bluuebunny/crossref_metadata_2025 huggingface dataset:
UHPLC-MS/MS-BASED PLASMA LIPIDOMICS REVEAL ALTERATIONS ASSOCIATED WITH EXCLUSIVE ENTERAL NUTRITION TREATMENT IN ADULT PATIENTS WITH ACTIVE CROHN’S DISEASE
Authors: Yang Qingfan , Huang ZiCheng , Liu Hailing , Chao Kang , Gao Xiang
Published: January 2022

BACKGROUND

Exclusive enteral nutrition (EEN) is an effective treatment for active Crohn’s disease (CD), although the mechanisms is unclear. Lipid metabolism and signaling have been suggested to play an important role in the pathophysiology of the disease, but their relationship with EEN therapy has not been reported. Hence, we assessed plasma lipid profiles of adult patients with active CD before and after EEN and compared them to those of healthy controls.

METHODS

Adult patients with active CD (n=11) who received EEN with an amino acid-based enteral nutrition formula for 12 weeks and age- and sex-matched healthy controls (n=17) were recruited. Plasma lipid profiles of 869 lipid species were measured before and after EEN in both groups using ultrahigh performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The CD activity index (CDAI), high-sensitivity C-reactive protein (hs-CRP) level, and nutrition-associated indices were evaluated. CDAI <150 and a Simple Endoscopic Score for CD (SES-CD) ≤2 indicated clinical remission and mucosal healing (MH), respectively.

RESULTS

After 12 weeks of EEN, 81.8% (9 of 11) patients achieved remission with a significant decrease in the CDAI (P<0.001) and hs-CRP levels (P<0.001). Ten patients had a SES-CD score of >2 before EEN, which declined after EEN (P=0.009), with four patients achieving MH. Before EEN initiation, 80 lipid species/17 lipid classes were significantly different between patients with CD and healthy controls. After EEN initiation, 103 lipid species/11 lipid classes were significantly different between patients with CD and healthy controls. Thirty-eight significantly different lipid species from eight lipid classes—cholesterolester (n=1), lysophosphatidylcholine (n=3), monogalactosyldiacylglycerol (n=1), phosphatidylcholine (n=18), phosphatidylethanolamine (n=3), phosphatidylinositol (n=4), phosphatidylserine (n=1), and phosphatidylglycerol (n=7)—were identified in patients with CD before and after EEN. Among these lipid classes, the levels of monogalactosyldiacylglycerol, phosphatidylinositol, and phosphatidylcholine decrased significantly and that of phosphatidylglycerol increased significantly before EEN in patients with CD compared to those in healthy controls (P<0.05). These lipids returned to similar levels of healthy controls after EEN (P>0.05). Lipid classes and species were significantly associated with clinical indices of CDAI, hs-CRP, and MH. Pathway analysis suggested that arachidonic acid, glycerophospholipid, linoleate, and phosphatidylinositol phosphate metabolisms were related to the mechanism of EEN treatment.

CONCLUSION

EEN leads to the alterations in multiple lipid classes and species, in keeping with improvement in clinical response. However, further studies are needed to confirm their precise roles.
CONCORDANCE BETWEEN REMISSION DEFINED BY PATIENTS VS PATIENT-REPORTED OUTCOME MEASURES IN INFLAMMATORY BOWEL DISEASE
Authors: Kamp Kendra , Tse Chung Sang , Hawes Steven , Oberai Ridhima , Weaver Alandra , Singh Siddharth , Melmed Gil , Siegel Corey , van Deen Welmoed
Published: January 2022

BACKGROUND

Although validated patient-reported outcome measurements (PRO) can categorize patients with inflammatory bowel disease (IBD) into remission or active disease, patients may have different definitions of remission. Patients may assume a new normal with altered bowel habits/abdominal pain after diagnosis or consider themselves to have active disease even though disease activity measures show remission. We aim to examine concordance between patient-defined remission and remission based on PRO-2 (ulcerative colitis; UC) or PRO-3 (Crohn’s disease; CD), and associations with demographic and disease-related factors.

METHODS

We retrospectively analyzed 3257 de-identified surveys from 2004 unique patients (806 UC; 1198 CD) who consented to participate in the Crohn’s and Colitis Foundation’s IBD Qorus Learning Health System. Surveys were collected at IBD clinic visits between September 2019 and February 2021. We used logistic regression models with generalized estimating equations to analyze the sensitivity, specificity, concordance, and discordance between patient-defined remission (yes/no) and PRO-defined remission (PRO-2: stool frequency, rectal bleeding; PRO-3: stool frequency, abdominal pain, wellbeing). We also examined steroid-free PRO remission (PRO-defined remission plus absence of steroids).

RESULTS

In CD, 63.3% of patients with inactive disease based on PRO-3 considered themselves in remission (adjusted sens=0.62). Discordance was more common among patients with <5 years disease duration (OR 1.6), and those who used prednisone (OR 4.2) or opioids (OR 5.3). Among patients with active disease based on PRO-3, 20.8% considered themselves in remission (adjusted spec=0.79) and discordance was more common with long disease duration (>15 years; OR 2.6) and those who did not use prednisone (OR 3.0) and opioids (OR 5.4).

