 minutes (normal), group 2 showed a GE T½ of 84.90 ± 53.80 minutes (delayed). The most striking significant difference between the 2 groups was the dopa-decarboxylase inhibitor mean dose that was significantly higher in the group of patients with delayed GE (201.32 ± 97.26 vs 127.65 ± 79.74; P = 0.005)., Conclusions: The impairment of gastric motility, frequently represented in PD patients, occurs in approximately 42% of patients with motor complications. A mechanism that may explain the GE delay is the effect of L-dopa on dopaminergic receptors in the stomach. Therefore, the dosage of dopa-decarboxylase inhibitor, increasing the L-dopa concentration, may contribute to GE delay and its consequent effect on drug delivery and efficacy.

Previous studies have shown that catecholamines in vivo and in vitro inhibit the activity of Ca 2+ -dependent proteolysis in skeletal muscles under basal conditions. In the present study we sought to investigate the role of catecholamines in regulating the Ca 2+ -dependent proteolysis in soleus and extensor digitorum longus (EDL) muscles from rats acutely exposed to cold. Overall proteolysis, the activity of proteolytic systems, protein levels and gene expression of different components of the calpain system were investigated in rats submitted to adrenodemedullation (ADMX) and exposed to cold for 24 h. ADMX drastically reduced plasma epinephrine and promoted an additional increase in the overall proteolysis, which was already increased by cold exposure. The rise in the rate of protein degradation in soleus muscles from adrenodemedullated cold-exposed rats was caused by the high activity of the Ca 2+ -dependent proteolysis, which was associated with the generation of a 145-kDa cleaved α-fodrin fragment, a typical calpain substrate, and lower protein levels and mRNA expression of calpastatin, the endogenous calpain inhibitor. Unlike that observed for soleus muscles, the cold-induced muscle proteolysis in EDL was not affected by ADMX. In isolated soleus muscle, clenbuterol, a selective β 2 -adrenoceptor agonist, reduced the basal Ca 2+ -dependent proteolysis and completely abolished the activation of this pathway by the cholinergic agonist carbachol. These data suggest that catecholamines released from the adrenal medulla inhibit cold-induced protein breakdown in soleus, and this antiproteolytic effect on the Ca 2+ -dependent proteolytic system is apparently mediated through expression of calpastatin, which leads to suppression of calpain activation. NEW & NOTEWORTHY Although many effects of the sympathetic nervous system on muscle physiology are known, the role of catecholamines in skeletal muscle protein metabolism has been scarcely studied. We suggest that catecholamines released from adrenal medulla may be of particular importance for restraining the activation of the Ca 2+ -dependent proteolysis in soleus muscles during acute cold exposure. This finding helps us to understand the adaptive changes that occur in skeletal muscle protein metabolism during cold stress., (Copyright © 2017 the American Physiological Society.)

This study tested the sensitivity and specificity of VE1 antibody raised against BRAFV600E protein, on 189 melanoma samples, compared with molecular testing. In addition, the therapeutic response to BRAF inhibitors was analysed in 27 patients, according to staining intensity (scored from weak to strong) and pattern (homogeneous or heterogeneous). BRAFV600E status during melanoma progression was evaluated in a cohort of 54 patients with at least paired-samples. High sensitivity (98.6%) and specificity (97.7%) of VE1 were confirmed. During melanoma progression different samples showed concordant phenotypes. Heterogeneous VE1 staining was observed in 28.5% of cases, and progression-free survival was higher in patients with tumour samples displaying such staining. These findings suggest that only VE1-negative tumours would be genotyped to detect other BRAFV600 mutations, and that either primary melanoma or metastasis can be tested using immunohistochemistry, according to the material available.

The potential impact of biofilm on healing in acute and chronic wounds is one of the most controversial current issues in wound care. A significant amount of laboratory-based research has been carried out on this topic, however, in 2013 the European Wound Management Association (EWMA) pointed out the lack of guidance for managing biofilms in clinical practice and solicited the need for guidelines and further clinical research. In response to this challenge, the Italian Nursing Wound Healing Society (AISLeC) initiated a project which aimed to achieve consensus among a multidisciplinary and multiprofessional international panel of experts to identify what could be considered part of 'good clinical practice' with respect to the recognition and management of biofilms in acute and chronic wounds. The group followed a systematic approach, developed by the GRADE working group, to define relevant questions and clinical recommendations raised in clinical practice. An independent librarian retrieved and screened approximately 2000 pertinent published papers to produce tables of levels of evidence. After a smaller focus group had a multistep structured discussion, and a formal voting process had been completed, ten therapeutic interventions were identified as being strongly recommendable for clinical practice, while another four recommendations were graded as being 'weak'. The panel subsequently formulated a preliminary statement (although with a weak grade of agreement): 'provided that other causes that prevent optimal wound healing have been ruled out, chronic wounds are chronically infected'. All members of the panel agreed that there is a paucity of reliable, well-conducted clinical trials which have produced clear evidence related to the effects of biofilm presence. In the meantime it was agreed that expert-based guidelines were needed to be developed for the recognition and management of biofilms in wounds and for the best design of future clinical trials. This is a fundamental and urgent task for both laboratory-based scientists and clinicians.

