Publications by authors named "Richard Parker"

434 Publications

Anterior Cruciate Ligament Reconstruction With Concomitant Meniscal Repair: Is Graft Choice Predictive of Meniscal Repair Success?

Orthop J Sports Med 2021 Sep 14;9(9):23259671211033584. Epub 2021 Sep 14.

CU Sports Medicine, Boulder, Colorado, USA.

Background: When meniscal repair is performed during anterior cruciate ligament (ACL) reconstruction (ACLR), the effect of ACL graft type on meniscal repair outcomes is unclear.

Hypothesis: The authors hypothesized that meniscal repairs would fail at the lowest rate when concomitant ACLR was performed with bone--patellar tendon--bone (BTB) autograft.

Study Design: Cohort study; Level of evidence, 3.

Methods: Patients who underwent meniscal repair at primary ACLR were identified from a longitudinal, prospective cohort. Meniscal repair failures, defined as any subsequent surgical procedure addressing the meniscus, were identified. A logistic regression model was built to assess the association of graft type, patient-specific factors, baseline Marx activity rating score, and meniscal repair location (medial or lateral) with repair failure at 6-year follow-up.

Results: A total of 646 patients were included. Grafts used included BTB autograft (55.7%), soft tissue autograft (33.9%), and various allografts (10.4%). We identified 101 patients (15.6%) with a documented meniscal repair failure. Failure occurred in 74 of 420 (17.6%) isolated medial meniscal repairs, 15 of 187 (8%) isolated lateral meniscal repairs, and 12 of 39 (30.7%) of combined medial and lateral meniscal repairs. Meniscal repair failure occurred in 13.9% of patients with BTB autografts, 17.4% of patients with soft tissue autografts, and 19.4% of patients with allografts. The odds of failure within 6 years of index surgery were increased more than 2-fold with allograft versus BTB autograft (odds ratio = 2.34 [95% confidence interval, 1.12-4.92]; = .02). There was a trend toward increased meniscal repair failures with soft tissue versus BTB autografts (odds ratio = 1.41 [95% confidence interval, 0.87-2.30]; = .17). The odds of failure were 68% higher with medial versus lateral repairs ( < .001). There was a significant relationship between baseline Marx activity level and the risk of subsequent meniscal repair failure; patients with either very low (0-1 points) or very high (15-16 points) baseline activity levels were at the highest risk ( = .004).

Conclusion: Meniscal repair location (medial vs lateral) and baseline activity level were the main drivers of meniscal repair outcomes. Graft type was ranked third, demonstrating that meniscal repairs performed with allograft were 2.3 times more likely to fail compared with BTB autograft. There was no significant difference in failure rates between BTB versus soft tissue autografts.

Registration: NCT00463099 (ClinicalTrials.gov identifier).
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http://dx.doi.org/10.1177/23259671211033584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445540PMC
September 2021

Robust and flexible inference for the covariate-specific receiver operating characteristic curve.

Stat Med 2021 Nov 1;40(26):5779-5795. Epub 2021 Sep 1.

Cambridge Urology Translational Research and Clinical Trials Office, Cambridge, UK.

Diagnostic tests are of critical importance in health care and medical research. Motivated by the impact that atypical and outlying test outcomes might have on the assessment of the discriminatory ability of a diagnostic test, we develop a robust and flexible model for conducting inference about the covariate-specific receiver operating characteristic (ROC) curve that safeguards against outlying test results while also accommodating for possible nonlinear effects of the covariates. Specifically, we postulate a location-scale regression model for the test outcomes in both the diseased and nondiseased populations, combining additive regression B-splines and M-estimation for the regression function, while the distribution of the error term is estimated via a weighted empirical distribution function of the standardized residuals. The results of the simulation study show that our approach successfully recovers the true covariate-specific area under the ROC curve on a variety of conceivable test outcomes contamination scenarios. Our method is applied to a dataset derived from a prostate cancer study where we seek to assess the ability of the Prostate Health Index to discriminate between men with and without Gleason 7 or above prostate cancer, and if and how such discriminatory capacity changes with age.
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http://dx.doi.org/10.1002/sim.9153DOI Listing
November 2021

Continuity of Genetic Risk for Aggressive Behavior Across the Life-Course.