In UC, 77% of patients with inactive disease based on PRO-2 considered themselves in remission (adjusted sens=0.77). Discordance was more common among patients with disease duration of <5 years compared to those >15 years (OR 2.3). Among patients with active disease based on PRO-2, 19.2% considered themselves in remission (adjusted spec=0.79) and discordance was more common in patients who did not use prednisone (OR: 2.2).

Age and gender were not associated with discordance. Results were similar with steroid-free PRO defined remission (Table 2).

CONCLUSION

Discordance between how patients and PRO measures define remission is common. Patients with shorter disease duration were more likely to report active disease when they were in remission while patients with longer disease duration were more likely to report remission while they still experienced symptoms. 1 in 3 (32%) assessments of disease remission were discordance among patients with CD, and 1 in 4 (22%) in patients with UC.
FECAL CALPROTECTIN TESTING: AN INVESTIGATION OF PATIENT COMPLIANCE AND PERCEPTIONS
Authors: Perry Courtney , Hashim Mahmoud , Elmoursi Ahmed , Elkheshen Ahmed , Dugan Adam , Flomenhoft Deborah , Stuffelbeam Amy , Barrett Terrence
Published: January 2022

INTRODUCTION

Inflammatory Bowel Disease (IBD) is a lifelong illness requiring close management. Prompt disease recognition and tight control of disease activity reduces disease morbidity and improves outcomes1. Endoscopy with histologic examination is the gold standard for assessing “deep remission2.” However, frequent endoscopic evaluation is not always feasible or cost effective. Fecal Calprotectin (FC), a paradigm shifting biomarker, is both sensitive and specific for histologic inflammation in IBD2. However, the efficacy of this test rests on patient’s willingness to handle and submit stool samples. Studies investigating FC non-compliance are scarce, and all have been performed outside the US. Thus, we elected to survey our patients to assess barriers to FC compliance.

METHODS

We recruited 104 participants with Crohn’s disease (CD) or Ulcerative Colitis (UC) from our IBD clinic to participate in a prospective cross-sectional study. We administered an author-designed mixed-method questionnaire consisting of 23 questions with multiple choice, yes/no, rank order, and open-ended questions. The primary outcomes of interest were risk factors for non-compliance. Patient compliance over a two year period (1/2018 through 1/2020) was self-reported and verified retrospectively by the authors. Responses to questions were grouped according to level of FC compliance (<50% compliance, 50-99% compliance, 100% compliant). Categorical variables were analyzed using chi2 and Fishers exact test. Continuous variables were analyzed using Mann-Whitney and Kruskal-Wallis tests.

RESULTS

Among the 104 participants surveyed, 56 were always compliant with FC testing (53.8%).The remaining 48 participants fell on a spectrum of compliance, with most participants completing between 50-75% of fecal calprotectin tests over the study period (n=29, 60.4%). Only 8 participants were “never” compliant. Physician determined compliance was significantly associated with participant completion (p=0.001). Number of “no-show” clinic visits was associated with FC compliance (p=0.013). Participants who reported FC testing embarrassing were significantly less likely to be compliant (p=0.037), and were less likely to report that they found stool testing important (p=0.020). In the qualitative portion of the survey, recurring frustrations included inconvenience of testing, embarrassment associated with stool submission, and lack of streamlined sample submission.

CONCLUSION

Fecal calprotectin is a valuable tool for IBD monitoring, but testing can be cumbersome and usefulness is limited by compliance. Embarrassment was a significant compliance barrier, suggesting that improved education and protocols for laboratory discretion would improve FC submission and patient experience.
STIGMA PERCEPTIONS IN NON-WHITE IBD PATIENTS AND RELATIONSHIPS WITH PATIENT OUTCOMES
Authors: Veracruz Nicolette , Taft Tiffany
Published: January 2022

INTRODUCTION

Disease-related stigmatization is present in IBD, with a substantial proportion of patients reporting that they perceive discriminatory attitudes or behaviors from others because of their IBD status. These perceptions are associated with poor outcomes. However, stigma perceptions are not well studied in patients from underrepresented racial and ethnic minority (URM) groups. As such, we aim to assess stigma perceptions in URM IBD patients and their relationship to Health Related Quality of Life (HRQoL).

METHODS

Adult patients 18+ recruited via social media and researchmatch.org website completed an anonymous online survey: demographics, disease information, Harvey Bradshaw Index (HBI) or simple clinical colitis activity index (SCCAI) with >4 = active IBD, NIH-PROMIS QoL module (anxiety, depression, fatigue, sleep disturbance, pain interreference, social function), and the Perceived Stigma Scale for IBS (“IBS” replaced with “IBD”). Elevated stigma was identified via median split (Median=28). Independent samples t-Test, Pearson’s correlation, and hierarchical linear regression statistics were used.

