Osteoporosis is the fourth most common chronic disease worldwide. The adoption of preventative measures and effective self-management interventions can help improve bone health. Mobile health  technologies can play a key role in the care and self-management of patients with osteoporosis.This study presents a systematic review and meta-analysis of the currently available mHealth apps targeting osteoporosis self-management, aiming to determine the current status, gaps, and challenges that future research could address, as well as propose appropriate recommendations.A systematic review of all English articles was conducted, in addition to a survey of all apps available in iOS and Android app stores as of May 2021. A comprehensive literature search (2010 to May 2021) of PubMed, Scopus, EBSCO, Web of Science, and IEEE Xplore was conducted. Articles were included if they described apps dedicated to or useful for osteoporosis  delivered on smartphone devices for adults aged ≥18 years. Of the 32 articles, a random effects meta-analysis was performed on 13 (41%) studies of randomized controlled trials, whereas the 19 (59%) remaining studies were only included in the narrative synthesis as they did not provide enough data.g −1.09, 95% CI −1.68 to −0.45) and disability . The posttreatment effect of the digital intervention was significant for physical function  but nonsignificant for well-being , physical activity , anxiety , fatigue , calcium , vitamin D intake , and trabecular score .In total, 3906 unique articles were identified. Of these 3906 articles, 32 (0.81%) articles met the inclusion criteria and were reviewed in depth. The 32 studies comprised 14,235 participants, of whom, on average, 69.5% (n=9893) were female, with a mean age of 49.8 (SD 17.8) years. The app search identified 23 relevant apps for osteoporosis self-management. The meta-analysis revealed that mHealth-supported interventions resulted in a significant reduction in pain (Hedges Osteoporosis apps have the potential to support and improve the management of the disease and its symptoms; they also appear to be valuable tools for patients and health professionals. However, most of the apps that are currently available lack clinically validated evidence of their efficacy and focus on a limited number of symptoms. A more holistic and personalized approach within a cocreation design ecosystem is needed.PROSPERO 2021 CRD42021269399; https://tinyurl.com/2sw454a9 Osteoporosis, or porous bone, is a serious chronic disease in which the density of bones is silently and progressively reduced, resulting in a more porous and fragile structure . This diThe current landscape of a rapidly aging population, accompanied by multiple chronic conditions, presents numerous challenges to optimally supporting the complex needs of this group. Therefore, it is essential to find better and affordable alternatives to hospital and institutional care that can support older adults in their homes rather than moving them to health care providers. The use of health-related mobile apps, or mobile health , has emerged as an important and useful tool for improving health outcomes in chronic disease self-management . Self-maThe number of apps available on the planet exceeds 8 million, of which 60% are available on both Android and iOS app stores . As of 2The motivation behind this systematic review stems from the fact that, to the best of our knowledge, there is no other review so far that explores mHealth apps dedicated to osteoporosis self-management available in both the web-based app market and in the research field. The present systematic review and meta-analysis were undertaken to come up with the identification of the current status of osteoporosis-related mHealth solutions, reveal any lack of functionalities, identify challenges and barriers, and propose recommendations for more personalized and effective remote health care monitoring and interventions. In this way, efforts toward the development and testing of a holistic mobile app to support patients at risk of or with osteoporosis are better informed. Osteoporosis self-management apps with a holistic approach should comprise a wide variety of features, including nutrition, physical exercise, medication, and performance monitoring, in addition to involving a wide spectrum of stakeholders, from rheumatologists to other health care professionals, and requiring patients to be well-informed and to take an active role in their own car, while providing an incentive for physicians to trust, integrate, and implement mHealth apps into their medical practice.Osteoporosis AND Technology OR mHealth OR eHealth OR Remote Care OR Digital health technologies OR smartphone OR mobile phone OR Mobile applications OR app or Self-Management OR Disease management OR Bone health. The titles and abstracts of all records were examined, whereas the full text was screened only for the potentially relevant studies for final inclusion; any duplicates were removed. Table S1 in For this systematic review, published sources were identified by searching PubMed, Scopus, Web of Science, IEEE Xplore, and EBSCO databases. A comprehensive combination of keywords was used to have the maximum possible coverage: The inclusion criteria were original studies or research papers, including people  aged ≥18 years with no mental health conditions. The selected studies evaluated digital health technology, primarily designed to support targeted patient communication, education, diagnosis, real-time monitoring, and empowerment in the form of mobile phone apps supported by other audiovisual technologies. Moreover, we considered studies that use intelligent wireless sensors to capture any critical vital signs to support patients with osteoporosis in the long-term self-management of the disease. We also included studies that proposed a design or framework for mHealth apps targeting patients with osteoporosis. As no mHealth apps dedicated to osteoporosis self-management were found before 2010, only full-text studies published in peer-reviewed journals and in English from January 2010 to May 2021 were included.Studies with participants who had mental disorders were excluded. In addition to studies that did not have full text available, we eliminated reviews, posters, letters, and expert opinion publications. We also did not consider studies with technological interventions not targeting or not useful for osteoporosis self-management, those that had no clear relationship with osteoporosis, those related to other musculoskeletal conditions, or those not useful for osteoporosis. Articles that did not use mobile apps were excluded, in addition to studies that examined social network platforms and services , emails, and the web. In the same context, we excluded studies that did not use any mobile app or use mobile technologies as an auxiliary tool, namely, by sending SMS text messages to engage patients in certain activities or behaviors.osteoporosis, bone health, and fracture in different web-based app stores, including Google Play Store, Apple Store (iTunes), Amazon App store, Samsung Galaxy store, and GetJar. We found 72 apps, among which we selected only apps that were in English, targeted patients with osteoporosis, and focused on health, fitness, nutrition, and health categories. We excluded apps that were in the games and entertainment categories, apps that only recorded users’ data without any feedback, and apps that provided access to magazine conferences or journals. The remaining apps were categorized according to the main features they provide, such as educational content, prediction and assessment tools, and users’ tracking of osteoporosis-related pain and symptoms or both.We searched for The following information was abstracted from each study: sample size, sample age range, app name, app purpose, app operating platform, study design, intervention period, and major outcome indices. Publication bias of randomized controlled trial (RCT) studies was evaluated using the Cochrane risk of bias  tool , whereasThe selection, screening, data abstraction, and quality appraisals were performed by 2 reviewers (GA and LH). Any disagreements between the reviewers were resolved through discussion.g [I2 tests, with high values (I2>50%) indicating high heterogeneity [P<.05 was considered significant in all the analyses. Statistical analyses were performed using random effects models. Moreover, statistical findings from the remaining 59% (19/32) of studies included in the review were narratively interpreted.Data from 41% (13/32) of studies were pooled in a statistical meta-analysis using meta-essential . A randog  effect sg  and I2 togeneity . A 2-taiOn the basis of the features provided by the apps, a scoring system was created for each app from the web-based market and those included from the research field. The selection of the scoring features stemmed from a combination of related theories. In particular, we followed the Technology Acceptance Model , which eThis systematic review was performed based on the recommendations of the PRISMA  statement . The PRIThe literature search yielded 4185 articles, of which 3906 (93.33%) were screened. After removing duplicates and excluding studies on the basis of their titles and abstracts, 3.02% (118/3906) full texts were assessed for eligibility. In the final stage, 74.6% (88/118) of full-text citations did not meet the inclusion criteria. After completely reviewing the corresponding full-text articles, of the 88 articles, the total number of accepted articles was reduced to 32 (36%), of which 13 (41%) were selected for the meta-analysis. A PRISMA flowchart  for the My Osteoporosis Journey. After the development stage, they also presented the testing of their collaboratively designed app with women newly diagnosed with asymptomatic osteoporosis [All selected articles were published in journals over the preceding 8 years (2014-2021), with a notable increase in publications since 2017. The publications comprised feasibility studies -39, desioporosis .As of May 2021, we found 33 relevant apps for osteoporosis. Most of the apps identified were found in Google Play  and Apple stores . Approximately 9% (3/33) of apps were available in the Amazon app store, 3% (1/33) in the GetJar app store, and none in the Galaxy app store.After removing the overlapping apps across stores, 70% (23/33) of unique apps remained B. Among The results of app ranking are presented in My Arthritis, offered more features to assist patients in the management of the disease  of studies were at critical ROB, 13% (2/16) at serious risk, and 6% (1/16) at moderate ROB. Among the 13 RCTs assessed using the Cochrane ROB (version 2.0) tool , 3 (23%)g –0.084, 95% CI –0.461 to 0.293) [g 0.108, 95% CI –0.106 to 0.322) [g 0.06, 95% CI –1.00 to 1.12; Z=0.702; P=.48), with no heterogeneity  of studies measured BMD T score at baseline and after 20 weeks  and 12 mo 0.293) , and a so 0.322) . The oveg –0.229, 95% CI –0.611 to 0.152) [g 0.424, 95% CI 0.101 to 0.749) [g 0.1, 95% CI –4.05 to 4.26; Z=0.32; P=.75), with heterogeneity among the studies  of studies compared the average (µg per