Clinical significance of the anti-Nucleolar Organizer Region 90 antibodies (NOR90) in systemic sclerosis: Analysis of the European Scleroderma Trials and Research (EUSTAR) cohort and a systematic literature review.

BACKGROUND: The anti-Nucleolar Organizer Region 90 antibodies (NOR90) are rare antinuclear antibodies (ANA) reported in systemic sclerosis (SSc). Especially due to low prevalence, the clinical relevance of NOR90 in SSc remains uncertain. OBJECTIVES: To analyze the clinical associations of NOR90 in patients with SSc in a multicentric cohort. METHODS: Post-hoc, cross-sectional study of prospectively collected data from the European Scleroderma Trials and Research (EUSTAR) database, with additional information on NOR90. Further, we performed a systematic literature search, using the terms "systemic sclerosis" and "NOR90" across three databases: Medline via PubMed, Scopus, and Thomson Reuters' Web of Science Core Collection, from inception to November 1st, 2023. RESULTS: Overall, 1318 patients with SSc were included (mean age 58.3 ± 13.7 years, 81.3 % female), of whom 44 (3.3 %) were positive for NOR90. Of these, 32 were also positive for one of the SSc-criteria antibodies: 9/44 (20.5 %) for anti-topoisomerase I, 18/42 (42.9 %) for anti-centromere, and 5/40 (12.5 %) for anti-RNA polymerase III. NOR90-positive patients were more frequently female, had lower modified Rodnan skin score (mRSS), and lower prevalence of upper and lower gastrointestinal (GI) symptoms compared to NOR90-negative patients. In multivariable analysis, NOR90 remained significantly associated with lower mRSS and less frequent GI symptoms. The literature search identified 17 articles, including a total number of 87 NOR90-positive out of 3357 SSc patients, corresponding to an overall prevalence of 2.6 %. CONCLUSION: To our best knowledge, this is the largest SSc cohort tested for NOR90 to date, confirming the NOR90 prevalence in SSc patients is around 3 %.

Contextual determinants influencing the implementation of fall prevention in the community: a scoping review.

Background: Successful implementation of multifactorial fall prevention interventions (FPIs) is essential to reduce increasing fall rates in community-dwelling older adults. However, implementation often fails due to the complex context of the community involving multiple stakeholders within and across settings, sectors, and organizations. As there is a need for a better understanding of the occurring context-related challenges, the current scoping review purposes to identify what contextual determinants (i.e., barriers and facilitators) influence the implementation of FPIs in the community. Methods: A scoping review was performed using the Arksey and O'Malley framework. First, electronic databases (Pubmed, CINAHL, SPORTDiscus, PsycINFO) were searched. Studies that identified contextual determinants that influence the implementation of FPIs in the community were included. Second, to both validate the findings from the literature and identify complementary determinants, health and social care professionals were consulted during consensus meetings (CMs) in four districts in the region of Utrecht, the Netherlands. Data were analyzed following a directed qualitative content analysis approach, according to the 39 constructs of the Consolidated Framework for Implementation Research. Results: Fourteen relevant studies were included and 35 health and social care professionals (such as general practitioners, practice nurses, and physical therapists) were consulted during four CMs. Directed qualitative content analysis of the included studies yielded determinants within 35 unique constructs operating as barriers and/or facilitators. The majority of the constructs (n = 21) were identified in both the studies and CMs, such as "networks and communications", "formally appointed internal implementation leaders", "available resources" and "patient needs and resources". The other constructs (n = 14) were identified only in the . Discussion: Findings in this review show that a wide array of contextual determinants are essential in achieving successful implementation of FPIs in the community. However, some determinants are considered important to address, regardless of the context where the implementation occurs. Such as accounting for time constraints and financial limitations, and considering the needs of older adults. Also, broad cross-sector collaboration and coordination are required in multifactorial FPIs. Additional context analysis is always an essential part of implementation efforts, as contexts may differ greatly, requiring a locally tailored approach.

Health-related quality-of-life trajectories during/after surgery and adjuvant chemotherapy in patients with colon cancer.