RESULTS

90 participants: 50% UC, 79% female, 66% South/Southeast Asian, 10% Hispanic, Age (Mean±SD))=34.8±9.8 years. 52% had active IBD (5.77±4.22) with “biologic” medications most used (38.9%). 59% reported high levels of perceived stigma (Mean IBD-PSS score: 30.57±16.3); no differences by IBD type, age, gender, race, or ethnicity. Patients with active IBD reported significantly more stigma experiences (36.0±2.7 vs. 23.3±10.9, p<.001). Stigma perception was significantly correlated with all HRQoL domains: anxiety r=0.414, depresison r=0.471, fatigue r=0.424, sleep disturbance r=0.293, pain interference r=0.474, social function r= -0.439 (all p<.01). When controlling for HBI/SCCAI, stigma was a larger predictor of anxiety (β=.365, p=.002), depression (β=.386, p<.001), social function (β= -.341, p=.003) than symptom severity, and smaller but significant predictor of fatigue (β=.254, p=.014) and pain interference (β=.290, p=.003). Stigma perceptions did not predict sleep disturbance (p=.087).

CONCLUSION

Approximately half of URM IBD patients reported high levels of stigma experiences. These perceptions were associated with negative outcomes across all HRQoL domains with the exception of sleep disturbance. Our results show stigma perceptions are an important consideration when evaluationg these outcomes in IBD, rather than disease activity alone. Further research on a larger scale and with more diverse population is needed in order to better understand the effects of disease stigmatization in URM IBD patients.
REAL-WORLD VEDOLIZUMAB PHARMACOKINETIC STUDY IN CHILDREN IDENTIFIES TWO NOVEL BIOMARKERS OF DRUG CLEARANCE
Authors: Colman Ruben , Mizuno Tomoyuki , Hyams Jeffrey , Noe Joshua , Boyle Brendan , Denson Lee , Vinks Alexander , Minar Phillip
Published: January 2022

INTRODUCTION

Use of vedolizumab in pediatric inflammatory bowel disease (IBD) often requires an interval intensification from standard dosing due to distinct pharmacokinetics (PK) in children. Adult population PK models found inclusion of albumin, weight, anti-TNF naivety and antibodies-to-vedolizumab (ATV) as covariates of drug clearance (CL) improved model accuracy. We aimed to build a population-PK model for children and identify novel covariates of drug CL to better account for pediatric-specific variability in vedolizumab PK.

METHODS

This was a prospective multicenter cohort study for pediatric IBD patients starting vedolizumab. Vedolizumab dosing regimens were managed by the treating clinician. Stool, serum and plasma were collected at standardized intervals for robust PK sampling and biomarker analysis. Population PK analysis were conducted with nonlinear mixed effects modeling (NONMEM 7.5). A 1-compartment model with proportional error model was created based on the PK data. In the final model, novel covariates were identified using a stepwise approach. A decrease in the objective function value (OFV) >3.84 was considered significant (P<0.05).

RESULTS

Twenty-one patients had a total of 277 infusions with 274 measured vedolizumab peak and trough concentrations. Among these, 57% were male, 76% had Crohn’s disease, and 81% had prior anti-TNF exposure. The median (IQR) age was 16 years (13-18), and median weight was 52kg (41-71). Baseline biomarkers are described in Table 1.

Baseline CL was inversely correlated with albumin (R=-0.54, P= 0.012), hemoglobin (R=-0.45, P= 0.048), and platelets (R=-0.5, P= 0.026). There was a positive correlation of CL with CRP (R=0.8, P< 0.001), neutrophil CD64 (nCD64, R=0.68, P= 0.001), fecal calprotectin (FCP, R=0.63, P= 0.009), and BSA (R=0.59, P= 0.007).

The final model estimated CL as 0.168 L/d (relative standard error (RSE), 13%) and volume (V) distribution as 3.97L (8%). The interindividual variability (IIV) of the final model was 62.2% (25%) of CL and 37% (8%) of V. Covariates that significantly decreased the OFV were incorporated into the final model including weight for V and albumin, ESR, and nCD64 for CL. Prior anti-TNF, immunomodulators (MTX, n=3) or ATV (n=1) did not impact CL.

Baseline CL <0.161 L/d predicted an end of induction FCP remission (<250μg/g) with an area under the curve (AUC) 0.7 (sensitivity 0.8, specificity 0.75) with the final model. A cut-off of 37 μg/mL at infusion-3 and 20 μg/mL at infusion-4 predicted end of induction clinical remission (Figure 1).

CONCLUSIONS

We describe a novel pediatric PK model for vedolizumab that identified novel covariates, including ESR and nCD64, that may guide model-informed precision dosing. Larger cohorts should establish whether additional compartments and pediatric-specific covariates can further decrease the remaining unexplained variability.
Testing behaviour may bias observational studies of vaccine effectiveness
Authors: Glasziou Paul , McCaffery Kirsten , Cvejic Erin , Batcup Carys , Ayre Julie , Pickles Kristen , Bonner Carissa
Published: January 2022

Backgroun

Recent observational studies have suggested that vaccines for the omicron variant of SARS-Cov2 may have little or no effect in preventing infection. However, the observed effects may be confounded by patient factors and preventive behaviours or vaccine-related differences in testing behaviour. To assess the potential degree of confounding, we aimed to estimate differences in testing behaviour between unvaccinated and vaccinated populations.

Methods

We recruited 1,526 Australian adults for an online randomised study about COVID testing between October and November 2021, and collected self-reported vaccination status and three measures of COVID-19 testing behaviour. We examined the association between testing intentions and vaccination status in the cross-sectional baseline data of this trial.