Objectives: Pycnodysostosis is a rare genetic disorder caused by a mutation of the cathepsin K gene involved in bone turnover. It is responsible, in particular, for a combination of dwarfism and bone fragility. Upper airway obstruction may be observed, but associated stridor has never been previously described., Materials and Methods: Single-centre retrospective study over a period of 15 years with review of the literature., Results: Three children (aged 2-18 months) were managed for stridor and obstructive sleep apnoea syndrome confirmed by polysomnography. Physical examination of these children revealed stridor with laryngomalacia, characteristic dysmorphic features and failure to thrive. Patient 1 presented typical laryngomalacia treated by surgical section of the aryepiglottic folds. Patient 2 presented upper airway obstruction with a narrow nasopharynx and long soft palate, treated by surgery and noninvasive ventilation. Patient 3 presented moderate laryngomalacia and nasal obstruction, treated by surgery and noninvasive ventilation., Conclusion: The diagnosis of pycnodysostosis must be considered in the presence of atypical laryngomalacia associated with multifactorial upper airway obstruction, failure to thrive and dysmorphic syndrome. A genetics consultation is essential in these patients., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Consensus recommendations are used to improve the methodology of research about rare disorders, but their uptake is unknown. We studied the uptake of consensus recommendations in steroid-refractory chronic graft-versus-host disease (SR-cGVHD). Although in 2006 the National Institutes of Health (NIH) cGVHD consensus project produced recommendations for clinical trials, guidelines have emphasised the scarcity of valuable evidence for all tested interventions., Methods: We searched Medline (PubMed) between Jan 1, 1998, and Oct 1, 2013, for non-randomised studies of systemic treatment for SR-cGVHD. To measure adherence to NIH recommendations, we applied a 61 item checklist derived from the NIH consensus document. We did a meta-analysis to measure pooled effect size for overall response rate (ORR) and meta-regression analyses to measure the effect of deviations from NIH recommendations on pooled effect size., Findings: We included 82 studies related to nine interventions. Conformity to NIH recommendations was evenly low across the analysed timeframe (1998-2013), and did not change significantly after publication of NIH recommendations. The pooled effect size for ORR for systemic treatment of SR-cGVHD was 0.66 (95% CI 0.62-0.70). Increased adherence to NIH recommendations in a score of items defining correct response assessment was associated with a significant reduction in ORR (-4.2%, 95% CI -6.6 to -1.9; p=0.001). We recorded no significant association between ORR and sets of items related to correct diagnostic definition of SR-cGVHD (change in ORR -3.1%, 95% CI -7.7 to 1.5), specification of primary intervention (0, -3.8 to 3.6), or concomitant treatments (-1.6%, -5.4 to 2.3). The score of items defining correct response assessment increased after publication of NIH recommendations., Interpretation: Our findings show evidence of bias in the reported efficacy of treatment of SR-cGVHD. The overall effect of NIH recommendations in scientific literature is scarce; however, NIH recommendations improved assessment of response, possibly reducing the overestimation bias. Better implementation of NIH recommendations might reduce false expectations about new interventions, and thus prevent clinical studies with ineffective treatments., Funding: None., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Castleman-Kojima disease (TAFRO Syndrome) is characterized by Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, Organomegaly, multiple lymphadenopathy and histopathology pattern of atypical Castleman's disease (CD). Only few cases of this recently identified unique variant of Multicentric CD (MCD) are described in literature, all Japanese. It therefore poses serious diagnostic and therapeutic challenges., Case Description: We describe a 21 year old woman with fever, asthenia, bilateral pleural effusion, ascites, hypoalbuminemia, severe thrombocytopenia, anemia, renal failure and proteinuria, whereas microbiological tests, immune serology (except ANA) and bone marrow biopsy were all negative. A CT-scan showed multiple lymphadenopathy and tissue samplings of mediastinal lymph nodes was compatible with a mixed-type CD. The diagnosis of MCD with TAFRO syndrome was made, but after an initial improvement with high dose corticosteroid therapy, clinical and laboratory features worsened. Based upon the high serum IL-6 levels and the high number of CD20-lymphocytes in lymph nodes tissue, we started tocilizumab (partial benefit), followed by rituximab combined with CVP (cyclophosphamide, vincristine and prednisone) chemotherapy, achieving a complete response. A total of six cycles of R-CVP were administered monthly, followed by maintenance with monthly rituximab. A complete remission persists at the 12th month of follow-up., Conclusions: In patients with massive immune system activation and lymphadenopathy it is mandatory to rule out Castleman-Kojima disease. In our patient a therapy aimed at the prominent pathophysiological abnormalities has been successful so far. However, since the rarity of TAFRO Syndrome, a multicenter registry is strongly desirable for a better understanding of the disease mechanisms, hopefully leading to evidence-based therapeutic choices.

