Case-control studies have shown that patients with Crohn’s disease (CD) have a microbial composition different from healthy individuals. Although the causes of CD are unknown, epidemiologic studies ...suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We hypothesized that long-term dietary clusters (DCs) are associated with gut microbiome compositions and gut inflammation. Our objectives were to identify dietary patterns and assess whether they are associated with alterations in specific gut microbial compositions and subclinical levels of gut inflammation in a cohort of healthy first-degree relatives (FDRs) of patients with CD.
As part of the Genetic, Environmental, Microbial (GEM) Project, we recruited a cohort of 2289 healthy FDRs of patients with CD. Individuals provided stool samples and answered a validated food frequency questionnaire reflecting their habitual diet during the year before sample collection. Unsupervised analysis identified 3 dietary and 3 microbial composition clusters.
DC3, resembling the Mediterranean diet, was strongly associated with a defined microbial composition, with an increased abundance of fiber-degrading bacteria, such as Ruminococcus, as well as taxa such as Faecalibacterium. The DC3 diet was also significantly associated with lower levels of subclinical gut inflammation, defined by fecal calprotectin, compared with other dietary patterns. No significant associations were found between individual food items and fecal calprotectin, suggesting that long-term dietary patterns rather than individual food items contribute to subclinical gut inflammation. Additionally, mediation analysis demonstrated that DC3 had a direct effect on subclinical inflammation that was partially mediated by the microbiota.
Overall, these results indicated that Mediterranean-like dietary patterns are associated with microbiome and lower intestinal inflammation. This study will help guide future dietary strategies that affect microbial composition and host gut inflammation to prevent diseases.
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Mediterranean-like dietary pattern was associated with lower level of gut inflammation and alterations in gut bacteria composition in a cohort of healthy individuals at risk of Crohn’s disease.
The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This ...treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up).
In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated.
This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option.
Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The rise in health spending in the United States and the prevalence of multimorbidity-having more than one chronic condition-are interlinked but not well understood. Multimorbidity is believed to ...have an impact on an individual's health spending, but how having one specific additional condition impacts spending is not well established. Moreover, most studies estimating spending for single diseases rarely adjust for multimorbidity. Having more accurate estimates of spending associated with each disease and different combinations could aid policymakers in designing prevention policies to more effectively reduce national health spending. This study explores the relationship between multimorbidity and spending from two distinct perspectives: (1) quantifying spending on different disease combinations; and (2) assessing how spending on a single diseases changes when we consider the contribution of multimorbidity (i.e., additional/reduced spending that could be attributed in the presence of other chronic conditions).
We used data on private claims from Truven Health MarketScan Research Database, with 16,288,894 unique enrollees ages 18 to 64 from the US, and their annual inpatient and outpatient diagnoses and spending from 2018. We selected conditions that have an average duration of greater than one year among all Global Burden of Disease causes. We used penalized linear regression with stochastic gradient descent approach to assess relationship between spending and multimorbidity, including all possible disease combinations with two or three different conditions (dyads and triads) and for each condition after multimorbidity adjustment. We decomposed the change in multimorbidity-adjusted spending by the type of combination (single, dyads, and triads) and multimorbidity disease category. We defined 63 chronic conditions and observed that 56.2% of the study population had at least two chronic conditions. Approximately 60.1% of disease combinations had super-additive spending (e.g., spending for the combination was significantly greater than the sum of the individual diseases), 15.7% had additive spending, and 23.6% had sub-additive spending (e.g., spending for the combination was significantly less than the sum of the individual diseases). Relatively frequent disease combinations (higher observed prevalence) with high estimated spending were combinations that included endocrine, metabolic, blood, and immune disorders (EMBI disorders), chronic kidney disease, anemias, and blood cancers. When looking at multimorbidity-adjusted spending for single diseases, the following had the highest spending per treated patient and were among those with high observed prevalence: chronic kidney disease ($14,376 12,291,16,670), cirrhosis ($6,465 6,090,6,930), ischemic heart disease (IHD)-related heart conditions ($6,029 5,529,6,529), and inflammatory bowel disease ($4,697 4,594,4,813). Relative to unadjusted single-disease spending estimates, 50 conditions had higher spending after adjusting for multimorbidity, 7 had less than 5% difference, and 6 had lower spending after adjustment.
We consistently found chronic kidney disease and IHD to be associated with high spending per treated case, high observed prevalence, and contributing the most to spending when in combination with other chronic conditions. In the midst of a surging health spending globally, and especially in the US, pinpointing high-prevalence, high-spending conditions and disease combinations, as especially conditions that are associated with larger super-additive spending, could help policymakers, insurers, and providers prioritize and design interventions to improve treatment effectiveness and reduce spending.