Results

Of the 1,526 participants (mean age 31 years): 22% had a COVID-19 test in the past month and 61% ever; 17% were unvaccinated, 11% were partially vaccinated (1 dose), 71% were fully vaccinated (2+ doses). Fully vaccinated participants were twice as likely (RR 2.2; 95% CI 1.8 to 2.8) to report positive COVID testing intentions than those who were unvaccinated (p<.001). Partially vaccinated participants had less positive intentions than those fully vaccinated (p<.001) but higher intentions than those who were unvaccinated (p=.002).

Discussion

For all three measures vaccination predicted greater COVID testing intentions. If the unvaccinated tested at half the rate of the vaccinated, a true vaccine effectiveness of 30% could appear to be a “negative” observed vaccine effectiveness of -40%. Assessing vaccine effectiveness should use methods to account for differential testing behaviours. Test negative designs are currently the preferred option, but its assumptions should be more thoroughly examined.
“Effectiveness of COVID-19 Vaccines in preventing Infectiousness, Hospitalization and Mortality: A Historical Cohort Study Using Iranian Registration Data During Vaccination program”
Authors: Mirahmadizadeh Alireza , Heiran Alireza , Lankarani Kamran Bagheri , Serati Mohammadreza , Habibi Mohammad , Eilami Owrang , Heiran Fatemeh , Moghadami Mohsen
Published: January 2022

Background

There are some concerns about the effectiveness of the inactivated and vector-based vaccines against SARS-CoV-2 in the real-world settings with the emergence of new mutations, especially variants of concern. Data derived from administrative repositories during mass-vaccination campaigns or programs are of interest to study vaccine effectiveness (VE).

Methods

Using 4-repository administrative data linkage, we conducted a historical cohort study on a target population of 3,628,857 inhabitants aged at least 18 years residing in Southern Iran.

Results

We estimated 71.9% [95% CI: 70.7-73.1%], 81.5% [95% CI: 79.5-83.4%], 67.5% [95% CI: 59.5-75.6%], and 86.4% [95% CI: 84.1-88.8%] hospitalization reduction for those who received the full vaccination schedule of BIBP-CorV, ChAdOx1-S/nCoV-19, rAd26-rAd5, and BIV1-CovIran vaccines, respectively. A high reduction in mortality – at least 85% – was observed in all age subgroups of fully immunized population.

Conclusion

The pragmatic implementation of a vaccination plan including all available vaccine options in the Iranian population was associated with a significant reduction in documented COVID-19 infection, hospitalization, and death associated with COVID-19.

Key points

The mass vaccination program with implementing a group of vaccines, that even for some of them (rAd26-rAd5, and BIV1-CovIran vaccines) have been only regionally authorized for emergency use, has been associated with a dramatic reduction in documented COVID-19 infection, as well as in hospitalization and deaths related to the COVID-19 diagnosis.
Single-nuclei paired multiomic analysis of young, aged, and Parkinson’s disease human midbrain reveals age- and disease-associated glial changes and their contribution to Parkinson’s disease
Authors: Adams Levi , Song Min Kyung , Tanaka Yoshiaki , Kim Yoon-Seong
Published: January 2022

Age is the primary risk factor for Parkinson’s disease (PD), but how aging changes the expression and regulatory landscape of the brain remains unclear. Here, we present a single-nuclei multiomic study profiling shared gene expression and chromatin accessibility of young, aged and PD post-mortem midbrain samples. Combined multiomic analysis along a pseudopathogenesis trajectory reveals all glial cell types are affected by age, but microglia and oligodendrocytes are further altered in PD. We present evidence for a novel disease-associated oligodendrocyte subtype and identify genes lost over the aging and disease process, including CARNS1, that may predispose healthy cells to develop a disease-associated phenotype. Peak-gene association analysis from paired data identifies 89 PD-associated SNP loci, including five in MAPT, that show differential association with gene expression in disease-associated oligodendrocytes. Our study suggests a previously undescribed role for oligodendrocytes in aging and PD pathogenesis.
Pregnancy outcomes and long-term patient and graft survival after kidney transplantation
Authors: Radaelli Eloísa , Meinerz Gisele , Jacobina Lázaro Pereira , Bruno Rosana Mussoi , Garcia Valter Duro , Stefani Eduarda Tanus , Lima Letícia Kortz Motta , Weber Natália Klaus , Keitel Elizete
Published: January 2022

Introduction

Kidney transplant is considered the method of choice in the treatment of end-stage chronic kidney disease, improving survival and quality of life, and often allowing the recovery of fertility among woman. Objective: This study aims to assess the outcomes of post-transplant pregnancy, newborn and patient graft survival, compared to a control group of transplanted women who weren’t pregnant.

Methods

A retrospective case-control study was conducted at the Kidney Transplant Service of Santa Casa de Misericórdia in Porto Alegre, among 1.253 female patients who underwent kidney transplantation and were of childbearing age between 1977 and 2016. They were compared to a control group matched for age, type of donor, date of transplant and immunological risk.