PURPOSE: This study aims to evaluate quality of life trajectory during the first year after surgical treatment in patients with resectable primary colon cancer. METHODS: Patients with resectable primary colon cancer diagnosed between 2013 and 2019 who received surgical treatment and adjuvant chemotherapy if indicated were selected from the Prospective Dutch ColoRectal Cancer cohort study (PLCRC). Health-related quality of life (HR-QoL) was assessed using EORTC-QLQ-C30 questionnaire before surgery, and three and twelve months after surgery. HR-QoL scores varied between 0 and 100 and outcomes were compared according to age (< 70 years, ≥ 70 years), comorbidity (yes, no) and treatment type (adjuvant chemotherapy, surgical treatment only). The extent of resilience, defined as a recovery of HR-QoL to baseline level after a clinically relevant decline in HR-QoL at months, was calculated twelve months post-surgery. RESULTS: For all 458 patients, the mean age was 66.4 years (SD 9.5), 40% were aged 70 years and older and 68% were men. Baseline level of HR-QoL summary score was relatively high with a mean of 87.9 (SD 11.5), and did not significantly differ between older and younger patients. The strongest decline of HR-QoL compared to baseline was observed at three months with a gradual recovery over time. Fourteen percent of all patients were non-resilient or showed a late decline at twelve months post-surgery. Compared to younger patients, older patients who received adjuvant chemotherapy were less resilient (respectively, 53 and 32%, p = 0.07) and at risk of a late decline in HR-QoL 1 year post-surgery (respectively, 3% versus 16%, p = 0.02). Comorbidity status had no significant impact on the HR-QoL trajectory. CONCLUSION: Colon cancer treatment was associated with a decline in HR-QoL three months post-surgery, but most patients return to baseline level within twelve months. Still, particularly older patients who received adjuvant chemotherapy were less resilient and at risk of a late decline in HR-QoL. These data could help in patients counselling regarding colon cancer treatment.

[Electroencephalography and connectivity in delirium]. / Eeg en innovatieve behandeling van verminderde hersenconnectiviteit bij delirium.

BACKGROUND: Delirium is associated with neurophysiological changes that can be identified with quantitative EEG analysis techniques (qEEG). AIM: To provide an overview of studies on neurophysiological changes in delirium using various qEEG analysis techniques. METHOD: Literature review. RESULTS: In delirium, there is an increase in delta and theta activity but a decrease in activity in the alpha frequency band. Additionally, there is a decrease in functional connectivity and efficiency of the brain network in the alpha frequency band. CONCLUSION: Delirium is characterized by diffuse slowing of the EEG, reduced functional connectivity, and decreased efficiency of the brain network. Improved functional connectivity could be a new approach to treat delirium.

Case report: A successful second autologous hematopoietic stem cell transplantation in refractory systemic sclerosis, with positive effect on skin involvement, pulmonary function and microcirculation.

Background: Systemic sclerosis (SSc) is a complex autoimmune disease characterized by inflammation, vasculopathy and fibrosis of the skin and internal organs. Treatment with autologous hematopoietic cell transplantation (HCT) for progressive SSc has improved overall and event-free survival rates significantly, but unfortunately disease progression after HCT is seen in a subset of patients. Data on the efficacy and safety of second HCT is scarce. Case: We present a patient with diffuse cutaneous SSc and associated interstitial lung disease (ILD) who successfully underwent a second HCT for progressive disease five years after a first HCT. We describe changes in skin involvement and pulmonary involvement as well as the changes observed in sequential nailfold microcapillaroscopy (NCM), performed from first presentation up to this moment. Conclusion: This case adds to the current limited literature on efficacy and safety of a second HCT in SSc refractory cases. Furthermore it outlines the potential of HCT on amelioration of microvasculopathy in SSc.

Right atrial and ventricular strain detects subclinical changes in right ventricular function in precapillary pulmonary hypertension.