Behav Genet 2021 Sep 14;51(5):592-606. Epub 2021 Aug 14.

Biological Psychology, Vrije Universiteit, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.

We test whether genetic influences that explain individual differences in aggression in early life also explain individual differences across the life-course. In two cohorts from The Netherlands (N = 13,471) and Australia (N = 5628), polygenic scores (PGSs) were computed based on a genome-wide meta-analysis of childhood/adolescence aggression. In a novel analytic approach, we ran a mixed effects model for each age (Netherlands: 12-70 years, Australia: 16-73 years), with observations at the focus age weighted as 1, and decaying weights for ages further away. We call this approach a 'rolling weights' model. In The Netherlands, the estimated effect of the PGS was relatively similar from age 12 to age 41, and decreased from age 41-70. In Australia, there was a peak in the effect of the PGS around age 40 years. These results are a first indication from a molecular genetics perspective that genetic influences on aggressive behavior that are expressed in childhood continue to play a role later in life.
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http://dx.doi.org/10.1007/s10519-021-10076-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390412PMC
September 2021

Improving menstrual equity in the USA: perspectives from trans and non-binary people assigned female at birth and health care providers.

Cult Health Sex 2021 Aug 8:1-15. Epub 2021 Aug 8.

Department of Sociomedical Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.

Menstruation research has largely focused on addressing menstrual management barriers facing cisgender women and girls in low and middle-income countries. Scant literature has assessed the menstrual management needs of trans and non-binary people assigned female at birth. To better understand these frequently invisibilised menstruation-related needs, we conducted a multi-method qualitative study in New York City which included: 17 in-depth interviews across trans and non-binary people ( = 10) and health care providers who serve them ( = 7); and seven anonymous post-interview participatory writing responses with trans and non-binary participants to further elucidate their lived experiences with menstrual management. Lack of health care provider transgender competency, public toilet design (i.e. gaps in cubicle doors and lack of in-cubicle menstrual product disposal bins), and the social dynamics of public toilets (i.e. work and school) were identified as significant barriers to managing menstruation safely and accessibly for trans and non-binary people. These findings have important implications for healthcare policy, public toilet legislation and advancing menstrual equity in the USA.
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http://dx.doi.org/10.1080/13691058.2021.1957151DOI Listing
August 2021

Politics and pandemics.

Glob Public Health 2021 Aug-Sep;16(8-9):1131-1140

Escola FIOCRUZ de Governo, Diretoria Regional de Brasília, Fundação Oswaldo Cruz, Brasília, Brazil.

This Special Issue of on brings together 26 articles and commentaries that address diverse aspects of the politics of COVID-19 and related issues. These papers are grouped together in six topical areas: , , , , and . The goal of the Special Issue is to give readers a sense of the range of topics that have been a focus for research in relation to the COVID-19 pandemic and to provide diverse examples of how research and analysis on the political dimensions of the pandemic can contribute to confronting the COVID-19 crisis.
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http://dx.doi.org/10.1080/17441692.2021.1947601DOI Listing
August 2021

Articular Cartilage and Meniscus Predictors of Patient-Reported Outcomes 10 Years After Anterior Cruciate Ligament Reconstruction: A Multicenter Cohort Study.

Am J Sports Med 2021 09 29;49(11):2878-2888. Epub 2021 Jul 29.

Department of Orthopaedics, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Background: Articular cartilage and meniscal damage are commonly encountered and often treated at the time of anterior cruciate ligament reconstruction (ACLR). Our understanding of how these injuries and their treatment relate to outcomes of ACLR is still evolving.

Hypothesis/purpose: The purpose of this study was to assess whether articular cartilage and meniscal variables are predictive of 10-year outcomes after ACLR. We hypothesized that articular cartilage lesions and meniscal tears and treatment would be predictors of the International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS) (all 5 subscales), and Marx activity level outcomes at 10-year follow-up after ACLR.

Study Design: Cohort study (prognosis); Level of evidence, 1.