Results

76 (6,1%) of the patients became pregnant, resulting in a total of 93 pregnancies. Compared to the control group, at 10 years after transplantation there was no significant difference in relation to graft loss (74% vs 66%, p=0.524), and the survival of pregnant patients was higher (97% vs 79%, p=0.018). We found that 40% pregnancies progressed to abortion, 30% of the deliveries were preterm, and 26% happened at term. Three pregnancies progressed to stillbirth. Of the 56 pregnancies that evolved, 23 (41%) resulted in pre-eclampsia, and one in eclampsia.

Conclusion

6,1% of the women in the study became pregnant, and 56% of these pregnancies were successful. Compared to the control group, we found that those who got pregnant had similar graft survival outcomes and longer patient survival.
The impact of repeated rapid test strategies on the effectiveness of at-home antiviral treatments for SARS-CoV-2
Authors: Menkir Tigist F , Donnelly Christl A
Published: January 2022

As has been consistently demonstrated, rapid tests administered at regular intervals can offer significant benefits to both individuals and their communities at large by helping identify whether an individual is infected and potentially infectious. An additional advantage to the tested individuals is that positive tests may be provided sufficiently early enough during their infections that treatment with antiviral treatments can effectively inhibit development of severe disease, particularly when PCR uptake is limited and/or delays to receipt of results are substantial. Here, we provide a quantitative illustration of the extent to which rapid tests administered at various intervals can deliver benefits accrued from the novel Pfizer treatment (nirmatrelvir) among high-risk populations. We find that strategies in which tests are administered more frequently, i.e. every other day or every three days, are associated with greater reductions in the risk of hospitalization with weighted risk ratios ranging from 0.17 (95% CI: 0.11-0.28) to 0.77 (95% CI: 0.69-0.83) and correspondingly, higher proportions of the infected population benefiting from treatment, ranging from 0.26 (95% CI: 0.18-0.34) to 0.92 (95% CI: 0.80-0.98). We further observed that reduced positive-test-to-treatment delays and increased testing and treatment coverage have a critical influence on average treatment benefits, confirming the significance of access.
SARS-CoV-2 surveillance (09/2020 - 03/2021) in elementary schools and daycare facilities in Bavaria
Authors: Kern Anna , Kuhlmann Pia H. , Matl Stefan , Ege Markus , Maison Nicole , Eckert Jana , von Both Ulrich , Behrends Uta , Anger Melanie , Frühwald Michael C. , Gerstlauer Michael , Woelfle Joachim , Neubert Antje , Melter Michael , Liese Johannes , Goettler David , Sing Andreas , Liebl Bernhard , Hübner Johannes , Klein Christoph ,   the COVID Kids Bavaria Consortium
Published: January 2022

Here we report our results of a multi-center, open cohort study (“COVID-Kids-Bavaria”) investigating the distribution of SARS-CoV-2 among children and staff in 99 daycare facilities and 48 elementary schools in Bavaria, Germany. Overall, 2568 children (1337 school children, 1231 preschool children) and 1288 adults (466 teachers, 822 daycare staff) consented to participate in the study and were randomly tested in three consecutive phases (September/October 2020, November/December 2020, March 2021). In total, 7062 throat swabs were analyzed for SARS-CoV-2 by RT-PCR. In phase I, only one daycare worker tested positive. In phase II, SARS-CoV-2 was detected in three daycare workers, two preschool children, and seven school children. In phase III, no sample tested positive. This corresponds to a positive test rate of 0.05% in phase I, 0.4% in phase II and 0% in phase III. After phase III, antibody testing was offered to 713 study participants in elementary schools. A seroprevalence rate of 7.7% (students) and 4.5% (teachers) was determined. We conclude that during the initial waves of the SARS-CoV-2 pandemic, the risk of a positive SARS-CoV-2 result correlated positively with the local 7-day incidence. Thus, an increased risk of SARS-CoV-2 transmission in the setting of daycare and elementary schooling was unlikely.
The organisation of nurse staffing in intensive care units: a qualitative study
Authors: Endacott Ruth , Dall’Ora Chiara , Richardson Annette , Griffiths Peter , Pattison Natalie , Pearce Susie ,   xSEISMIC research team
Published: January 2022

Aims

To examine the organisation of the nursing workforce in intensive care units and identify factors that influence how the workforce operates.

Background

Pre-pandemic UK survey data show that up to 60% of intensive care units (ICUs) did not meet locally agreed staffing numbers and 40% of ICUs were closing beds at least once a week because of workforce shortages, specifically nursing. Nurse staffing in ICUs is based on the assumption that sicker patients need more nursing resource than those recovering from critical illness. These standards are based on historical working, and expert professional consensus, deemed the weakest form of evidence.

Methods

Focus groups with health care professionals working in ICUs (n= 52 participants) and individual interviews with critical care network leads and policy leads (n= 14 participants) in England between December 2019 and July 2020. Data were analysed using framework analysis.

Findings

Three themes were identified: the constraining or enabling nature of ICU and hospital structures; whole team processes to mitigate nurse staffing shortfalls; and the impact of nurse staffing on patient, staff and ICU flow outcomes. Staff made decisions about staffing throughout a shift and were influenced by a combination of factors illuminated in the three themes.