day) Vitamin D intake before and after app intervention ,58. TherZ=−1.06; P=.29; Hedges g −0.05, 95% CI −0.59 to 0.50), with no heterogeneity  of studies measured the differences in the average mg per day of calcium intake ,57. The Z=1.78; P=.08; Hedges g 0.09, 95% CI −0.53 to 0.70). There was no heterogeneity between the 2 studies  of studies measured the average number of hours per week of physical activities before and after 15 months  or 9 weeg 1.08, 95% CI −5.09 to 7.25; Z=2.22; P=.03) with heterogeneity  of studies evaluated physical function before and after 4 weeks  or 3 weeg 0.17, 95% CI –0.84 to 2.17; Z=1.05; P=.29), with no heterogeneity  of studies observed changes in well-being from baseline after 12 weeks  and 12 mg –0.29, 95% CI –6.11 to 5.53; Z=–0.635; P=.53), with heterogeneity , or fatigue , with heterogeneity  of studies measured changes in anxiety and fatigue at baseline and after 3 months  or 4 weeg –1.09, 95% CI –1.68 to –0.45; Z=−4.09; P<.001), with heterogeneity  were observed when excluding individual studies from the analysis (Approximately 25% (8/32) of studies recorded pain intensity before and after initiation of the interventions -51,53-55g –0.77, 95% CI –1.59 to 0.05; Z=−2.42; P=.02), with heterogeneity ; Approximately 19% (6/32) of studies evaluated disability ,50,54-56The focus of this review was placed on a systematic examination of the available literature on mHealth technologies and apps that can support the self-management of osteoporosis and decision-making for young and older adults. Although some of these apps showed promising results for the use of mHealth technologies in osteoporosis management, there is a lack of evidence in the research to prove the effectiveness of these apps, as validation studies have not been run on all the included apps.Most  of the analyzed mHealth apps did not conduct premarket prospective multicenter RCTs. This might be because of the elevated cost of the trials and the long time required to recruit patients ,67. In aFrom the scoring system created in Our meta-analysis showed that by using the apps, pain scores were significantly reduced in 25% (8/32) of studies ,53-55,64According to our results, app use had no impact on the physical activity of app users. The meta-analysis also revealed that digital health interventions had no significant impact on the daily intake of calcium and vitamin D or on the BMD trabecular score. It is important to note that patients’ adherence to and compliance with the use of mHealth apps are pivotal in ensuring improved health outcomes and successful intervention programs. Some studies reported a high dropout rate in patients who found the intervention boring, time consuming ,58, or iThe data yielded by the meta-analysis demonstrated that using the app had no significant impact on well-being, anxiety, and fatigue scores. This might be explained by the fact that patients self-reported these outcomes in all the evaluated studies without any validation ,50,54,71A review of apps related to osteoporosis in the web-based marketplace resulted in 23 apps. Most of these apps provided information and education, such as disease definition, common symptoms, and suggested exercises to strengthen the bones and enhance physical activity or instructions on healthy nutrition. In addition, none of these available apps addressed the management of the disease after fracture, although fracture is the main complication of osteoporosis. Although osteoporosis is widespread in society, especially among adults, our findings revealed that the number of people who downloaded these osteoporosis-related apps is very limited, as it can barely reach 1000 downloads. Some of these apps did not report any downloads at all. This also indicates that patients or clinicians are hesitant toward the adoption of these new technologies. Unfortunately, these results revealed the poor contribution of research and development toward the field of mHealth apps designed for osteoporosis management and the untrustworthy content that does not have any strong reference .Information privacy is an important issue in mHealth apps because of the sensitive nature of information gathered from users . All ideOur findings show that only one of the identified studies  used a pThis review shows that mHealth apps that use self-management support principles in primary care have the potential to have a positive effect on the management of chronic diseases. However, there is reluctance in the adoption of these digital technologies in health care. The main obstacles delaying the integration of these technological tools in osteoporosis care could be summarized as (1) weak or no involvement of health care professionals in the design process, (2) reluctance of clinicians who believe that mHealth apps might replace them, (3) lack of reliable tools and strict regulations, (4) privacy and security concerns, (5) data availability and visualization, (6) inconsistent data collection standards, (7) difficulties in acquiring and analyzing data, and (8) low retention rates of participants .To overcome these obstacles, we propose design-related and clinical recommendations for mHealth apps to support patients at risk of or diagnosed with osteoporosis in self-management and involve them in decision-making regarding treatment and intervention options with clinicians. These guidelines are not only limited to apps targeting osteoporosis self-management but can also be applied to any chronic disease self-management app.Before creating an app, we should emphasize the role of end users, including patients and health professionals, in the development process. Users should be involved at various points and levels in the design process to improve their understanding of their needs, requirements, interactions, and appreciations before, during, and after developing the app. This co-design will ensure that the developed app meets end user purposes, leading to more effective results .An enhanced and intelligent version of the mHealth app can perform long-term management of osteoporosis through internet-based coaching using AI and big data analysis. In addition to health care professionals, AI can play an important role in the decision-making process and in the entire self-management process of osteoporosis. Conventional systems used for processing health data are less accurate and lack convergence compared with AI-supported systems . MachineOwing to the significant advances and progress in AI in the past few years, chatbots have been gaining momentum in the eHealth world. Therefore, we believe that a bot framework can be incorporated with virtual reality technology and low-cost Internet of Things to create a user engagement schema for long-term monitoring of osteoporosis, where the patient will be active and maintain an improved quality of life.An innovative technological tool  should offer an integrated platform for informed healthy living indoors or outdoors to assist patients with osteoporosis (or at risk) in different aspects of life, including physical activity, nutrition, medication intake, fall prevention, emotional wellness, and socialization. The design of such tools could include monitoring, combining both passive (via the interaction with smartphone or smartwatch or wearables) and active gathering of data . Then, on the basis of the gathered data, AI-driven data analysis processes could be involved in providing personalized feedback to the patient and informing the related physician, guiding personalized recommendations and interventions for osteoporosis risk assessment . In thismHealth app developers must ensure that collected user data are secured to maintain the integrity, availability, confidentiality, and resilience of the data . SecuritThe success and effectiveness of any mHealth app intervention are directly related to user retention . TherefoConformité Européenne–marked) cases only, prescription of these apps can be envisioned, as a form of digital therapeutics, along with wearable devices to allow remote and real-time health monitoring and care delivery [As patients increasingly turn to mHealth apps and devices, clinicians must consider the value of these apps and embrace them to deliver enhanced care. They should adopt more mHealth technologies in their daily practices or workflows and integrate the data into electronic medical records. However, physicians should refrain from recommending apps that have been created without the involvement of medical experts or appropriate testing validation, especially if claims made by app developers are fraudulent. To ensure that their requirements are met and to deliver better outcomes, physicians should actively participate in the design, development, and testing of these mHealth apps . In validelivery .mHealth apps create a sense of partnership between patients and health care professionals by allowing patients to play a more active role in their health care. Moreover, digital health will improve patients’ engagement with their treatment, something that physicians have previously struggled to do between visits . They aluseful for osteoporosis. As no articles in any other language were identified as eligible, the risk of language bias in our selection was negligible. Regarding other biases in the selection, we were cautious in our selection by selecting all related articles in the fields regardless of their outcomes or study design. Finally, some feasibility and development studies were included with the intention of understanding any novel approaches being tested or developed. Such studies seem promising to achieve potential outcomes; however, as these apps were either not tested or tested but with a relatively small sample size, it is difficult to determine whether such solutions can be adopted in the mainstream.Despite this in-depth analysis, some limitations can be identified in this review. In particular, we refrained from excluding studies based on certain quality criteria, such as study design or sample size, which resulted in large variations in the measurements of outcomes. Moreover, there is a lack of apps that only target osteoporosis; therefore, we included apps that we thought were Given the identified lack of effective mHealth apps with a holistic approach to osteoporosis self-management, this review holds the potential to bridge this gap by proposing a technological tool that goes beyond apps that simply provide information about osteoporosis and creates an individualized care management plan that goes beyond clinical measures. The latter perspective extends the view of mHealth apps from the initial focus on promoting specific behavior, such as healthy nutrition, physical activity, or adherence to medications, to patients’ engagement and empowerment. Moreover, it strengthens collaboration between patients and caregivers by not limiting it to health institutions. In view of the vast quantity of mHealth apps available, it is important for app developers and researchers to identify the proper needs of patients with osteoporosis, adopting a cocreation strategy to create more patient-centered and effective disease management solutions.