Methods: Between 2002 and 2008, individuals with ACLR were prospectively enrolled and followed longitudinally using the IKDC, KOOS, and Marx activity score completed at entry, 2, 6, and 10 years. A proportional odds logistic regression model was built incorporating variables from patient characteristics, surgical technique, articular cartilage injuries, and meniscal tears and treatment to determine the predictors (risk factors) of IKDC, KOOS, and Marx outcomes at 10 years.

Results: A total of 3273 patients were enrolled (56% male; median age, 23 years at time of enrollment). Ten-year follow-up was obtained on 79% (2575/3273) of the cohort. Incidence of concomitant pathology at the time of surgery consisted of the following: articular cartilage (medial femoral condyle [MFC], 22%; lateral femoral condyle [LFC], 15%; medial tibial plateau [MTP], 4%; lateral tibial plateau [LTP], 11%; patella, 18%; trochlea, 8%) and meniscal pathology (medial, 37%; lateral, 46%). Variables that were predictive of poorer 10-year outcomes included articular cartilage damage in the patellofemoral ( < .01) and medial ( < .05) compartments and previous medial meniscal surgery (7% of knees; < .04). Compared with no meniscal tear, a meniscal injury was not associated with 10-year outcomes. Medial meniscal repair at the time of ACLR was associated with worse 10-year outcomes for 2 of 5 KOOS subscales, while a medial meniscal repair in knees with grade 2 MFC chondrosis was associated with better outcomes on 2 KOOS subscales.

Conclusion: Articular cartilage injury in the patellofemoral and medial compartments at the time of ACLR and a history of medial meniscal surgery before ACLR were associated with poorer 10-year ACLR patient-reported outcomes, but meniscal injury present at the time of ACLR was not. There was limited and conflicting association of medial meniscal repair with these outcomes.
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http://dx.doi.org/10.1177/03635465211028247DOI Listing
September 2021

Mechanochromic, Structurally Colored, and Edible Hydrogels Prepared from Hydroxypropyl Cellulose and Gelatin.

Adv Mater 2021 Sep 29;33(37):e2102112. Epub 2021 Jul 29.

Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.

Hydroxypropyl cellulose (HPC) is an edible, cost-effective and widely used derivative of cellulose. Under lyotropic conditions in water, HPC forms a photonic, liquid crystalline mesophase with an exceptional mechanochromic response. However, due to insufficient physical cross-linking photonic HPC can flow freely as a viscous liquid, preventing the exploitation of this mechanochromic material in the absence of any external encapsulation or structural confinement. Here this challenge is addressed by mixing HPC and gelatin in water to form a self-supporting, viscoelastic, and edible supramolecular photonic hydrogel. It is demonstrated that the structural coloration, mechanochromism and non-Newtonian shear-thinning behavior of the lyotropic HPC solutions can all be retained into the gel state. Moreover, the rigidity of the HPC-gel provides a 69% shorter mechanochromic relaxation time back to its initial color when compared to the liquid HPC-water only system, broadening the dynamic color range of HPC by approximately 2.5× in response to a compressive pressure. Finally, the ability to formulate the HPC-gels in a scalable fashion from only water and "food-grade" constituents unlocks a wide range of potential applications, from response-tunable mechanochromic materials and colorant-free food decoration, to short-term sensors in, for example, biodegradable "smart labels" for food packaging.
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http://dx.doi.org/10.1002/adma.202102112DOI Listing
September 2021

Neither Residual Anterior Knee Laxity Up to 6 mm nor a Pivot Glide Predict Patient-Reported Outcome Scores or Subsequent Knee Surgery Between 2 and 6 Years After ACL Reconstruction.

Am J Sports Med 2021 08 16;49(10):2631-2637. Epub 2021 Jul 16.

Department of Orthopaedics, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Background: A primary goal of anterior cruciate ligament reconstruction (ACLR) is to reduce pathologically increased anterior and rotational laxity of the knee, but the effects of residual laxity on patient-reported outcomes (PROs) after ACLR remain unclear.

Hypothesis: Increased residual laxity at 2 years postoperatively is predictive of a higher risk of subsequent ipsilateral knee surgery and decreases in PRO scores from 2 to 6 years after surgery.

Study Design: Cohort study; Level of evidence, 2.