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Interleukin (IL)‐10‐deficient (IL‐10−/−) mice develop colitis under specific pathogen‐free (SPF) conditions and remain disease free if kept sterile (germ free GF). We used four different protocols ...that varied the time‐points of oral administration of Lactobacillus plantarum 299v (L. plantarum) relative to colonization with SPF bacteria to determine whether L. plantarum could prevent and treat colitis induced by SPF bacteria in IL‐10−/− mice and evaluated the effect of this probiotic organism on mucosal immune activation. Assessment of colitis included blinded histologic scores, measurements of secreted colonic immunoglobulin isotypes, IL‐12 (p40 subunit), and interferon (IFN)‐γ production by anti‐CD3‐stimulated mesenteric lymph node cells. Treating SPF IL‐10−/− mice with L. plantarum attenuated previously established colonic inflammation as manifested by decreased mucosal IL‐12, IFN‐γ, and immunoglobulin G2a levels. Colonizing GF animals with L. plantarum and SPF flora simultaneously had no protective effects. Gnotobiotic IL‐10−/− mice monoassociated with L. plantarum exhibited mild immune system activation but no colitis. Pretreatment of GF mice by colonization with L. plantarum, then exposure to SPF flora and continued probiotic therapy significantly decreased histologic colitis scores. These results demonstrate that L. plantarum can attenuate immune‐mediated colitis and suggest a potential therapeutic role for this agent in clinical inflammatory bowel diseases.
Oral administration of dextran sulfate sodium (DSS) has been reported to induce colitis in mice. The purpose of this study was to determine whether the possible pathogenic mechanism involved the ...acquired immune system.
Normal BALB/c and related C.B17 severe combined immunodeficient mice were fed 5% DSS (40 kilodaltons) in their drinking water for 7 days; controls were fed only water. Colons were scored for histological activity at various times. Cytokine production by cultures of colon and of draining lymph node cell was measured. The effect of DSS on the proliferation of the MCA-38 colonic epithelial cell line was assessed.
DSS feeding resulted in a very reproducible acute distal colitis in both BALB/c and C.B17 severe combined immunodeficient mice. The lesions of BALB/c mice had an increased production of macrophage-derived cytokines, such as interleukin (IL) 1 beta, IL-6, tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor, but not the T-cell cytokines IL-3 or interferon gamma. Draining lymph node cells produced these cytokines plus interferon gamma and IL-3. DSS inhibited MCA-38 cells at doses that would be easily achieved in the distal colon.
Acute DSS-induced colitis does not require the presence of T cells or B cells because it occurred in C.B17 severe combined immunodeficient mice that lack these cells. Its induction may result from a toxicity of DSS for colonic epithelial cells.
A major challenge in monitoring universal health coverage (UHC) is identifying an indicator that can adequately capture the multiple components underlying the UHC initiative. Effective coverage, ...which unites individual and intervention characteristics into a single metric, offers a direct and flexible means to measure health system performance at different levels. We view effective coverage as a relevant and actionable metric for tracking progress towards achieving UHC. In this paper, we review the concept of effective coverage and delineate the three components of the metric - need, use, and quality - using several examples. Further, we explain how the metric can be used for monitoring interventions at both local and global levels. We also discuss the ways that current health information systems can support generating estimates of effective coverage. We conclude by recognizing some of the challenges associated with producing estimates of effective coverage. Despite these challenges, effective coverage is a powerful metric that can provide a more nuanced understanding of whether, and how well, a health system is delivering services to its populations.
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IMPORTANCE: US health care spending has continued to increase and now accounts for 18% of the US economy, although little is known about how spending on each health condition varies by payer, and how ...these amounts have changed over time. OBJECTIVE: To estimate US spending on health care according to 3 types of payers (public insurance including Medicare, Medicaid, and other government programs, private insurance, or out-of-pocket payments) and by health condition, age group, sex, and type of care for 1996 through 2016. DESIGN AND SETTING: Government budgets, insurance claims, facility records, household surveys, and official US records from 1996 through 2016 were collected to estimate spending for 154 health conditions. Spending growth rates (standardized by population size and age group) were calculated for each type of payer and health condition. EXPOSURES: Ambulatory care, inpatient care, nursing care facility stay, emergency department care, dental care, and purchase of prescribed pharmaceuticals in a retail setting. MAIN OUTCOMES AND MEASURES: National spending estimates stratified by health condition, age group, sex, type of care, and type of payer and modeled for each year from 1996 through 2016. RESULTS: Total health care spending increased from an