Immune checkpoint inhibitors (ICIs) affect immunologic homeostasis, leading to immune-related adverse events (irAEs). Early irAE detection and management can prevent significant morbidity and mortality. A retrospective chart review was performed to characterize irAEs associated with nivolumab, ipilimumab, and nivolumab plus ipilimumab in adult medical oncology patients in Nova Scotia Health-Central Zone from 2013–2020, and to describe adherence to toxicity management guidelines. Diarrhea/colitis, hepatitis, pneumonitis, nephrotoxicity, and cardiotoxicity were studied. Of 129 charts reviewed, 67 patients (51.9%) experienced at least one irAE for a total of 98 irAEs and a 1.5% fatality rate. Of these irAEs, 33.7% led to an emergency room visit. Patients were admitted to hospital and steroids were used in 24.5% and 35.7% of cases, respectively. In 17.3% of irAEs, ICIs were permanently discontinued. In 20.4% of irAEs, ICIs were held, and patients were monitored; while in 18.4%, ICIs were held until the irAE was Grade 0–1 (and until steroids were tapered). Almost 47% of irAEs were managed according to guidelines (14.3% were not), and 38.8% had no documented management. Patients receiving immunotherapy frequently experience irAEs with half of irAEs having documented management adhering to guidelines. As immunotherapy indications expand, it is important to ensure irAEs are documented and managed appropriately. In the past several years, the field of oncology has evolved rapidly. While traditional cytotoxic chemotherapy and targeted medications continue to be used, treatment options for many cancers now include immunotherapy agents, or immune checkpoint inhibitors (ICIs). By blocking checkpoint proteins, ICIs allow the immune system cells (T cells) to better identify and destroy cancerous cells . Drugs iSystematic reviews (SRs) and meta-analyses of randomized controlled trials (RCTs) have shown an increased risk of irAEs with CTLA-4, PD-1, and PD-L1 inhibitors versus non-immunotherapy control treatments ,3,4. HypIn addition to information about irAEs from clinical trials, there has been interest in characterizing incidence and severity in real-world populations ,13,14. AEarly detection and management of irAEs are necessary to prevent significant morbidity and mortality . CommonlWith mild irAEs, treatment with ICIs can usually continue, and increased monitoring may be recommended . HoweverWhile irAEs are well-characterized in clinical trials and with observational data, there is insufficient literature on whether real-world management of these irAEs adheres to clinical practice guidelines. A retrospective observational study of patients with a confirmed diagnosis of stage III/IV melanoma, treated with ipilimumab 3 mg/kg every three weeks, aimed to report on the management and outcomes of the irAE colitis (diarrhea) . AlthougIn this study, it was hypothesized that the increasing use of ICIs in oncology patients in Nova Scotia Health-Central Zone (NSH-CZ) has led to irAEs that require proper characterization, early detection, and appropriate management. By characterizing these toxicities and their management in a real-world setting, opportunities for quality improvement and to enhance patient care can be identified. As studies have shown a higher risk of adverse events with anti-PD-1 agents  in combination with anti-CTLA-4 agents  ,9,10,11,A retrospective chart review of the medical oncology pharmacy department and electronic records, at a single center, the Victoria General Hospital, was performed to characterize irAEs  associated with nivolumab, ipilimumab, and the nivolumab plus ipilimumab combination. The irAEs reviewed were diarrhea/colitis, hepatitis, pneumonitis, nephrotoxicity, and cardiotoxicity. Due to the difficulty in ascertaining the exact cause of an adverse event in some cases , irAEs were categorized as ‘definitely’, ‘probably’, or ‘possibly’ based on clinical evidence and/or physician documentation. The chart review analyzed how these irAEs were managed and whether this management adhered to current guidelines ,16,17,18n = 1). Patients receiving immunotherapy agents in combination with chemotherapy or targeted therapy were excluded due to the potential for overlap in toxicity profiles that could confound results. Patients receiving immunotherapy as part of a clinical trial or as compassionate supply outside of a PSP were also excluded.Participants were identified using two lists that are maintained by the pharmacy department: (1) the Department of Health and Wellness New Cancer Drug Fund approvals list and (2) the list of patients who have received an ICI as part of a pharmaceutical company-sponsored patient support program (PSP). Adult medical oncology patients (≥18 years of age) with an NSH-CZ postal code who had received at least one dose of nivolumab, ipilimumab, or the nivolumab plus ipilimumab combination for cancer treatment at the Victoria General Hospital were selected for this study. Patients must have received the ICI through a PSP or with funding from the Department of Health and Wellness, between 1 January 2010 and 31 December 2020. Patients who switched from another ICI to these agents were also included in the study (The primary outcomes were to (a) categorize irAEs  associated with nivolumab, ipilimumab, or nivolumab plus ipilimumab by organ, grade and likelihood and (b) compare the management of irAEs to current ICI toxicity management guidelines.Medical and electronic records were utilized to characterize irAEs. Data collected included sex, age, and time to and cause of death (if applicable). Immunotherapy-related data collection included ICI drug name, dose, cycle frequency, number of cycles of treatment, indication (cancer diagnosis), emergency room visit, and/or hospital admission for irAE (if applicable), and time to and cause of ICI discontinuation (where applicable). Time to first documentation of irAE (from the first cycle) was also collected. Grading and management of irAEs for data collection were based on a compilation of available guidelines ,16,17,18Descriptive statistics were utilized for the characterization of irAEs. Immune-related adverse events were categorized into ‘definitely’, ‘probably’, or ‘possibly’. The number of irAEs was aggregated by organ/system and by severity grade. Frequency and percentages were used for categorical variables . Means and standard deviations were utilized for continuous variables . The median and interquartile ranges were used for the number of cycles, time to death, time to discontinuation, and time to first documentation of irAE (from the first dose of ICI). Analysis of toxicity management and guideline adherence was descriptive. Management of ‘clinically relevant’ irAEs (≥grade 2) was also reviewed. Fatality rates were calculated as the number of fatal events divided by the total number of patients who received ICIs. Only fatal events that were thought to be due to the irAEs of interest were included in the fatality rate. Microsoft Excel was utilized for data collection and statistical analyses.A total of 242 patients were identified who received nivolumab, ipilimumab, or nivolumab plus ipilimumab for cancer treatment . Of thosA total of 51.9% (67/129) of patients experienced at least one new irAE for a total of 98 irAEs. Of the 98 irAEs, 25.5% were ‘definitely’, 8.2% ‘probably’, and 66.3% ‘possibly’ caused by the ICI(s). There were 42 new irAEs in the nivolumab plus ipilimumab group, 48 in the nivolumab group, and 8 in the ipilimumab group . There wOverall, 33.7% (33/98) of the new irAEs led to an ER visit. There were 52.4% (22/42) ER visits in the nivolumab plus ipilimumab group, 20.8% (10/48) in the nivolumab group, and 12.5% (1/8) in the ipilimumab group . In patiOf 129 patients, 68 (52.7%) discontinued therapy and 57 (44.2%) died during the study period . Drug inManagement of irAEs was in accordance with guidelines in 46.9% of cases, not in accordance with guidelines in 14.3% of cases and 38.8% had no documented management . Many ofWhen reviewing irAEs managed prior to and after guideline publication (2017), it was identified that 10 of 98 irAEs were documented from 2013–2016. Of these 10 irAEs, seven were managed according to guidelines, one was not, and two had no documented management. For irAEs documented from 2017 onwards, 44.3% (39/88) were managed according to guidelines, 14.8% (13/88) were not, and 40.9% (36/88) had no documented management.Of the 45 clinically relevant irAEs (≥grade 2), 10 (22.2%) were not managed according to guidelines. In seven of these 10 cases, therapy was continued despite guideline suggestions to hold or discontinue therapy. In two cases, therapy was held but steroids were not started, and/or regular monitoring was not completed as per guidelines. In one case, management at grade 2 was not initiated and the irAE progressed to grade 3. Of these 10 irAEs, seven were grade 2, one was grade 3, and two were characterized as grade 4. Two of these patients died; however, in both cases, the cause of death was documented as disease progression.Immune checkpoint inhibitor use is increasing throughout cancer care. Therefore, there is a greater need to better understand and manage irAEs with ICIs in the real world due to the high risk of morbidity and mortality with these events. Literature has shown that ICIs used in combination, such as nivolumab plus ipilimumab, increase the risk for adverse events ,9,10,11.To our knowledge, this is the first study to include guideline adherence as an outcome and to report the proportion of irAEs that were managed according to guidelines. This study provides insight into real-world irAE management guideline adherence, with 14.3% of all irAEs and 22.2% of clinically relevant irAEs not managed according to guidelines. Of these clinically relevant irAEs, two patients died during the study period; however, these deaths were documented as due to disease progression. Almost 40% of all irAEs and 8.9% of clinically relevant irAEs (≥grade 2) had no documented management. Reasons for a lack of documentation may be related to the grade of irAEs: most were grade 1 and may have been monitored/managed without official documentation as part of the patient record. In support of this idea, when only clinically relevant irAEs