Methods: From a prospective multicenter cohort, 433 patients aged <36 years were identified at a minimum 2 years after primary ACLR. These patients underwent a KT-1000 arthrometer assessment and pivot-shift test and completed PRO assessments with the Knee injury and Osteoarthritis Outcome Score and International Knee Documentation Committee (IKDC) scores. Patients completed the same PROs at 6 years postoperatively, and any subsequent ipsilateral knee procedures during this period were recorded. Subsequent surgery risk and change in PROs from 2 to 6 years postoperatively were compared based on residual side-to-side KT-1000 arthrometer differences (<-1 mm, -1 to 2 mm, 2 to 6 mm, and >6 mm) in laxity at 2 years postoperatively. Multiple linear regression models were built to determine the relationship between 2-year postoperative knee laxity and 2- to 6-year change in PROs while controlling for age, sex, body mass index, smoking status, meniscal and cartilage status, and graft type.

Results: A total of 381 patients (87.9%) were available for follow-up 6 years postoperatively. There were no significant differences in risk of subsequent knee surgery based on residual knee laxity. Patients with a difference >6 mm in side-to-side anterior laxity at 2 years postoperatively were noted to have a larger decrease in PROs from 2 to 6 years postoperatively ( < .05). No significant differences in any PROs were noted among patients with a difference <6 mm in side-to-side anterior laxity or those with pivot glide (IKDC B) versus no pivot shift (IKDC A).

Conclusion: The presence of a residual side-to-side KT-1000 arthrometer difference <6 mm or pivot glide at 2 years after ACLR is not associated with an increased risk of subsequent ipsilateral knee surgery or decreased PROs up to 6 years after ACLR. Conversely, patients exhibiting a difference >6 mm in side-to-side anterior laxity were noted to have significantly decreased PROs at 6 years after ACLR.
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http://dx.doi.org/10.1177/03635465211025003DOI Listing
August 2021

Association Between Graft Choice and 6-Year Outcomes of Revision Anterior Cruciate Ligament Reconstruction in the MARS Cohort.

Am J Sports Med 2021 08 14;49(10):2589-2598. Epub 2021 Jul 14.

University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Although graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome.

Hypothesis: In the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up.

Study Design: Cohort study; Level of evidence, 2.

Methods: Patients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery.

Results: A total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores ( = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized ( = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts ( = .87) or between BTB autografts and soft tissue allografts ( = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft ( = .010; OR, 0.56; 95% CI, 0.36-0.87).

Conclusion: BTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.
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http://dx.doi.org/10.1177/03635465211027170DOI Listing
August 2021

Using Monozygotic Twins to Dissect Common Genes in Posttraumatic Stress Disorder and Migraine.

Front Neurosci 2021 22;15:678350. Epub 2021 Jun 22.

Centre for Genomics and Personalised Health, School of Biomedical Science, Faculty of Health, Queensland University of Technology, Kelvin Grove, QLD, Australia.

Epigenetic mechanisms have been associated with genes involved in Posttraumatic stress disorder (PTSD). PTSD often co-occurs with other health conditions such as depression, cardiovascular disorder and respiratory illnesses. PTSD and migraine have previously been reported to be symptomatically positively correlated with each other, but little is known about the genes involved. The aim of this study was to understand the comorbidity between PTSD and migraine using a monozygotic twin disease discordant study design in six pairs of monozygotic twins discordant for PTSD and 15 pairs of monozygotic twins discordant for migraine. DNA from peripheral blood was run on Illumina EPIC arrays and analyzed. Multiple testing correction was performed using the Bonferroni method and 10% false discovery rate (FDR). We validated 11 candidate genes previously associated with PTSD including , , and 1. In the epigenome-wide scan, seven novel CpGs were significantly associated with PTSD within/near , , , , , and , with all CpGs except the CpG hypermethylated in PTSD. These results were significantly enriched for genes whose DNA methylation was previously associated with migraine (-value = 0.036). At 10% FDR, 132 CpGs in 99 genes associated with PTSD were also associated with migraine in the migraine twin samples. Genes associated with PTSD were overrepresented in vascular smooth muscle, axon guidance and oxytocin signaling pathways, while genes associated with both PTSD and migraine were enriched for AMPK signaling and longevity regulating pathways. In conclusion, these results suggest that common genes and pathways are likely involved in PTSD and migraine, explaining at least in part the co-morbidity between the two disorders.
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http://dx.doi.org/10.3389/fnins.2021.678350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258453PMC
June 2021

Low dose dexamethasone as treatment for women with heavy menstrual bleeding: A response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM).