Right ventricular (RV) ejection fraction (EF) by cardiac magnetic resonance (CMR) correlates to outcome in precapillary pulmonary hypertension (pPH) patients, but is insensitive to early changes. Strain might provide incremental information. In this study, we compare right atrial (RA) and RV strain in pPH patients to healthy controls, and evaluate the prognostic value of strain in pPH. In this cross-sectional study, 45 pPH patients and 20 healthy controls underwent CMR, and feature-tracking derived RA and RV strain were evaluated. pPH patients had impaired RA reservoir and conduit strain, and RV longitudinal strain (LS), compared to healthy controls. In pPH patients with preserved RVEF (≥ 50%, n = 18), RA reservoir (35% ± 9 vs. 41% ± 6, p = 0.02) and conduit strain (16% ± 8 vs. 23% ± 5, p = 0.004), and RV-LS (-25% ± 4 vs. -31% ± 4, p < 0.001) remained impaired, compared to healthy controls. The association of strain with the primary endpoint (combination of all-cause death, lung transplantation, and heart failure hospitalization) was evaluated using a multivariable Cox regression model. RV-LS (HR 1.18, 95%-CI 1.04-1.34, p = 0.01) and RA strain (reservoir: HR 0.87, 95%-CI 0.80-0.94, p = 0.001; conduit: HR 0.85, 95%-CI 0.75-0.97, p = 0.02, booster: HR 0.81, 95%-CI 0.71-0.92, p = 0.001) were independent predictors of outcome, beyond clinical and imaging features. In conclusion, pPH patients have impaired RA strain and RV-LS, even when RVEF is preserved. In addition, RA strain and RV-LS were independent predictors of adverse prognosis. These results emphasize the incremental value of RA and RV strain analyses, to detect alterations in RV function, even before RVEF declines.

Physical therapy in patients with systemic sclerosis: physical therapists' perspectives on current delivery and educational needs.

OBJECTIVE: To assess the perspectives of physical therapists treating patients with systemic sclerosis (SSc) on their current practice and educational needs. METHOD: In July 2019, 405 SSc patients attending a multidisciplinary SSc programme received a survey on physical therapy. Patients who indicated having received physical therapy in the past 2 years were asked to invite their treating physical therapist to complete a questionnaire including sociodemographic characteristics, referral process, content of treatment, perceived knowledge and skills, and educational needs (mostly yes/no answers). RESULTS: Forty-eight of 80 possibly eligible physical therapists treating SSc patients returned the questionnaire [median age 44 years (interquartile range 35-58); 52% female; median number of SSc patients currently treated: 1 (range 1-4)]. Eighty-one per cent (n = 39) of physical therapists had received a referral, with 69% (n = 27/39) judging its content as insufficient. The most often provided types of exercises were range of motion (96%), muscle-strengthening (85%), and aerobic (71%) exercises, followed by hand (42%) and mouth (10%) exercises. Concerning manual treatment, 65% performed either massage or passive mobilization. Regarding competences, 65% indicated feeling capable of treating SSc patients. Nevertheless, 85% expressed the need for an information website on physical therapy in SSc, and 77% for postgraduate education on SSc. CONCLUSION: Primary care physical therapists treating patients with SSc used a wide range of treatment modalities. Although most stated that they treated very few patients, the majority felt capable of treating SSc patients. Nevertheless, the large majority expressed a need for additional information and educational activities concerning SSc.

Change of the microvascularization in systemic sclerosis, a matter of air.

Systemic sclerosis (SSc) is a rare complex disease, characterized by microvascular damage, auto-immunity, and fibrosis. Nailfold capillary microscopy (NCM), a safe and noninvasive imaging technique, can be used to visualize specific microvascular alterations in SSc. In this review, we discuss an interesting case of a patient with changes in microvascular pattern on NCM after pulmonary transplantation. We provide an overview of microvascular alterations in systemic sclerosis and the evidence in the literature about the effect of vasoactive and immunomodulation therapy on these vascular changes. We also outline the influence of pulmonal pathology, such as interstitial lung disease and pulmonary arterial hypertension, on the capillaroscopic pattern, and finally, we discuss how NCM could possibly serve as a biomarker of treatment.

Study objectives in clinical trials in older patients with solid malignancies: do we measure what matters?