were reviewed, there were fewer cases where documentation was lacking.Despite an overall lack of evidence for how to best manage toxicities, guidelines ,16,17,18Further, the data about the potential impact of corticosteroids on the efficacy of ICI therapy is mixed, and some data suggest that patients who are receiving corticosteroids as management for irAEs may have worse outcomes from a cancer perspective . This maWith time and experience, we have come to understand that the immunomodulatory cause underlying different irAEs may vary. For instance, some irAEs, including myocarditis and toxic epidermal necrolysis, have been recognized as arising when T-cells react to antigens in healthy tissue, while other irAEs including colitis and arthritis develop via cytokine-mediated mechanisms. Other irAEs occur in the setting of antibody-mediated inflammation, including several immune-mediated neurologic conditions and bullous pemphigoid ,25. IndeProgress has been made in this direction in large part with the engagement of subspecialists who are experts in the body system in which the irAE arises. For example, several irAE management guidelines in subspecialty literature outside oncology have already been published: gastroenterology , dermatoAs an observational, retrospective study, this study is limited in design and prone to biases associated with retrospective studies. Inconsistent documentation and the inability of the paper and electronic medical records to capture all data  also limit the results. There was a focus on irAE characterization in patients with cancer receiving nivolumab plus ipilimumab, nivolumab or ipilimumab in NSH-CZ. The decision to only review these agents, and therefore, omitting all other ICIs and their indications, may have skewed results, in terms of both the patients being treated and individual differences in practice between different oncologists. Despite this, there were no other CTLA4 inhibitors in use in NSH-CZ outside of clinical trials, and data suggests similar rates of irAEs for all anti-PD-1/PD-L1 inhibitors. Additionally, different prescribers may manage irAEs differently, and these results may, therefore, not be reflective of irAE management by all oncology prescribers. Similarly, the decision to only review five of the most common irAEs may have limited findings. Patients were excluded if they received therapy in satellite chemotherapy units and analysis was limited to patients being treated and followed at NSH-CZ, which is a university-affiliated academic center where management would have been overseen presumably by a medical oncologist. Patients treated in the community have more care provided by general practitioners in oncology (GPOs) who have a different experience and skill set, and hence these results may be less generalizable outside of the academic center. Categorization of irAEs as ‘definitely’, ‘probably’, or ‘possibly’ was also difficult to ascertain at times . Where possible, this was controlled by utilizing clinical evidence and team members’ clinical expertise to categorize irAEs. Furthermore, this study was not designed to complete statistical analyses or comparisons. Therefore, no statistical inferences can be made from the results. Finally, the earliest patients included were treated at the advent of ICI therapy, at the beginning of the learning curve for recognition and management of irAEs. Indeed, the guidelines used to gauge adherence to recommended irAE management in this study were all published later than the earliest patients were treated, and with each iteration of irAE management guidelines, recommendations are becoming more refined as more data is available to inform their content.This study focused on irAE characterization in patients with cancer receiving nivolumab plus ipilimumab, nivolumab, or ipilimumab at a single center. The results of this study can be utilized to increase patient safety, improve patient outcomes, and increase patients’ quality of life through increasing awareness, and thus better detection and management of irAEs. In the next five years, ICI use is likely to increase, and therefore better detection and management of irAEs are required. Knowledge gaps with regards to clinical irAE management currently exist, with oncology guidelines based on clinical trial protocols and consensus. Researchers may consider data from future real-world studies for organ system-specific irAE management. Further research can expand to include other commonly used ICIs such as pembrolizumab as well as irAEs that affect other organ systems  to provide further insight into the incidence of these irAEs and their management in NSH-CZ. Future interventions to improve irAE management and documentation may include system-specific standardized order sets outlining how to manage each irAE, as well as pharmacists working in multidisciplinary clinics and being involved in irAE management and documentation. It will also be important to analyze the impact of such interventions on patient care. Including data from patients treated outside of the academic center may also offer unique and interesting insights and increase the generalizability of the results. Additionally, more quality assurance research could be done prospectively to inform best practice for utilizing broad and site-specific guidelines.


Socioeconomic factors have been consistently associated with suicide, and economic recessions are linked to rising suicide rates. However, evidence on the impact of socioeconomic interventions to reduce suicide rates is limited. This study investigates the association of the world’s largest conditional cash transfer programme with suicide rates in a cohort of half of the Brazilian population.p < 0.001) and 10.7  per 100,000 individuals, respectively. BFP beneficiaries had a lower suicide rate than nonbeneficiaries . This association was stronger among women , and individuals aged between 25 and 59 . Study limitations include a lack of control for previous mental disorders and access to means of suicide, and the possible under-registration of suicide cases due to stigma.We used data from the 100 Million Brazilian Cohort, covering a 12-year period (2004 to 2015). It comprises socioeconomic and demographic information on 114,008,317 individuals, linked to the “Bolsa Família” programme (BFP) payroll database, and nationwide death registration data. BFP was implemented by the Brazilian government in 2004. We estimated the association of BFP using inverse probability of treatment weighting, estimating the weights for BFP beneficiaries (weight = 1) and nonbeneficiaries by the inverse probability of receiving treatment (weight = E(ps)/(1-E(ps))). We used an average treatment effect on the treated (ATT) estimator and fitted Poisson models to estimate the incidence rate ratios (IRRs) for suicide associated with BFP experience. At the cohort baseline, BFP beneficiaries were younger (median age 27.4 versus 35.4), had higher unemployment rates (56% versus 32%), a lower level of education, resided in rural areas, and experienced worse household conditions. There were 36,742 suicide cases among the 76,532,158 individuals aged 10 years, or older, followed for 489,500,000 person-years at risk. Suicide rates among beneficiaries and nonbeneficiaries were 5.4  pandemic. In a quasi-experimental study, Daiane Borges Machado and colleagues investigate the association between rates of suicide and the Bolsa Familia cash transfer program in the 100 Million Brazilian Cohort. Suicide is a serious global public health problem and ranks in the top 20 leading causes of death worldwide.Socioeconomic factors have been consistently associated with suicide, but there is limited evidence on the impact of socioeconomic interventions to reduce suicide rate.This study investigates the association of the world’s largest conditional cash transfer programme on suicide rates in a cohort comprising half of the Brazilian population.We observed that beneficiaries of the cash transfer program had a lower suicide rate than nonbeneficiaries, and that this association was stronger among women and individuals aged between 25 and 59.Targeting social determinants using cash transfer programmes could be important in limiting suicide, which is predicted to rise with the economic recession consequent to the COVID-19 pandemic and war in Ukraine. Suicide is a serious global public health problem. It is among the top 20 leading causes of death worldwide, with approximately 800,000 deaths per year globally. Suicide causes more deaths than malaria, breast cancer, war, or homicide . The ageThere is growing evidence that economic recessions lead to a rise in suicide rates in various countries –6, incluThe Coronavirus Disease 2019 (COVID-19) pandemic is expected to lead to a severe global recession, increasing poverty, and resulting in massive unemployment worldwide , with poSocial and economic factors, such as poverty, economic uncertainty, unemployment, and income inequality, have been consistently associated with increased suicide rates –17, inclIn 2004, Brazil implemented one of the largest poverty alleviation programmes in the world—the “Bolsa Família” programme (BFP), a conditional cash transfer (CCT). By 2015, approximately 46 million people had benefited from the programme . It has Brazil’s continental size, and the availability of data, create a unique opportunity to investigate the association of a CCT programme with suicide, and other relevant health outcomes ,27. BaseThis study had a quasi-experimental design, comparing a group who participated in a cash transfer intervention with those who did not. We utilised linked Brazilian administrative data from the 100 Million Brazilian Cohort, covering a 12-year period (2004 to 2015); this data is stored at the Centre for Data and Knowledge Integration for Health (CIDACS/FIOCRUZ) . Data afThe 100 Million Brazilian Cohort is an open cohort that links data from a number of national databases ,29. The The cohort baseline ,27,29 coWith over 12 years in the cohort, most eligible individuals registered on CadÚnico received the benefit within a short period following registration. Therefore, in order to achieve a fair comparison group , we defined BFP experience depending on whether the individual started receiving