EBioMedicine 2021 Jul 2;69:103434. Epub 2021 Jul 2.

MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.

Background: The symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB?

Methods: In our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data.

Trial Registration: ClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects.

Interpretation: Our adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation.

Funding: UK MRC DCS/DPFS grant MR/J003611/1.
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http://dx.doi.org/10.1016/j.ebiom.2021.103434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261537PMC
July 2021

Identification of optimal therapeutic window for steroid use in severe alcohol-associated hepatitis: A worldwide study.

J Hepatol 2021 Nov 21;75(5):1026-1033. Epub 2021 Jun 21.

Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, CIBERehd, Barcelona, Spain.

Background & Aims: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH.

Methods: We performed a retrospective, international multicenter cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method.

Results: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p <0.001). Steroids only improved survival in patients with MELD scores between 21 (HR 0.61; 0.39-0.95; p = 0.027) and 51 (HR 0.72; 0.52-0.99; p = 0.041). The maximum effect of corticosteroid treatment (21-30% survival benefit) was observed with MELD scores between 25 (HR 0.58; 0.42-0.77; p <0.001) and 39 (HR 0.57; 0.41-0.79; p <0.001). No corticosteroid benefit was seen in patients with MELD >51. The type of corticosteroids used (prednisone, prednisolone, or methylprednisolone) was not associated with survival benefit (p = 0.247).

Conclusion: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39.

Lay Summary: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90- or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51).
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http://dx.doi.org/10.1016/j.jhep.2021.06.019DOI Listing
November 2021

The Placebo Response in Randomized Trials in Nonalcoholic Steatohepatitis Simply Explained.

Clin Gastroenterol Hepatol 2021 Jun 4. Epub 2021 Jun 4.

Leeds Liver Unit, St James's University Hospital, Leeds, United Kingdom.

Background & Aims: Liver histology is the primary endpoint in phase III trials in nonalcoholic steatohepatitis (NASH). There is an appreciable response to placebo that confounds endpoint assessment. The aim of this study was to quantify contributors to the placebo response and its impact on liver fibrosis improvement.

Methods: Estimates of fibrosis improvement in placebo-treated participants were made using probabilistic simulation. Each simulated trial included 120 participants. Parameters considered in the model included sampling and observer variability, regression to the mean, and net fibrosis progression calibrated to reported trial outcomes.

Results: In large phase IIb and III trials, 22% of placebo-treated participants with fibrosis stage 2 or 3 NASH at baseline improved by at least 1 fibrosis stage with minimal net disease progression. Estimates of sampling and observer variability in simultaneous biopsy studies highlighted an imbalance where apparent fibrosis improvement was more likely than worsening. Using these estimates and known trial outcomes, net fibrosis progression was estimated at 0.05 stages per year. Simulations of the placebo response rate showed a rate of 22% with 80% of trials falling between 15 and 30%, in keeping with trials reported to date. Additional increases in observer variability further increased the placebo response.

Conclusions: The analyses presented simply define the placebo response in liver fibrosis in trials in NASH in terms of sampling and observer variability, regression to the mean, and fibrosis progression. Factors relating to liver biopsy are largely unmodifiable, and the variation in placebo response rates, both simulated and observed, challenges the role of biopsy in trial endpoint assessment.
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http://dx.doi.org/10.1016/j.cgh.2021.05.059DOI Listing
June 2021

Early expressions of psychopathology and risk associated with trans-diagnostic transition to mood and psychotic disorders in adolescents and young adults.

PLoS One 2021 4;16(6):e0252550. Epub 2021 Jun 4.

Brain and Mind Centre, The University of Sydney, Sydney, Australia.

Objectives: The heterogeneity and comorbidity of major mental disorders presenting in adolescents and young adults has fostered calls for trans-diagnostic research. This study examines early expressions of psychopathology and risk and trans-diagnostic caseness in a community cohort of twins and non-twin siblings.