PURPOSE: We set out to determine study objectives of clinical trials which included older patients with the four most common malignancies, to assess the extent to which the inclusion of patient-related outcomes (PROs) has changed over the last fifteen years. METHOD: A search of the National Institutes of Health clinical trial registry was performed to identify currently recruiting or completed phase II or III clinical trials started between 2005 and 2020, which addressed chemotherapy or immunotherapy in patients aged > 65 years with the four most common solid malignancies. Trial characteristics and study objectives were extracted from the registry website. RESULTS: Compared to disease- and treatment-related outcomes, PROs were the least measured outcomes. Of the 1,663 trials, PROs were addressed in only 21% of all trials, in which quality of life as primary objective was found in less than 1% of all trials. Compared to all trials, trials exclusively for older patients addressed more often PROs (respectively, 30% vs 21%, p < 0.001). Over the last fifteen years, there was an incremental trend in the reporting of PROs from 17 to 24% of all trials (p = 0.007). CONCLUSION: Despite a slight incremental trend over the past 15 years, PROs appear to be underrepresented in clinical trials which include patients with a solid malignancy. In order to provide physicians and older patients with cancer realistic information about the impact of chemo- or immunotherapy on quality of life or functioning, researchers should strongly consider including PROs in their future clinical trials.

Treatment patterns and primary reasons for adjusted treatment in older and younger patients with stage II or III colorectal cancer.

OBJECTIVE: This study aims to assess age-related treatment patterns and primary reasons for adjusted treatment in patients with colorectal cancer. METHODS: Patients with colorectal cancer stage II or III diagnosed between 2015 and 2018 in the Netherlands were eligible for this study. Data were provided by the Netherlands Cancer Registry and included socio-demographics, clinical characteristics, treatment patterns and primary reasons for adjusted treatment. Treatment patterns and reasons for adjusted treatment were analysed according to age groups. RESULTS: Of all 29,620 patients, 30% were aged <65 years (n = 8994), 34% between 65 and 75 years (n = 10,173), 27% between 75 and 85 years (n = 8102) and 8% were ≥85 years (n = 2349). Irrespective of cancer location or stage, older patients received less frequently a combination of surgery and (neo)adjuvant therapy compared to younger patients (decreasing from 55% to 1% in colon cancer patients, and from 71% to 23% in rectal cancer patients aged <65 years and ≥85 years respectively). Omission of surgical treatment increased with age in both patients with colon cancer (ranging from 1% in patients aged <65 years to 16% in those ≥85 years) and rectal cancer (ranging from 12% in patients aged <65 years to 56% in those ≥85 years). The most common reasons for adjusted treatment were patient preference (27%) and functional status (20%), both reasons increased with advancing age. CONCLUSIONS: Guideline non-adherence increased with advancing age and omission of standard treatment was mainly based on patient preference and functional status. These findings provides insight in the treatment decision-making process in patients with colorectal cancer. Future research is necessary to further assess patient's role in the treatment decision-making process.

[The use of telemedicine with frail elderly patients in the Netherlands - experience of caregivers in an outpatient setting]. / Teleconsulten op de polikliniek geriatrie in Nederland ­ ervaringen van zorgverleners.

The use of telemedicine (telephone and video consultations) has increased over the past decades and has grown substantially during the COVID-19 pandemic. Multimorbidity, visual - and hearing impairment, cognitive impairment and lack of technical skills might complicate the use of telemedicine in frail elderly patients. Limited research on this topic is has been performed. The aim of this article is to investigate which elements of care could be performed by telemedicine and what patient characteristics are useful in selecting patients for telemedicine. To get more information about the use of telemedicine in frail elderly patients, an online survey was conducted amongst caregivers working in geriatric outpatient care departments in the Netherlands. 67 caregivers completed the survey. The results indicate there is limited experience in video consultations in this population. The experience so far is mainly positive. Caregivers indicate the following elements of care could be performed by telemedicine: follow-up consultations, taking an (hetero)anamnesis, medication review, conversations with multiple contacts or caregivers and informing about test results. Our advice is to decide in dialogue with patient and caregiver, which form of consultation is feasible, desirable and appropriate for every individual process and consultation.

Prognostic value of screening instrument based on the Dutch national VMS guidelines for older patients in the emergency department.