the benefit within 6 months of registration. We considered the comparison group (unexposed to the intervention) as individuals who had applied in the same year, with similar characteristics, but did not receive BFP within 6 months, and stopped following them when they started receiving the benefit. Further details are provided below.BFP, the Brazilian CCT programme, is the flagship and largest socioeconomic programme implemented in 2004. It forms part of the Brazilian government initiative to eradicate extreme poverty.BFP implementation has enabled 22.2 million Brazilian people to overcome extreme poverty. In February 2014, 14 million Brazilian families were receiving benefits, to which BRL 2.1 billion has been invested .This programme has much stricter eligibility criteria, and is designed as a subset of CadÚnico eligible families. In 2014, BFP eligibility criteria (unlike CadÚnico) was a monthly per capita income of under BRL 70.00, or less than BRL 140.00 in cases where there was a child, adolescent, or pregnant woman in the family. In the same year, the benefit was BRL 70.00 per month, equivalent to 9% of the Brazilian minimum wage  see Sup. BFP recIn order to estimate suicide rates, cause-specific mortality data (for the baseline people who died during the study period) was collected from the Brazilian Ministry of Health’s Mortality Information System . SuicideWe estimated suicide rates among those who were BFP beneficiaries and nonbeneficiaries, overall, by sex and age groups, using the person-year as the denominator between 2004 and 2015.Linkage was performed by a team of statisticians and information technology professionals in a security-controlled environment at CIDACS/FIOCRUZ. The analysis of linkage accuracy included manual verification and assessing the receiver operating characteristic (ROC) curve . DetailsFor the current study, and other similar studies ,27,35, BSince BFP was only implemented in 2004, individuals registered on CadÚnico before 2004 were considered as first registered to benefit from social programmes on 1 January 2004. For those not benefiting from BFP, follow-up began on: the CadÚnico registration date (A), or 1 January 2004, if registered before that time (B), and follow-up ended either on the individual’s death by any cause (C), when they became a BFP beneficiary (D), or on 31 December 2015 (E), if C and D were not satisfied.For beneficiary individuals, follow-up began when they started to receive BFP benefits (within 6 months) and ended on: the individual’s death by any cause (C), when the beneficiary stopped receiving BFP benefits (F), or on 31 December 2015 (E), if C and F were not satisfied. The contribution of each individual’s person-years was calculated by subtracting the start date from the end of follow-up expressed in years.p-values, and were performed using STATA version 15.0. We fitted Poisson models to estimate IRRs for suicide associated with BFP experience, unadjusted and adjusted for age (as a continuous variable), sex, education level , unemployment, living alone, location of residence , and household characteristics, as a proxy for socioeconomic status  and year of registration on the cohort baseline [All analyses used an alpha of 0.05, and 2-sided baseline ,38–41. Cbaseline ,27. We iWe estimated the association of BFP using inverse probability of treatment weighting (IPTW) . IPTW usThe following analyses were performed to assess the robustness of the results: (A) We performed propensity score matching (PSM) analyses to investigate possible biases due to differences between the intervention and control group  . See SupThis study was approved by the 2 research ethics committees of the (i) Federal University of Bahia (registration no. 1023107) and (ii) London School of Hygiene & Tropical Medicine (registration no. 11581) , had higher unemployment rates (56% versus 32%), a lower level of education, resided in rural areas, and experienced worse household conditions . In the p < 0.001) and 10.7  per 100,000 individuals in the original cohorts, and 5.5  and 11.1  in the matched cohort (p < 0.001)  .p < 0.001) and 5.1  per 100,000 individuals in the original cohorts, and 2.1  and 5.6  in the matched cohort. It was also more prominent among individuals aged 25 to 59, with a suicide rate of 6.6  among beneficiaries, and 12.34  among nonbeneficiaries per 100,000 individuals in the original cohorts, and 6.8  and 13.42  in the matched cohort (p < 0.001), and individuals aged 25 to 59 , followed by younger individuals, aged 10 to 24   .p < 0.001) and adjusted Poisson models estimated a 56% lower suicide rate . PS matching generated similar estimates to the primary analysis, with rates 61% lower  among beneficiaries (p < 0.001)  .The study results consistently found that lower suicide rates occurred in the group of BFP beneficiaries, when compared to nonbeneficiaries. The association remained strong following adjustment for other measured variables, and after generating a propensity score-matched cohort. BFP was associated with 56% lower suicide rates, and all of the sensitivity tests showed similar results. To the best of our knowledge, our study is the first using individual-level data to show that a large-scale cash transfer programme is associated with lower suicide rates.There has been a growing awareness that social and economic factors play a role in determining suicide ,38–41. AIt is plausible that BFP could help to prevent suicide, since poverty is directly related to factors that can lead to suicide, such as unemployment, financial strain, family instability, or violence, as well as a greater predisposition to mental disorders, such as alcoholism and depression ,39,46–50Poverty may also be a barrier to accessing goods, resources, and services  contributing to the feeling of social injustice generated from inequities ,51. CashWe have demonstrated the potential public impact of targeting a social determinant, such as poverty, to prevent a phenomenon that has been studied as an exclusively psychiatric matter. When interpersonal problems, psychological, or psychiatric factors are added to socioeconomic stressors, it can make life much harder, especially in low- and middle-income countries, where a large proportion of the population struggles to have their basic needs met. It could also indicate that in these settings, targeting social determinants through a cash transfer programme may have more potential to prevent suicide at the population level than an exclusively clinical approach. Furthermore, our results indicate the need to perform further investigation of the potential of such programmes to help prevent suicide, for example, studies trying to understand the mechanisms and investigating the potential of using a combination of programmes to try to prevent suicide.Priorities in the suicide prevention field should be urgently established, since the current pandemic has increased economic instability, making many people more vulnerable to mental health problems –54, inclThe overall response to the COVID-19 crisis should consider suicide prevention measures .The 100 Million Brazilian Cohort  has a wiIncome is the main eligibility criteria for BFP and, as a consequence, may be more susceptible to manipulation. Therefore, instead of using self-declared income as a covariate, we included proxy variables that may represent income in Brazil . However, this approach limited the possibility of using the income variable to run regression discontinuity design (RDD) models. Proxies can sometimes introduce errors to the estimations, but our results remained similar in all of the models, when included and not included.An added concern is that suicide can be under-registered, due to stigma ,20,56. HSuicide is a complex multicausal phenomenon and, therefore, many other variables could influence the event, such as previous mental disorders, and access to means of suicide. Although measuring all of these variables would not be feasible in a large study such as this, there is no strong reason to believe that these factors would occur differently among the beneficiary and nonbeneficiary groups.Unmeasured confounders in observational studies could result in biased effect estimates. However, we performed several sensitivity analyses and subgroups analysis to handle uncontrolled confounding. We obtained similar results in standard Poisson models, using next neighbour matching, and kernel matching suggests there is a low chance that bias was introduced from our sampling and/or matching. In addition, we ran models for BFP participation in the original cohort (before matching), and the results were similar .We have stratified our analysis by sex and age groups. For additional studies, stratifying among diverse race groups, and by Brazilian regions, could also answer whether more vulnerable groups and poorer regions would have stronger effects. Future studies could also analyse pathways to identify potential mediators that may make BFP associated with a lower risk of suicide and the long-term effectiveness.Cash transfer programmes mitigate extreme poverty and provide improvements to the beneficiaries’ well-being, potentially protecting individuals from becoming a victim of suicide. Other countries with a similar economic status as Brazil can potentially benefit from introducing similar measures to reduce suicides. These findings convey important considerations for designing and implementing suicide prevention strategies at the population level. They are especially important in the ensuing financial recession, in which rising unemployment levels and suicide rates are predicted to increase.S1 RECORD Checklist(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.S3 Text(DOCX)Click here for additional data file.S4 Text(DOCX)Click here for additional data file.S5 Text(DOCX)Click here for additional data file.S6 Text(DOCX)Click here for additional data file.S7 Text(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S2 FigDistribution of the PS in the sample with no missing data (A), in the sample accounting for missing data (B). BFP, Bolsa Família programme; PS, propensity score.(DOCX)Click here for additional data file.S3 FigBFP, Bolsa Família programme; H, Health; MH, Mental Health.(DOCX)Click here for additional data file.