Conclusions

Whilst nurse: patient ratios were clearly used to set the nursing establishment, it was clear that rostering and allocation/re-allocation during a shift took into account many other factors, such as patient and family nursing needs, staff wellbeing, ICU layout and the experience, and availability, of other members of the multi-professional team. This has important implications for future planning for ICU nurse staffing and highlights important factors to be accounted for in future research studies.

Implications for Nursing Management

The potential opportunities for different staffing models are likely to be highly dependent on other professions. Hence, any change to staffing models needs to take into account how different professions work together.

Factors such as ICU layout, reported to influence nurse staffing decisions, suggest that patient safety in ICU may not be best served by blanket ‘ratio’ approaches to nurse staffing, intended to apply uniformly across health services.

The findings have the potential to feed into discussions about funding tariffs for critical care and quality metrics to be included in commissioning contracts.
DRAGON-Data: A platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts
Authors: Hubbard Leon , Lynham Amy J. , Knott Sarah , Underwood Jack F. G. , Anney Richard , Bisson Jonathan I. , van den Bree Marianne.B.M , Craddock Nick , O’Donovan Michael , Jones Ian , Kirov George , Langley Kate , Martin Joanna , Rice Frances , Roberts Neil , Thapar Anita , Owen Michael J. , Hall Jeremy , Pardiñas Antonio F. , Walters James T.R.
Published: January 2022

Introduction

Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptomatology and shared genetic liability is still poorly understood. Well-characterised, cross-disorder samples are needed to investigate this matter, but currently few exist, and severe mental disorders are poorly represented in existing biobanking efforts. Purposely curated and aggregated data from individual research groups can fulfil this unmet need, resulting in rich resources for psychiatric research.

Methods and analyses

As part of the Cardiff MRC Mental Health Data Pathfinder, we have curated and harmonised phenotypic and genetic information from 15 studies within the MRC Centre for Neuropsychiatric Genetics and Genomics to create a new data repository, DRAGON-DATA. To date, DRAGON-DATA includes over 45,000 individuals: adults or children with psychiatric diagnoses, affected probands with family members and individuals who carry a known neurodevelopmental copy number variant (ND-CNV). We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all datasets with genotype information have undergone rigorous quality control, imputation, CNV calling and polygenic score generation.

Ethics and Dissemination

DRAGON-DATA combines genetic and non-genetic information and is available as a resource for research across traditional psychiatric diagnostic categories. Its structure and governance follow standard UK ethical requirements (at the level of participating studies and the project as a whole) and conforms to principles reflected in the EU data protection scheme (GDPR). Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with HDR UK.
Association of Age-Related Macular Degeneration With Mortality: A Propensity Score-Matched Analysis
Authors: Chen Yifan , Wang Yueye , Shang Xianwen , Wang Wei , Zhu Zhuoting
Published: January 2022

Purpose

To investigate the association between age-related macular degeneration (AMD) and 10-year all-cause and cause-specific mortality using a large-scale population-based sample.

Methods

Data from the 2005-2008 cycles of the National Health and Nutrition Examination Survey were used to assess the risk of mortality in relation to AMD in a propensity score-matched cohort. AMD status was assessed by retinal images with the standardized grading scheme. Mortality data until 31st December 2015 were derived from mortality archives. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for survival.

Results

A total of 4691 participants were included. After a median follow-up of 8.42 (IQR: 7.58-9.67) years, 698 participants died. Participants with any AMD had an increased risk of all-cause mortality (HR, 2.02; 95% CI, 1.37-2.98). Similar results were observed for early (HR, 1.93; 95% CI, 1.31-2.85) and late AMD (HR, 4.29; 95% CI, 2.10-8.79). For cause-specific mortality, any (HR, 2.17; 95% CI, 1.39-3.39), early (HR, 2.18; 95% CI, 1.36-3.51), and late AMD (HR, 3.95; 95% CI, 1.65-9.46) were associated with significantly higher mortality due to causes other than cardiovascular disease (CVD) or cancer. Late AMD independently predicted a higher risk of CVD mortality (HR, 2.48; 95% CI, 1.32-4.65).

Conclusions

The current study showed that any, early, and late AMD were associated with increased risks of all-cause mortality and mortality due to causes other than CVD or cancer. In addition, we found that late AMD was associated with increased risks of CVD mortality.

Synopsis

Late macular degeneration independently predicted higher cardiovascular disease mortality. Any, early and late age-related macular degeneration were associated with higher all-cause mortality and mortality due to causes other than cardiovascular disease or cancer.
Mutations in TIC100 impair and repair chloroplast protein import and impact retrograde signalling
Authors: Loudya Naresh , Maffei Douglas P. F. , Bédard Jocelyn , Ali Sabri Mohd. , Devlin Paul , Jarvis R. Paul , López-Juez Enrique
Published: January 2022