PURPOSE: It is important to identify which older patients attending the emergency department are at risk of adverse outcomes to introduce preventive interventions. This study aimed to assess the prognostic value of a shortened screening instrument based on the Dutch national Safety Management System [Veiligheidsmanagementsysteem (VMS)] guidelines for adverse outcomes in older emergency department patients. METHODS: A cohort study was performed including patients aged 70 years or older who visited the emergency department. Adverse outcomes included hospital admission, return emergency department visits within 30 days, and 90-day mortality. The prognostic value of the VMS-score was assessed for these adverse events and, in addition, a prediction model was developed for 90-day mortality. RESULTS: A high VMS-score was independently associated with an increased risk of hospital admission [OR 2.26 (95% CI 1.32-3.86)] and 90-day mortality [HR 2.48 (95% CI 1.31-4.71)]. The individual VMS-questions regarding history of delirium and help in activities of daily living were associated with these outcomes as well. A prediction model for 90-day mortality was developed and showed satisfactory calibration and good discrimination [AUC 0.80 (95% CI 0.72-0.87)]. A cut-off point that selected 30% of patients at the highest risk yielded a sensitivity of 67.4%, a specificity of 75.3%, a positive predictive value of 28.5%, and a negative predictive value of 94.1%. CONCLUSION: The shortened VMS-based screening instrument showed to be of good prognostic value for hospitalization and 90-day mortality. The prediction model for mortality showed promising results and will be further validated and optimized.

Intestinal hypomotility in systemic sclerosis: a histological study into the sequence of events.

OBJECTIVES: The pathogenesis of intestinal involvement in systemic sclerosis (SSc) is thought to be a sequential process (vascular, neuronal, and consecutive muscular impairment), but understanding of the underlying histological changes and how they translate to symptoms, is still lacking. Therefore, we systematically investigated histological characteristics of SSc in the intestines, compared to controls. METHODS: Autopsy material from the small bowel and colon was used for histological semiquantitative evaluation of the vasculature, enteric nervous system, interstitial cells of Cajal (ICC), and muscle layers, using a combination of histochemical and immunohistochemical stainings, according to guidelines of the Gastro 2009 International Working Group. RESULTS: Vascular changes were most frequently encountered, represented by intima fibrosis in both arteries and small vessels, and represented by venous dilatation. Second, generalized fibrosis of the circular muscle layer was significantly more found in SSc patients than in controls. Third, reduction of submucosal nerve fibers and myenteric neurons was shown in the colon of four SSc patients, which may explain severe symptoms of intestinal dysmotility. The density of myenteric ICC network was decreased in the small bowel of SSc patients. CONCLUSIONS: The postulated sequential processes of intestinal involvement in SSc could not be supported by our histological evaluation. The interpatient diversity suggests that parallel processes occur, explaining the variety of histological features and clinical symptoms. Key Points • Histological analysis showed vascular changes, fibrosis in the muscularis propria, and reduction of the ENS and ICC network in the intestines of SSc patients. • Pathophysiological mechanisms leading to intestinal dysmotility in SSc may be parallel rather than sequential. • The interpatient diversity suggests parallel pathophysiological processes, explaining the variety of histological features and clinical symptoms.

The outcome of pulmonary hypertension and its association with pulmonary artery dilatation.

BACKGROUND: Pulmonary artery (PA) dilatation is often seen in pulmonary hypertension (PH) and is considered a long-term consequence of elevated pressure. The PA dilates over time and therefore may reflect disease severity and duration. Survival is related to the stage of the disease at the time of diagnosis and therefore PA diameter might be used to predict prognosis. This study evaluates the outcome of patients with pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH) and investigates whether PA diameter at the time of diagnosis is associated with mortality. METHODS: Patients visiting an outpatient clinic of a tertiary centre between 2004 and 2018 with a cardiac catheterisation confirmed diagnosis of PAH or CTEPH and a CT scan available for PA diameter measurement were included. PA diameter and established predictors of survival were collected (New York Heart Association (NYHA) class, N­terminal pro-brain natriuretic peptide (NT-proBNP) level and 6­min walking distance (6MWD)). RESULTS: In total 217 patients were included (69% female, 71% NYHA class ≥III). During a median follow-up of 50 (22-92) months, 54% of the patients died. Overall survival was 87% at 1 year, 70% at 3 years and 58% at 5 years. The mean PA diameter was 34.2 ± 6.2 mm and was not significantly different among all the diagnosis groups. We found a weak correlation between PA diameter and mean PA pressure ( r = 0.23, p < 0.001). Male sex, higher age, shorter 6MWD and higher NT-proBNP level were independently associated with mortality, but PA diameter was not. CONCLUSION: The prognosis of PAH and CTEPH is still poor. Known predictors of survival were confirmed, but PA diameter at diagnosis was not associated with survival in PAH or CTEPH patients.