Background: Recent reports suggest increased frequency of peripheral neuropathy (PN) in Parkinson's disease (PD) patients on levodopa compared with age-matched controls particularly during continuous levodopa delivery by intestinal infusion (CLDII). The aim of this study is to compare frequency, clinical features, and outcome of PN in PD patients undergoing different therapeutic regimens., Methods: Three groups of consecutive PD patients, 50 on intestinal levodopa (CLDII), 50 on oral levodopa (O-LD) and 50 on other dopaminergic treatment (ODT), were enrolled in this study to assess frequency of PN using clinical and neurophysiological parameters. A biochemical study of all PN patients was performed., Results: Frequency of PN of no evident cause was 28% in CLDII, 20% in O-LD, and 6% in ODT patients. Clinically, 71% of CLDII patients and all O-LD and ODT PN patients displayed a subacute sensory PN. In contrast, 29% of CLDII patients presented acute motor PN. Levodopa daily dose, vitamin B12 (VB12) and homocysteine (hcy) levels differed significantly in patients with PN compared to patients without PN., Conclusions: Our findings support the relationship between levodopa and PN and confirm that an imbalance in VB12/hcy may be a key pathogenic factor. We suggest two different, possibly overlapping mechanisms of PN in patients on CDLII: axonal degeneration due to vitamin deficiency and inflammatory damage. Whether inflammatory damage is triggered by vitamin deficiency and/or by modifications in the intestinal micro-environment should be further explored. Proper vitamin supplementation may prevent peripheral damage in most cases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Although it is well established that carbohydrate and lipid metabolism are profoundly altered by cold stress, the effects of short-term cold exposure on protein metabolism in skeletal muscle are still poorly understood. Because cold acclimation requires that an organism adjust its metabolic flux, and muscle amino acids may be an important energy source for heat production, we hypothesize that muscle proteolysis is increased and protein synthesis is decreased under such a stress condition. Herein, cold exposure for 24 h decreased rates of protein synthesis and increased overall proteolysis in both soleus and extensor digitorum longus (EDL) muscles, but it did not affect muscle weight. An increase in proteolysis was accompanied by hyperactivity of the ubiquitin-proteasome system (UPS) in both soleus and EDL, and Ca(2+)-dependent proteolysis in EDL. Furthermore, muscles of rats exposed to cold showed increased mRNA and protein levels of atrogin-1 and muscle RING finger enzyme-1 (MuRF1). Additionally, cold stress reduced phosphorylation of Akt and Forkhead box class O1 (FoxO1), a well-known effect that increases FoxO translocation to the nucleus and leads to activation of proteolysis. Plasma insulin levels were lower, whereas catecholamines, corticosterone, and thyroid hormones were higher in cold-exposed rats compared with control rats. The present data provide the first direct evidence that short-term cold exposure for 24 h decreases rates of protein synthesis and increases the UPS and Ca(2+)-dependent proteolytic processes, and increases expression of atrogin-1 and MuRF1 in skeletal muscles of young rats. The activation of atrophy induced by acute cold stress seems to be mediated at least in part through the inactivation of Akt/FoxO signaling and activation of AMP-activated protein kinase.

The bioinspired approach has been key in combining the disciplines of robotics with neuroscience in an effective and promising fashion. Indeed, certain aspects in the field of neuroscience, such as goal-directed locomotion and behaviour selection, can be validated through robotic artefacts. In particular, swimming is a functionally important behaviour where neuromuscular structures, neural control architecture and operation can be replicated artificially following models from biology and neuroscience. In this article, we present a biomimetic system inspired by the lamprey, an early vertebrate that locomotes using anguilliform swimming. The artefact possesses extra- and proprioceptive sensory receptors, muscle-like actuation, distributed embedded control and a vision system. Experiments on optimised swimming and on goal-directed locomotion are reported, as well as the assessment of the performance of the system, which shows high energy efficiency and adaptive behaviour. While the focus is on providing a robotic platform for testing biological models, the reported system can also be of major relevance for the development of engineering system applications.