Chloroplast biogenesis requires synthesis of proteins in the nucleocytoplasm and the chloroplast itself. Nucleus-encoded chloroplast proteins are imported via multiprotein translocons in the organelle’s envelope membranes. Controversy exists around whether a 1 MDa complex comprising TIC20, TIC100 and other proteins constitutes the inner membrane TIC translocon. The Arabidopsis cue8 virescent mutant is broadly defective in plastid development. We identify CUE8 as TIC100. The tic100cue8 mutant accumulates reduced levels of 1 MDa complex components and exhibits reduced import of two nucleus-encoded chloroplast proteins of different import profiles. A search for suppressors of tic100cue8 identified a second mutation within the same gene, tic100soh1, which rescues the visible, 1 MDa complex-subunit abundance, and chloroplast protein import phenotypes. tic100soh1 retains but rapidly exits virescence, and rescues the synthetic lethality of tic100cue8 when retrograde signalling is impaired by the gun1 mutation. Alongside the strong virescence, changes in RNA editing and the presence of unimported precursor proteins show that a strong signalling response is triggered when TIC100 function is altered. Our results are consistent with a role for TIC100, and by extension the 1 MDa complex, in the chloroplast import of photosynthetic and non-photosynthetic proteins, a process which initiates retrograde signalling.

One sentence summary

Complementary mutations in TIC100 of the chloroplast inner envelope membrane cause reductions or corrective improvements in chloroplast protein import, and highlight a signalling role.
An early decline in ETPs reflects fewer pre-thymic progenitors and altered signals from the thymus microenvironment
Authors: Srinivasan Jayashree , Vasudev Anusha , Selden Hilary J. , Perez Encarnacion , LaFleur Bonnie , Sinari Shripad A. , Krueger Andreas , Richie Ellen R. , Ehrlich Lauren I. R.
Published: January 2022

Age-related thymus involution results in decreased T-cell production, contributing to increased susceptibility to pathogens. Elucidating mechanisms underlying involution will inform strategies to restore thymopoiesis. The thymus is colonized by circulating bone marrow (BM)-derived thymus seeding progenitors (TSPs) that differentiate into early T-cell progenitors (ETPs). We find ETP cellularity declines as early as 3 months (3MO) in mice. This initial ETP reduction could reflect changes in pre-thymic progenitors and/or thymic stromal niches. We demonstrate that the number of functional TSP/ETP niches is not reduced with age. Instead, the number of pre-thymic BM and circulating lymphoid progenitors is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM progenitors and ETPs declines by 3MO, indicating defective niche quality contributes to the reduction in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to the initial decline in ETPs, setting the stage for progressive thymus involution.

Summary statement

The number of early T-cell progenitors declines by 3 months of age in mice. This decline reflects a sharp drop in circulating thymus seeding progenitors, fewer bone marrow lymphoid progenitors, and reduced Notch signaling in both bone marrow and thymus.
Investigating causal relations between sleep duration and risks of adverse pregnancy and perinatal outcomes: Linear and nonlinear Mendelian randomization analyses in up to 356,069 European women
Authors: Yang Qian , Magnus Maria C , Kilpi Fanny , Santorelli Gillian , Soares Ana Gonçalves , West Jane , Magnus Per , Wright John , Håberg Siri Eldevik , Sanderson Eleanor , Lawlor Deborah A , Tilling Kate , Borges Maria Carolina
Published: January 2022

Background

Observational studies have reported maternal short/long sleep duration to be associated with adverse pregnancy and perinatal outcomes. However, it remains unclear whether there are nonlinear causal effects. Our aim was to use multivariable regression (MVreg) and Mendelian randomization (MR) to examine nonlinear effects of sleep duration on stillbirth, miscarriage, gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth, low/high offspring birthweight (LBW/HBW).

Methods

We used data from European women in UK Biobank (UKB, N=208,140), FinnGen (N=∼123,579), Avon Longitudinal Study of Parents and Children (N=6826), Born in Bradford (N=2940) and Norwegian Mother, Father and Child Cohort Study (MoBa, N=14,584). We used 78 previously identified genetic variants as instruments for sleep duration, and investigated its effectsusing two-sample MR and one-sample nonlinear MR (in UKB only). We compared MR findings with MVreg in MoBa (N=76,669), where maternal sleep duration was measured at 30 weeks.

Results

In UKB, MR provided evidence of nonlinear effects of sleep duration on stillbirth, perinatal depression and LBW, but not for other outcomes. Shorter and longer duration increased stillbirth and LBW; shorter duration increased perinatal depression. For example, there was a lower risk of LBW with increasing duration (odds ratio 0.79 per one-hour/day (95% confidence interval (CI): 0.68, 0.93) in the shortest duration group and a higher risk (odds ratio 1.38 (95% CI: 1.06, 1.81) in the longest duration group, suggesting shorter and longer duration increased the risk. These were supported by the lack of evidence of a linear effect of sleep duration with any outcome using two-sample MR. In MVreg, risks of all outcomes (except for stillbirth showing opposite directions) were higher in the women reporting <5- and ≥10-hours/day sleep compared with the reference category of 8-9-hours/day, despite some wide CIs including the null. Nonlinear models fitted the data better than linear models for most outcomes(likelihood ratio P-value=0.02 to 3.2×10−52), except for stillbirth and gestational diabetes.