In recent decades, many studies on mouth breathing (MB) have been published; however, little is known about many aspects of this syndrome, including severity, impact on physical and academic performances.Compare the physical performance in a six minutes walk test (6MWT) and the academic performance of MB and nasal-breathing (NB) children and adolescents.This is a descriptive, cross-sectional, and prospective study with MB and NB children submitted to the 6MWT and scholar performance assessment.We included 156 children, 87 girls (60 NB and 27 MB) and 69 boys (44 NB and 25 MB). Variables were analyzed during the 6MWT: heart rate (HR), respiratory rate, oxygen saturation, distance walked in six minutes and modified Borg scale. All the variables studied were statistically different between groups NB and MB, with the exception of school performance and HR in 6MWT.MB affects physical performance and not the academic performance, we noticed a changed pattern in the 6MWT in the MB group. Since the MBs in our study were classified as non-severe, other studies comparing the academic performance variables and 6MWT are needed to better understand the process of physical and academic performances in MB children. Breathing is a vital function, closely dependent on proper nasal patencyMB consequences may stem from: (i) changes to physiological mechanisms: especially due to local inflammation and allergy; and (ii) facial changes: especially due to congenital anatomical changes. As a consequence of nasal obstruction, there may be reduction in olfactory stimuli, increase in pulmonary hyperresponsiveness, stuffed nose, dry lips, sleepiness, lack of attention, snoring, low physical strength, obstructive sleep apnea syndrome (OSAS), open mouth, crowding teeth, long face, dropped eyes, deep dark circles under the eyes, postural changes, nasal itching and behavioral vices (nervous twitches)There are controversies as to the definition and diagnosis of MB, since mouth-breathing individuals may breathe through their noses in varied degrees, and others, despite breathing through their mouths, may not have anatomical obstruction of their noses. It is paramount to make the etiological diagnosis of MB, especially as to the presence of allergic rhinitis and pharyngeal and palatine tonsil hyperplasiaIn recent decades, there has been a great interest in understanding the ethological and pathophysiological mechanisms involved in MB, with numerous papers published in the national and international scientific literature. On the other hand, very little is known about numerous aspects associated with this syndrome, including its levels of severity and repercussions on athletic and academic performance.With the knowledge acquired by our group from previous studiesWe carried out a cross-sectional, descriptive, prospective study, with a control group, made up of mouth-breathing (MB) and nasal-breathing (NB) children and adolescents, with ages varying between 7 and 11 years. The study was carried out at UNASP (Adventist University Center of São Paulo) Hortolândia campus - IASP with the Basic Education I students, between March of 2010 and April of 2011.The children from both genders had their MB diagnoses carried out by means of a clinical assessment, rhinos-copy, oroscopy and otoscopyPersonal Caprice Sanny ®, São Paulo, São Bernardo, Brazil) and weight . The body mass index (BMI) was calculated utilizing the weight/height2) formula and, posteriorly, compared to the Central Disease Control (2000) for BMI, at the cutting points: malnutrition (< percentile 5); adequate (> percentile 5 and ≤ percentile 85); overweight (> percentile 85 and ≤ percentile 95) and obesity (> percentile 95)We measured their height (Staturometer - 2) and heart rate (HR) - measured by the portable pulse oximeter  and the modified Borg scale (MBS)The 6MWT was carried out according to the standards from the American Thoracic Society (ATS)2 and the MBS with the individual seating down.The children were educated about the 6MWT by means of a previous demonstration. Every minute we told the child about the remaining time for the end of the test and we verbally encouraged the children to continue . After the sixth minutes, the individual was instructed to stop where he/she was, and we measured the distance from the cone all the way to the point the child had stopped, we also measured the RR (respiratory rate), HR, SpOSince the ATS does not establish the minimum time interval for the 6MWT repetition which is not intended for training, we establish a 15-minute rest time. Following that, the same individual was asked to perform the second 6MWTSchool performance was assessed by the summation of the report card grades, obtained during the school year of 2010, divided by the total number of courses taken.This study was approved by the Ethics in Research Committee of the School of Medical Sciences (FCM)/UNICAMP (#1066/2009) and all the parents/guardians signed the Informed Consent Form.The sample power calculation was carried out by the G*Power 3.1.2 software, with a mean sample size effect for the test carried out with the two groups (MB and NB); α= 0.05 and β= 0.80; the sample size was 143 individuals.SAS System for Windows version 9.2 , Microcal Origin, version 5.0  and SPSS vs 17.0  software packages.In the statistical analysis we used the t-Student test by data distribution. The level of significance adopted for the statistical tests was 5%In order to compare proportions, we used the Chi-square test. To compare the continuous or ordering measures or between tests along time, we used the ANOVA variance analysis for repetitive measures with transformation by posts. For multiple comparison purposes, we employed the profile test by contrasts. In comparing the MB and NB groups as far as distance walked is concerned, we used the p = 0.494). The frequency of obesity (BMI ≥ percentile 95) was high in the two groups analyzed - 37 (23.72%) -, without statistically significant differences between the groups (p = 0.105). In the NB group, among the 104 patients, 30 (28.85%) were obese, with BMI ≥ P95; while of the 52 patients in the MB group, seven (15.56%) were obese, with BMI ≥ P95.Our study included 156 children, 104 NB (66.67%) and 52 MB (33.33%). All MB children were classified as not severe . The gender distribution between NB and MB groups was similar. MB incidence was higher among boys - 25 (36.23%) - when compared to girls - 27 (31.03%), with no statistically significant difference (p > 0.05).The following variables: age, grade point average, weight and height were statistically similar for both genders, considering the two groups: NB and MB (p = 0.4632)  . The RR  0.4632) . SpO2 vaond 6MWT . There wond 6MWT .Figure 2p < 0.001). In the second test, the mean value for the 6MWT was, 543.40 m (±79.406 m) and 667.13 m (±90.678 m) for the MB and NB groups, respectively (p < 0.001)  and 667.14 m (±88.979 m), for the MB group and NB (< 0.001) .Figure 5p = 0.372). Just as in the Spearman's linear correlation test, MB first test (p = 0.624) and second test (p = 0.422) and NB in the first test (p = 0.935) and second test (p = 0.738). When we compared the percentages of NB and MB with the best performances, we did not find statistically significant differences between the groups  worst performance - school mean values lower than the median and (ii) better performance - school mean values higher than the median; 57.7% of the patients with MB and 46.2% with NB had the worst school performance) (p = 0.234).The school performance analysis in relation to the 6MWT by the Student's t-test did not show differences between the MB (35.117 ± 2.506) and NB (35.502 ± 2.544) groups  were similar in both groups, which speaks for sample homogeneity, although some studies have found a greater prevalence of anorexia and low weight and height gain in MB children. Other authors have reported weight gain in MB children after surgical removal of the adenoidsConsidering the findings of respiratory mechanics reduction in MB, we deem it is necessary to investigate its repercussion in physical performance. The reduction in respiratory muscle power is triggered by the disorganization of the postural pattern, inadequate use of respiratory muscles and nasal reflex block, which control how deep breathing gets and airway gauge. These factors establish lower pulmonary volumes and capacities, impacting chest expansion and alveolar ventilation, causing a reduction in arterial oxygen pressure, reflecting on exercise tolleranceThe 6MWT is a practical and inexpensive test, able to estimate the submaximal functional capacity in individuals with chronic diseases. It is one of the tests that best mimics daily life activities, being an alternative to maximum exercise tests which, despite being considered gold standard to estimate exercise tolerance, require high cost equipment, specialized personnel and they are difficult to performThe ATS guideline for the 6MWT was created for use with the adult population. There are physical differences between adults and children, which are more complex than anthropometric measures. The physiological characteristics of children and adolescents are in constant change, their systems are under a stage of growth, development and maturation, under the influence of genetics and extrinsic factors: level of physical activity, body composition, nutritional status, socioeconomic status, gender, ethnics, climate and geographic location. Children have a different pattern of change to their bodies when compared to adults, which affects physical performance and may cause physiological changes during physical exerciseWe have noticed that MB children have different values when compared to their NB counterparts, insofar as the 6MWT variables are concerned. The results confirm that the search for simple tests, such as the 6MWT, may be useful to characterize the cardiorespiratory condition of MB children and adolescents. And such fact was confirmed in another study2 and MBS variables in MB and NB groupsAlthough the 6MWT is an instrument utilized to calculate and standardize PD in distinct populationsAccording to the ATS, there are numerous factors which may affect the PD in the 6MWT in a negative way  and, in a positive way In our study, the MB group showed 6PD values near the ones found by Okuro et al.In the literature, only Okuro et al. Used the 6MWT in MB and NB children; however, the MB sample was recruited from a clinic specialized in MB individuals, encompassing individuals with severe MB. In our sample, MB individuals were recruited from a school with non-severe MB We did not find changes in school performance between NB and MB individuals. We believe that this is due to the fact that we analyzed only the average grade of the school report card (information provided by the school), and we were unaware of the grade recovery criterion. Other studies assessing the learning in MB individuals used specific tests. As it happened in our study, the results were not statistically significantThe school performance results between NB and MB, in our study, may be associated with the characteristics of the population analyzed. MB children and adolescents did not have the severity characteristics of those described by Conti et al.As a limitation in our study, we may include the lack of an assessment instrument for a more accurate school performance assessment and comparative analysis with severe MB individuals, which must be further studied in the future.2 and MBS reduction in the second 6MWT test, when compared to the group of NB individuals. Other studies are needed to assess cardiorespiratory, physical and school performance changes in MB children.MB children show a significant increase in RR; SaPOWe would like to thank the physicians and collaborators of the Pediatrics Ward and Pediatrics Department.www.laboratoriomultiusuario.com.br) for their help in statistical data analysis.We would also like to thank the Laboratory of Molecular Genetics (We would like to thank Professor Thatia Regina Bonfim for her support, and all the students, parents, employees and IASP managers.