[Tailored care for elderly patients; the importance of geriatric expertise]. / Zorg op maat voor ouderen.

Treating elderly patients can be challenging. It is very important to carefully weigh the risks and benefits of potential treatments in individual patients. This treatment decision making can be guided by geriatric parameters. With the accumulating evidence on the added value on prediction of outcomes of (comprehensive) geriatric assessment in older patients with intensive treatment options, the question shifts from whether performing a (comprehensive) geriatric assessment is useful, to how to implement this into standard practice in a feasible and effective way. This paper discusses several issues regarding (comprehensive) geriatric assessment in elderly patients, like how to distinguish fit and frail patients and when performing a geriatric screening, geriatric assessment or a comprehensive geriatric assessment.

Reasons for guideline non-adherence in older and younger women with advanced stage ovarian cancer.

OBJECTIVE: This study aims to assess the reasons for guideline non-adherence in women with advanced stage ovarian cancer and whether these reasons differ according to age. METHODS: All women diagnosed with advanced stage ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) IIb-IV, between 2015 and 2018 were selected from the Netherlands Cancer Registry. Treatment patterns and reasons for guideline non-adherence were analyzed according to age groups. RESULTS: 4210 women were included, of whom 34%, 33%, 26%, and 8% were aged <65, 65-75, 75-85, and ≥85 years respectively. With advancing age, less women received guideline-adherent treatment (decreasing from 70% to 2% in women aged <65 and ≥85 years respectively) and more women received best supportive care only (ranging from 4% to 69% in women aged <65 and ≥85 years respectively). The most prevalent reasons for guideline non-adherence differed according to age and included patient preference in older women, and functional status and extent of disease in younger women. CONCLUSIONS: Most older women did not receive guideline-adherent care and patient preference was the most common reason for this decision. This knowledge provides insight in the current treatment decision-making process and highlights the importance of eliciting patient treatment preferences. Further prospective research is necessary to study the underlying motivation for women to decline guideline care and the extent to which shared decision-making influences treatment choice.

TGFß-mediated expression of TGFß-activating integrins in SSc monocytes: disturbed activation of latent TGFß?

INTRODUCTION: The pathophysiology of systemic sclerosis (SSc) is closely linked to overactive TGFß signaling. TGFß is produced and circulates in latent form, making its activation crucial for signaling. This activation can be mediated via integrins. We investigated the balance between active and latent TGFß in serum of SSc patients and investigated if this correlates with integrin expression on monocytes. METHODS: A TGFß/SMAD3- or BMP/SMAD1/5-luciferase reporter construct was expressed in primary human skin fibroblasts. Both acidified and non-acidified sera of ten SSc patients and ten healthy controls were tested on these cells to determine total and active TGFß and BMP levels respectively. A pan-specific TGFß1/2/3 neutralizing antibody was used to confirm TGFß signaling. Monocytes of 20 SSc patients were isolated using CD14+ positive selection, and integrin gene expression was measured using qPCR. Integrin expression was modulated using rhTGFß1 or a small molecule inhibitor of TGFBR1: SB-505124. RESULTS: SSc sera induced 50% less SMAD3-reporter activity than control sera. Serum acidification increased reporter activity, but a difference between healthy control and SSc serum was no longer observed, indicating that total TGFß levels were not different. Addition of a pan-specific TGFß1/2/3 neutralizing antibody fully inhibited SMAD3-reporter activity of both acidified and not-acidified control and SSc sera. Both HC and SSc sera induced similar SMAD1/5-reporter activity, and acidification increased this, but not differently between groups. Interestingly, expression of two integrin alpha subunits ITGA5 and ITGAV was significantly reduced in monocytes obtained from SSc patients. Furthermore, ITGB3, ITGB5, and ITGB8 expression was also reduced in SSc monocytes. Stimulation of monocytes with TGFß1 induced ITGA5 and ITGAV but lowered ITGB8 expression, whereas the use of the TGFß receptor inhibitor SB-505124 had the opposite effect. CONCLUSION: Total TGFß serum levels are not different between SSc patients and controls, but TGFß activity is. This coincides with a reduced expression of TGFß-activating integrins in monocytes of SSc patients. Because TGFß regulates expression of these integrins in monocytes, a negative feedback mechanism possibly underlies these observations.