Conclusions

Our results supported possible nonlinear sleep duration effects on perinatal depression and LBW. Statistical support for nonlinear models across outcomes suggests potential nonlinear effects on other outcomes that larger studies could detect.
CSF sphingomyelins in Alzheimer’s disease, neurodegeneration, and neuroinflammation
Authors: Morrow Autumn , Panyard Daniel J. , Deming Yuetiva K. , Jonaitis Erin , Dong Ruocheng , Vasiljevic Eva , Betthauser Tobey J , Kollmorgen Gwendlyn , Suridjan Ivonne , Bayfield Anna , Van Hulle Carol A. , Zetterberg Henrik , Blennow Kaj , Carlsson Cynthia M. , Asthana Sanjay , Johnson Sterling C. , Engelman Corinne D.
Published: January 2022

INTRODUCTION

Sphingomyelin (SM) levels have been associated with Alzheimer’s disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available.

METHODS

Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n=502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models.

RESULTS

No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, α-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs.

DISCUSSION

The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.
Tissue volume estimation and age prediction using rapid structural brain scans
Authors: Hobday Harriet , Cole James H. , Stanyard Ryan A. , Daws Richard E. , Giampietro Vincent , O’Daly Owen , Leech Robert , Váša František
Published: January 2022

The multicontrast EPImix sequence generates 6 contrasts, including a T1-weighted scan, in ∼1 minute. EPImix shows comparable diagnostic performance to conventional scans under qualitative clinical evaluation, and similarities in simple quantitative measures including contrast intensity. However, EPImix scans have not yet been compared to standard MRI scans using established quantitative measures. In this study, we compared conventional and EPImix-derived T1-weighted scans of 64 healthy participants using tissue volume estimates and predicted brain-age. All scans were pre-processed using the SPM12 DARTEL pipeline, generating measures of grey matter, white matter and cerebrospinal fluid volume. Brain-age was predicted using brainageR, a Gaussian process regression model previously trained on a large sample of standard T1-weighted scans. Estimates of both global and voxel-wise tissue volume showed significantly similar results between standard and EPImix-derived T1-weighted scans. Brain-age estimates from both sequences were significantly correlated, although EPImix T1-weighted scans showed a systematic offset in predictions of chronological age. Supplementary analyses suggest that this is likely caused by the reduced field of view of EPImix scans, and the use of a brain-age model trained using conventional T1-weighted scans. However, this systematic error can be corrected using additional regression of T1-predicted brain-age onto EPImix-predicted brain-age. Finally, retest EPImix scans acquired for 10 participants demonstrated high test-retest reliability in all evaluated quantitative measurements. Quantitative analysis of EPImix scans holds potential to reduce scanning time, increasing participant comfort and reducing cost, as well as to support automation of scanning, utilising active learning for faster and individually-tailored (neuro)imaging.
Inhibition of the IL-17A axis Protects against Immune-related Adverse Events while Supporting Checkpoint Inhibitor Anti-tumor Efficacy
Authors: Lechner Melissa G. , Patel Anushi Y. , Hugo Willy , Angell Trevor E. , Cheng Mandy I. , Pioso Marissa S. , Hoang Aline T. , Yakobian Natalie , McCarthy Ethan C. , Chen Ho-Chung , Rodriguez Eduardo D. , Guo Lily , Astourian Michael , Drakaki Alexandra , Famini Pouyan , Ribas Antoni , Su Maureen A.
Published: January 2022

Checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) may lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+RORγt+CD4+(T helper 17 or Th17) and gamma delta 17 (γδT17) T cells promote thyroid IrAE development. IL-17A+T cells were similarly found in thyroid specimens from cancer patients treated with ICI who developed thyroid IrAE. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in multiple tumor models did not reduce ICI anti-tumor efficacy. These studies suggest that targeting Th17 and γδ17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.
Characterization of second-order mixing effects in reconstructed cross-spectra of random neural fields
Authors: Hindriks Rikkert
Published: January 2022

Functional connectivity in electroencephalography (EEG) and magnetoencephalography (MEG) data is commonly assessed by using measures that are insensitive to instantaneously interacting sources and as such would not give rise to false positive interactions caused by instantaneous mixing of true source signals (first-order mixing). Recent studies, however, have drawn attention to the fact that such measures are still susceptible to instantaneous mixing from lagged sources (i.e. second-order mixing) and that this can lead to a large number of false positive interactions. In this study we relate first- and second-order mixing effects on the cross-spectra of reconstructed source activity to the properties of the resolution operators that are used for the reconstruction. We derive two identities that relate first- and second-order mixing effects to the transformation properties of measurement and source configurations and exploit them to establish several basic properties of signal mixing. First, we provide a characterization of the configurations that are maximally and minimally sensitive to second-order mixing. It turns out that second-order mixing effects are maximal when the measurement locations are far apart and the sources coincide with the measurement locations. Second, we provide a description of second-order mixing effects in the vicinity of the measurement locations in terms of the local geometry of the point-spread functions of the resolution operator. Third, we derive a version of Lagrange’s identity for cross-talk functions that establishes the existence of a trade-off between the magnitude of first- and second-order mixing effects. It also shows that, whereas the magnitude of first-order mixing is determined by the inner product of cross-talk functions, the magnitude of second-order mixing is determined by a generalized cross-product of cross-talk functions (the wedge product) which leads to an intuitive geometric understanding of the trade-off. All results are derived within the general framework of random neural fields on cortical manifolds.