Monosodium glutamate  is the most widely used food additive in the world for enhancing flavour. The number of flavour-enhancers added to foods is very important for the health of consumers. It has been determined by many researchers that MSG has negative effects on various organs of the body. Since chicken embryos develop without the influence of the maternal organism and allow toxicity to be evaluated very quickly and precisely, they have become a preferred experimental model for investigating the embryotoxic and teratogenic effects of chemicals, toxins, drugs, and numerous food additives and flavour-enhancing agents. This study aimed to investigate the effects of in ovo MSG administration at different doses on the embryonic development of the eye using histological and histometric techniques. The results of the present work have shown that in ovo-administered MSG can adversely affect embryonic eye development.p < 0.05). The total retinal thickness, thickness of the outer nuclear layer (ONL), inner nuclear layer (INL), ganglion cell layer (GL), and nerve fibre layers (NFL), as well as the number of ganglion cells decreased significantly at incubation days 15, 18, and 21 (p < 0.05), and degenerative changes such as vacuolar degeneration and retinal pigment epithelial detachment were also observed. In conclusion, MSG in ovo administration can affect the cornea and distinct layers of retinal cells.MSG is the most ubiquitous food additive in the food industry. The aim of this report was to investigate the effects of in ovo MSG administration on embryonic chicken eye development using histological and histometric methods. A total of 410 fertilized eggs obtained from Babcock Brown laying hens  were used and divided into 5 groups: I (untreated control), II (vehicle control), III (0.12 mg/g egg MSG), IV (0.6 mg/g egg MSG), and V (1.2 mg/g egg MSG), and injections were performed via the egg yolk. At incubation day 15, 18, and 21, 6 embryos from each group were sacrificed by decapitation and pieces of eye tissue were obtained. In all MSG groups, it was determined that both corneal epithelium thickness and total corneal thickness decreased at incubation time points 15, 18, and 21 days compared with the controls ( Monosodium glutamate (MSG) has been used extensively to enhance the flavour of seasonings in the food industry and restaurants. MSG can be found in processed food without an indication on the label, especially to increase the consumption and flavour of processed food such as snack food, chips, sauces, and soups ,2. NaturGlutamate is the primary neurotransmitter stimulant for brain networks and stimulates respective receptors, which have important effects in both physiological and pathological processes . ExcessiThe toxic effects of MSG on the central nervous system, adipose tissue, hepatic tissue, reproductive organs, and liver and kidney functions were determined by several studies ,10,11. TMSG can cause neurotoxicity, neurodegeneration , and neuReports have demonstrated that MSG can be toxic to foetal development, children, and adults . MaternaStudies have shown that exposure to MSG causes significant degenerative effects on the eye and retinal layers ,52,53,54It has been suggested that MSG administration in newborn rats leads to degeneration of retinal ganglion cells, as well as degeneration of the optic nerve ,56. It h3 in a closed cabin. The eggs were divided into 5 groups: Group I , which includes non-treated eggs; Group II , which injected only distilled water; and three MSG-injected groups as Group III , Group IV , and Group V . Embryonic deaths were considered in numbers of eggs per group. The eggs were injected just before starting the incubation period. In the injection groups, the injection sites on the eggs were wiped with 96% ethanol for further disinfection. All injections were performed in egg yolks at the beginning of the incubation period. By drilling a hole on the side of the egg with a special egg driller, the test solution was injected through a sterile insulin injector  and then the hole was sealed with liquid paraffin. Incubations were carried out in an incubator , under optimal conditions (37.5 °C temperature and 65% relative humidity). The eggs were subjected to turning angles of 45 with a turning frequency of 12 times daily.For the experiments, 410 Babcock Brown fertilized eggs (50–55 g) obtained from Babcock Brown laying hens  were examined. The MSG doses were adjusted for 55 g egg weight. MSG  was diluted with sterilized distilled water. MSG doses of 0.12 mg/g, 0.6 mg/g, and 1.2 mg/g egg were prepared and given in a volume of 100 μL. Prior to MSG injection, the eggs were disinfected for 15 min under steam obtained from mixing 21 g of potassium permanganate with 42 mL of formaldehyde/mAt incubation days 15, 18, and 21, 6 embryos from each group were sacrificed by decapitation. The stages of development of the living embryos were determined according to the Hamburger–Hamilton (1951) scale  . Eye tisNext, prepared sections were examined with a Leica DM-2500 model light microscope. Digital images of the required areas were captured using an attached DFC-320 model camera and analysed for histometric measurements. All histometric measurements were performed using the Leica IM50 measurement program  and numerical data of the investigated parameters were obtained.p-value of less than 0.05 was considered statistically significant. Total corneal thickness, corneal epithelial thickness, total retinal thickness, retinal layers thickness, and the number of ganglion cells were evaluated with ANOVA and the Tukey test. This was performed by using SPSS 26 .The collected data were given in mean ± SD. A On day 15 of incubation, the transparent structures that refract and focus light (cornea and lens), muscle structures (iris and ciliary body), retina, pecten oculi, and optic nerve have developed A–D.p < 0.05, It was noted that in the MSG-treated groups, corneal epithelium thickness and total corneal thickness decreased depending on the dose in comparison to untreated and vehicle controls , photoreceptor layer (PR), outer limiting membrane, outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), ganglion cell layer (GL), and nerve fibre layer (NFL) D. In thep < 0.05, On incubation day 18, in MSG-treated groups retinal degenerations such as detachment of the retinal pigment epithelium C,D and vp < 0.05, p < 0.05, In the MSG groups, corneal epithelium and total corneal thickness decreased depending on the dose in comparison with controls  corrected the acceptable daily intake (ADI) for glutamic acid and salts from 120 mg to 30 mg per kilogram of body weight. While the average daily intake of MSG ranges from 0.3 to 0.5 g per day among European Union member countries, the average daily intake of MSG ranges are higher in Asian countries, ranging from 1.6–2.3 g/day in South Korea, 1.5–3.0 g/day in Taiwan, 1.1–1.6 g/day in Japan, and 4 g/day in China ,72. MSG Plasma glutamate concentration has been reported to increase significantly after MSG supplementation in humans . High orChicken embryos are a common model for investigation of embryotoxicity ,85, neurChanges in corneal thickness with age were still unclear in humans and animals. While some studies reported no significant change in corneal thickness over time ,94, othep < 0.05, p < 0.05, p < 0.05, In this study, it was observed that corneal epithelium and total corneal thickness increased considerably from day 15 to day 21 of incubation. In the MSG groups, both corneal epithelium and total corneal thickness significantly decreased depending on the dose on days 15, 18, and 21 of incubation compared with controls, (This study has certain limitations that should be noted. First, it is difficult to calculate the rate of MSG uptake from the yolk sac of the developing embryo; however, it can be argued that this rate is proportional to the rate of embryo development. Moreover, the chicken embryo model has the advantage of allowing potentially hazardous chemicals to be investigated directly on the embryo. On the other hand, the detachments seen in the cornea and retina bring to mind artificial separations in the sections. However, the absence of such detachment in the control groups was evaluated as the effect of MSG.It was observed that different doses of in ovo MSG administration caused histometric and histopathological changes in both the cornea and retina. Since the data obtained from studies using chicken embryos can also be adapted to mammals, the findings of this study suggest that animals and humans exposed to MSG during the prenatal period may have increased susceptibility to certain eye diseases during their lifetime. Given these results, our study adds a new perspective to the literature. Nowadays, while exposure to and/or consumption of MSG in various ways is rapidly and unsafely increasing, it may be advisable to minimize or even prohibit eating foods containing MSG, especially during pregnancy.