estimated $1.4 trillion in 1996 (13.3% of gross domestic product GDP; $5259 per person) to an estimated $3.1 trillion in 2016 (17.9% of GDP; $9655 per person); 85.2% of that spending was included in this study. In 2016, an estimated 48.0% (95% CI, 48.0%-48.0%) of health care spending was paid by private insurance, 42.6% (95% CI, 42.5%-42.6%) by public insurance, and 9.4% (95% CI, 9.4%-9.4%) by out-of-pocket payments. In 2016, among the 154 conditions, low back and neck pain had the highest amount of health care spending with an estimated $134.5 billion (95% CI, $122.4-$146.9 billion) in spending, of which 57.2% (95% CI, 52.2%-61.2%) was paid by private insurance, 33.7% (95% CI, 30.0%-38.4%) by public insurance, and 9.2% (95% CI, 8.3%-10.4%) by out-of-pocket payments. Other musculoskeletal disorders accounted for the second highest amount of health care spending (estimated at $129.8 billion 95% CI, $116.3-$149.7 billion) and most had private insurance (56.4% 95% CI, 52.6%-59.3%). Diabetes accounted for the third highest amount of the health care spending (estimated at $111.2 billion 95% CI, $105.7-$115.9 billion) and most had public insurance (49.8% 95% CI, 44.4%-56.0%). Other conditions estimated to have substantial health care spending in 2016 were ischemic heart disease ($89.3 billion 95% CI, $81.1-$95.5 billion), falls ($87.4 billion 95% CI, $75.0-$100.1 billion), urinary diseases ($86.0 billion 95% CI, $76.3-$95.9 billion), skin and subcutaneous diseases ($85.0 billion 95% CI, $80.5-$90.2 billion), osteoarthritis ($80.0 billion 95% CI, $72.2-$86.1 billion), dementias ($79.2 billion 95% CI, $67.6-$90.8 billion), and hypertension ($79.0 billion 95% CI, $72.6-$86.8 billion). The conditions with the highest spending varied by type of payer, age, sex, type of care, and year. After adjusting for changes in inflation, population size, and age groups, public insurance spending was estimated to have increased at an annualized rate of 2.9% (95% CI, 2.9%-2.9%); private insurance, 2.6% (95% CI, 2.6%-2.6%); and out-of-pocket payments, 1.1% (95% CI, 1.0%-1.1%). CONCLUSIONS AND RELEVANCE: Estimates of US spending on health care showed substantial increases from 1996 through 2016, with the highest increases in population-adjusted spending by public insurance. Although spending on low back and neck pain, other musculoskeletal disorders, and diabetes accounted for the highest amounts of spending, the payers and the rates of change in annual spending growth rates varied considerably.
To investigate roles in intestinal inflammation for the 2 cyclooxygenase (COX) isoforms, we determined susceptibility to spontaneous and induced acute colitis in mice lacking either the COX-1 or ...COX-2 isoform. We treated wild-type, COX-1(-/-), COX-2(-/-), and heterozygous mice with dextran sodium sulfate (DSS) to provoke acute colonic inflammation, and we quantified tissue damage, prostaglandin (PG) E(2), and interleukin-1beta. No spontaneous gastrointestinal inflammation was detected in mice homozygous for either mutation, despite almost undetectable basal intestinal PGE(2) production in COX-1(-/-) mice. Both COX-1(-/-) and COX-2(-/-) mice showed increased susceptibility to a low-dose of DSS that caused mild colonic epithelial injury in wild-type mice. COX-2(-/-) mice were more susceptible than COX-1(-/-) mice, and selective pharmacologic blockade of COX-2 potentiated injury in COX-1(-/-) mice. At a high dose, DSS treatment was fatal to 50% of the animals in each mutant group, but all wild-type mice survived. DSS treatment increased PGE(2) intestinal secretion in all groups except COX-2(-/-) mice. These results demonstrate that COX-1 and COX-2 share a crucial role in the defense of the intestinal mucosa (with inducible COX-2 being perhaps more active during inflammation) and that neither isoform is essential in maintaining mucosal homeostasis in the absence of injurious stimuli.
Bovine embryos produced in vitro differ considerably in quality from embryos developed in vivo. The in vitro production system
profoundly affects the competence to form blastocysts, the number of ...cells of the total embryo and of the inner cell mass
(ICM), and the incidence of apoptosis. To our knowledge, the effects of different postfertilization regimens before and after
completion of the fourth embryonic cell cycle on these aspects have not yet been investigated. In the present study, we assessed
the blastulation rate by stereomicroscopy and the cell number of the total embryo, of the ICM, and of the cells with apoptotic
changes by confocal laser-scanning microscopy after staining with propidium iodide and TUNEL. Two groups of embryos were developed
in heifers, after superovulation, until 45 or 100 h postovulation (po) and, after collection on slaughter, were further cultured
in vitro until Day 7 po. A third and fourth group comprised embryos that were produced entirely in vitro or in vivo. The results
indicate that passage in vivo of the fourth cell cycle does not prevent acceleration of the formation of the blastocoele in
vitro but may be the critical factor contributing to a higher cell number in the total blastocyst and its ICM. The lower quality
of in vitro-produced embryos can be attributed to the ICM having less viable cells because of a lower number of cells and
a higher incidence of apoptosis that appears to be determined before completion of the fourth cell cycle.
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