Altered microbial community structure and metabolism in cow's milk allergic mice treated with oral immunotherapy and fructo-oligosaccharides.

Previously, we showed enhanced efficacy of oral immunotherapy (OIT) using fructo-oligosaccharides (FOS, prebiotics) added to the diet of cow's milk allergic mice indicated by a reduction in clinical symptoms and mast cell degranulation. Prebiotics are fermented by gut bacteria, affecting both bacterial composition and availability of metabolites (i.e. short-chain fatty acids (SCFA)). It is thus far unknown which microbial alterations are involved in successful outcomes of OIT with prebiotic supplementation for the treatment of food allergy. To explore potential changes in the microbiota composition and availability of SCFA induced by OIT+FOS. C3H/HeOuJ mice were sensitised and received OIT with or without a FOS supplemented diet. After three weeks, faecal samples were collected to analyse gut microbiota composition using 16S rRNA sequencing. SCFA concentrations were determined in cecum content. FOS supplementation in sensitised mice changed the overall microbial community structure in faecal samples compared to sensitised mice fed the control diet (P=0.03). In contrast, a high level of resemblance in bacterial community structure was observed between the non-sensitised control mice and the OIT+FOS treated mice. OIT mice showed an increased relative abundance of the dysbiosis-associated phylum Proteobacteria compared to the OIT+FOS mice. FOS supplementation increased the relative abundance of genus Allobaculum (Firmicutes), putative butyrate-producing bacteria. OIT+FOS reduced the abundances of the genera's unclassified Rikenellaceae (Bacteroidetes, putative pro-inflammatory bacteria) and unclassified Clostridiales (Firmicutes) compared to sensitised controls and increased the abundance of Lactobacillus (Firmicutes, putative beneficial bacteria) compared to FOS. OIT+FOS mice had increased butyric acid and propionic acid concentrations. OIT+FOS induced a microbial profile closely linked to non-allergic mice and increased concentrations of butyric acid and propionic acid. Future research should confirm whether there is a causal relationship between microbial modulation and the reduction in acute allergic symptoms induced by OIT+FOS.

The association between chronic kidney disease, falls, and fractures: a systematic review and meta-analysis.

Patients with chronic kidney disease (CKD) are more likely to experience falls and fractures due to renal osteodystrophy and the high prevalence of risk factors for falls. However, it is not well established how great the risk is for falls and fractures for the different stages of CKD compared to the general population. The objective of this systematic review and meta-analysis was to assess whether, and in which degree, CKD was associated with falls and fractures in adults. A systematic search in PubMed, Embase, CINAHL, and The Cochrane Library was performed on 7 September 2018. All retrospective, cross-sectional, and longitudinal studies of adults (18 years of older) that studied the association between CKD, fractures, and falls were included. Additional studies were identified by cross-referencing. A total of 39 publications were included, of which two publications assessed three types of outcome and four publications assessed two types of outcome. Ten studies focused on accidental falling; seventeen studies focused on hip, femur, and pelvis fractures; seven studies focused on vertebral fractures; and thirteen studies focused on any type of fracture without further specification. Generally, the risk of fractures increased when kidney function worsened, with the highest risks in the patients with stage 5 CKD or dialysis. This effect was most pronounced for hip fractures and any type of fractures. Furthermore, results on the association between CKD and accidental falling were contradictory. Compared to the general population, fractures are highly prevalent in patients with CKD. Besides more awareness of timely fracture risk assessment, there also should be more focus on fall prevention.