Helicobacter pylori (HP) infection and evaluation of gastric functional status. The aim of this study was to evaluate the utility of gastric functional tests to define the acid output, as well as HP status, in order to better direct PPI therapy prescription. Dyspeptic patients without alarm symptoms from a primary care population were evaluated. For each patient, serum Pepsinogen I (PGI) and II (PGII), gastrin 17 (G17) and anti-HP IgG antibodies  were determined. For each subject, data were collected regarding symptoms, past medical history of HP infection, and PPI use. Therapeutic response to PPIs was determined according to PGI and G17 values, where G17 > 7 in the presence of elevated PGI and absence of chronic atrophic gastritis (CAG) was considered an adequate response. Among 2583 dyspeptic patients, 1015/2583 (39.3%) were on PPI therapy for at least 3 months before serum sampling, and were therefore included in the study. Active HP infection and CAG were diagnosed in 206 (20.2%) and 37 (3.6%) patients, respectively. Overall, an adequate therapeutic response to PPIs was observed in 34.9%, reaching 66.7% at the highest dose. However, 41.1% and 20.4% of patients showed low (G17 1-7) or absent (G17 < 1) response to PPI, regardless of the dosage used. According to gastric functional response, most patients currently on PPI maintenance therapy lack a proper indication for continuing this medication, either because acid output is absent (as in CAG) or because gastrin levels fail to rise, indicating absence of gastric acid negative feedback. Lastly, HP eradication is warranted in all patients, and gastric function testing ensures this pathogen is sought for and adequately treated prior to initiating long-term PPI therapy. Inappropriate prescription of proton pump inhibitors (PPI) has been widely reported, often lacking initial exclusion of  Proton pump inhibitors (PPIs) are first-choice drugs for the treatment of acid-related disorders, such as gastroesophageal reflux disease and peptic ulcer disease, due to their ability to effectively inhibit gastric acid secretion. PPI use and ensuing hypochlorhydria are associated with compensatory hypergastrinemia, which, in fact, was one of the initial concerns of long-term therapy .Clostridium difficile, amongst other pathogens, and may contribute to bacterial overgrowth [PPIs are among the most widely prescribed drugs in the world, and their use is continuously increasing, especially for long-term treatment, mainly due to their effectiveness combined with a good safety profile. However, PPIs are being increasingly used in inappropriate scenarios, such as for unregistered indications and cases not in line with the NHS prescription criteria ,3. Inadoergrowth ,12,13. Determination of gastric function, including acid output and infection with HP, are useful tools to guide the clinician in evaluating gastric morphology and function, and represent an invaluable tool to guide prescription and/or suspension of PPIs, when appropriate ,15,16. TThe aim of this study was to evaluate the usefulness and efficacy of PPI therapy using gastric function testing, identifying patients in whom a different therapeutic strategy is warranted, including patients with active HP infection, patients with chronic atrophic gastritis, or patients in whom response to therapy is very low or absent, in terms of G17 elevation. A total number of 2583 of patients undergoing gastric function test were evaluated, 1015 of whom had been on PPI therapy for at least 3 months prior to examination, and thus constituted the study population. Most patients complained of more than one symptom, and symptoms were distributed as follows: 55% of patients complained of pain ; 60.8% of patients complained of reflux; 47.5% of symptoms of maldigestion; and 38.6% of cardiac or ENT  symptoms. The main endoscopic and histological findings are reported in p = 0.0001). Overall, mean values of PGI, PGII, PGI/PGII, G17 and anti-HP IgG were 139.1 μg/L, 12.8 μg/L, 12.4, 11.7 pmol/L and 25.3 EIU, respectively. No statistical differences were observed between genders, with the exception of G17, which was significantly higher in females with respect to males , as shown in A total of 206 patients , were diagnosed with active HP infection and were significantly younger (mean age 49.2 ± 14.7 years) than the 37 patients identified as CAG , with a mean age of 62.9 ± 17.3 (p < 0.001).PGI levels correlated with PPI efficacy, increasing parallel to G17 elevation , as shown in A significant difference regarding response rates was observed between generic and brand drugs  and good specificity (83%) ,25,26,27p = 0.0001). Autoimmune thyroiditis was present in 13.4%, with higher prevalence in women than in men (p = 0.0001); patients who had a previous HP eradication represent 20.4% of the total, with a significant difference between men and women (p = 0.002).As shown above, 18.2% of the patients enrolled in the study were smokers, without a significant difference between males and females; alcohol consumption (at least 1–2 units/day) was reported in 47.5%, and was notably higher in men than women (p = 0.007).Patients with familiarity for gastric cancer were 10.5% and, as expected, there was no difference between sexes. Aspirin therapy was reported in 7.4% of patients, whereas 19.4% of patients reported being on NSAIDs therapy during the 3 months prior to study enrollment  with respect to males on PPI therapy. This observation could respond to a more elevated frequency of PPI prescription in females in general, which has been reported by other researchers. Tosetti et al. found that, in the general practice in a population of Europeans, patients who are more frequently prescribed PPIs are generally older, female, and more frequently diagnosed with gastroesophageal reflux disease, gastric or duodenal ulcers, arthropathy, heart disease, and cancer than the rest of the population [Of note, female gender is significantly overrepresented in the study (62.9%), with a mean age which is significantly higher  or absent (G < 1) response to PPI, regardless of the dosage used. A global response rate of 34.9% can arguably be considered disappointingly low, considering the fact that PPIs are often regarded as efficacious drugs. Notably, in spite of showing lack of response to PPI, 20.4% receive this drug daily, and the proportion of patients with inappropriate PPI prescription rises even more when CAG patients are considered as well. The proportion of patients on half, full, and high dosing is not distributed differently amongst non-responders, intermediate-responders, and responders, suggesting that the response to PPI may be dose-independent. Cytochrome P450 isoenzyme 2C19 genotype differences may account, at least in part, for such variability in response rates that are unrelated to dosing, although this determination may be unfeasible in clinical practice . Other cIn this study, we have found that patients on branded drugs therapy showed a better therapeutic response than patients on generic drugs therapy, which Otten et al. suggest can be due to: (1) biphasic metabolism, where the raised pH in the stomach may prematurely inactivate the PPI, with an unpredictable effect; (2) differences in acid-resistant coating of the generic products; and (3) the influence of multiple dosing of PPIs after several days’ use . The autRegardless of the underlying reason for poor response to PPI, gastric function testing allows its rapid and quantifiable determination, identifying patients who will not benefit from continuation of therapy with the same drug. Furthermore, a possibility that can be explored readily is the switching of drugs, be it from generic to brand, or between generics, or to a different molecule, whenever the first showed no or poor response . GastricThe presence of HP infection could theoretically hamper the Gastropanel’s capacity of quantifying the effectiveness of PPI therapy, by causing an elevation of G17 and PGII, and altering the levels of PGI. However, when the subpopulation of patients with active HP infection were removed from the analysis, results did not vary, and all variables retained their statistical significance. There are some limitations of this retrospective, observational study. The data collection sheet does not allow for specification of whether several types of drugs (either different molecules or different brand/generic drugs) have been used in the same patient. This could partly explain the high percentage of non-responders to therapy; on the other hand, this data probably better expresses what happens in real life, and the use of this serological test has proved to be a very reliable tool in identifying these patients, whether they are non-compliant with therapy, have not received adequate instructions on the correct use of these drugs, or are fast metabolizers. Another limitation lies in the small size of the subgroups of different response categories, which renders the further division into branded vs. generic drugs void of statistical significance. A larger study would be necessary to more accurately establish differences in measured PPI response according to brand vs. generic drugs at the different dosing schemes. Moreover, one of the limits of the present study is the lack of statistically determined cut-off values for G17 determination as a discriminant between no-, low- or adequate-responders, as values were arbitrarily selected. Finally, another limitation of the study is the fact that basal levels of studied parameters , while off PPI therapy, were not obtained. A study including basal levels and comparing them to post-PPI therapy levels would allow for a finer tuning in identifying acid refluxers and establishing possible causes of non-response or low response.This retrospective study considered consecutive patients evaluated in a tertiary hospital in Northeastern Italy from 2015 to 2018 for dyspepsia without alarm symptoms. Records of patients evaluated with gastric function testing were retrieved and matched to histological reports of biopsy samples taken during upper gastrointestinal endoscopy , Esomeprazole , Rabeprazole (Pariet®), and Lansoprazole .PPI use for at least 3 months prior to evaluation. Therapy with PPI included the following generic and brand drugs: Omeprazole ; reflux symptoms ; maldigestion symptoms ; otorhinolaryngological symptoms ; and chest/cardiac symptoms .The inclusion criteria were as follows:-Alarm symptoms or signs as an indication for upper endoscopic and/or gastric functional evaluation, such as weight loss, anemia, presence of bright red blood per rectum, coffee-ground stools, ematochezia, dysphagia, persistent vomiting or vomiting of coffee-ground material or hematemesis, and persistent diarrhea.-History of Zollinger-Ellison syndrome.-Pyloric stenosis.-Previous surgery of the esophagus and/or gastrointestinal tract (except for appendectomy and cholecystectomy).-Malignant gastrointestinal tumors.-Therapy with H2-blockers.Subjects with the following conditions, which may alter gastric function and warrant a different diagnostic approach, were excluded:®, Biohit Oyj, Helsinki, Finland) kit was used based on an enzyme immunoassays quantitative investigation: Enzyme Linked Immunosorbent Assay (ELISA). Detailed information on sample processing is available as A 5 mL of blood sample was drawn from each patient after 12 h of fasting. The sample was centrifuged for 10 min at a 3000-rpm speed. The obtained serum was used for the determination of PGI, PGII, G17 and IgG anti-HP. A specific Biohit , both branded and generic, were considered. Patients were divided into groups according to dosing: half dose, full dose or high dose, as shown in p values were two-tailed with statistical significance indicated by a value of p < 0.05. The Spearman correlation test was used to analyze the association between PGI levels and response to PPI in terms of G17 elevation. All variables with a p > 0.10 were considered for inclusion through a manual forward stepwise variable selection process in a multivariable logistic regression analysis. Statistical analysis was performed with the SPSS statistical software program for Windows (version 20.1). The analysis of the differences between groups in the event of normal data distribution was performed by means of one-way analysis of variance (ANOVA). In the event that the verification of normal data distribution was negative, the Kruskall–Wallis test was used. The study of differences between dichotomous qualitative groups and variables was carried out using Pearson’s chi-square test. Data were expressed as mean ± standard deviation (DS) for qualitative variables and as a percentage of the total for quantitative ones. All This study was conducted in accordance with the Declaration of Helsinki, and approved by the local Ethics committee of the ULSS7 “Pedemontana”, with the protocol number 92687. According to the study protocol, patients who did not give their consent at the time of the gastric function testing were excluded. The low overall PPI response rate suggests that clinicians must come to terms with the fact that a large number of patients with symptoms of presumably upper gastrointestinal nature have actually no connection with excessive acid production, and therefore a need for reassessment of PPI prescription is warranted. This study revealed that the use of a panel composed of four serological markers  is a valid tool to be used as a first-level test to be carried out before undertaking a therapy with PPIs, to evaluate the state of the mucosa, HP infection and, more generally, the prescribing appropriateness of these drugs. Such a strategy may be adopted within the diagnostic algorithms and in prescribing guidelines, avoiding unnecessary and harmful side effects related to PPI therapy or to invasive diagnostic procedures. Nonetheless, the use of pre-emptive gastric function testing may lead to important burden reduction in the healthcare system.