Methods: Using data from the Brisbane Longitudinal Twin Study, we estimated median number of self-rated psychiatric symptoms, prevalence of subthreshold syndromes, family history of mood and/or psychotic disorders, and likelihood of subsequent trans-diagnostic caseness (individuals meeting diagnostic criteria for mood and/or psychotic syndromes). Next, we used cross-validated Chi-Square Automatic Interaction Detector (CHAID) analyses to identify the nature and relative importance of individual self-rated symptoms that predicted trans-diagnostic caseness. We examined the positive and negative predictive values (PPV; NPV) and accuracy of all classifications (Area under the Curve and 95% confidence intervals: AUC; 95% CI).

Results: Of 1815 participants (Female 1050, 58%; mean age 26.40), more than one in four met caseness criteria for a mood and/or psychotic disorder. Examination of individual factors indicated that the AUC was highest for subthreshold syndromes, followed by family history then self-rated psychiatric symptoms, and that NPV always exceeded PPV for caseness. In contrast, the CHAID analysis (adjusted for age, sex, twin status) generated a classification tree comprising six trans-diagnostic symptoms. Whilst the contribution of two symptoms (need for sleep; physical activity) to the model was more difficult to interpret, CHAID analysis indicated that four self-rated symptoms (sadness; feeling overwhelmed; impaired concentration; paranoia) offered the best discrimination between cases and non-cases. These four symptoms showed different associations with family history status.

Conclusions: The findings need replication in independent cohorts. However, the use of CHAID might provide a means of identifying specific subsets of trans-diagnostic symptoms representing clinical phenotypes that predict transition to caseness in individuals at risk of onset of major mental disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252550PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177455PMC
June 2021

Do Narcotic Use, Physical Therapy Location, or Payer Type Predict Patient-Reported Outcomes After Anterior Cruciate Ligament Reconstruction?

Orthop J Sports Med 2021 Apr 26;9(4):2325967121994833. Epub 2021 Apr 26.

Investigation performed at Cleveland Clinic, Cleveland, Ohio, USA.

Background: Opioid use and public insurance have been correlated with worse outcomes in a number of orthopaedic surgeries. These factors have not been investigated with anterior cruciate ligament reconstruction (ACLR).

Purpose/hypothesis: To evaluate if narcotic use, physical therapy location, and insurance type are predictors of patient-reported outcomes after ACLR. It was hypothesized that at 1 year postsurgically, increased postoperative narcotic use would be associated with worse outcomes, physical therapy obtained within the authors' integrated health care system would lead to better outcomes, and public insurance would lead to worse outcomes and athletic activity.

Study Design: Cohort study; Level of evidence, 2.

Methods: All patients undergoing unilateral, primary ACLR between January 2015 and February 2016 at a large health system were enrolled in a standard-of-care prospective cohort. Knee injury and Osteoarthritis Score (KOOS) and the Hospital for Special Surgery Pediatric-Functional Activity Brief Scale (HSS Pedi-FABS) were collected before surgery and at 1 year postoperatively. Concomitant knee pathology was assessed arthroscopically and electronically captured. Patient records were analyzed to determine physical therapy location, insurance status, and narcotic use. Multivariable regression analyses were used to identify significant predictors of the KOOS and HSS Pedi-FABS score.

Results: A total of 258 patients were included in the analysis (mean age, 25.8; 51.2% women). In multivariable regression analysis, narcotic use, physical therapy location, and insurance type were not independent predictors of any KOOS subscales. Public insurance was associated with a lower HSS Pedi-FABS score (-4.551, = .047) in multivariable analysis. Narcotic use or physical therapy location was not associated with the HSS Pedi-FABS score.

Conclusion: Increased narcotic use surrounding surgery, physical therapy location within the authors' health care system, and public versus private insurance were not associated with disease-specific KOOS subscale scores. Patients with public insurance had worse HSS Pedi-FABS activity scores compared with patients with private insurance, but neither narcotic use nor physical therapy location was associated with activity scores. Physical therapy location did not influence outcomes, suggesting that patients be given a choice in the location they received physical therapy (as long as a standardized protocol is followed) to maximize compliance.
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http://dx.doi.org/10.1177/2325967121994833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085373PMC
April 2021

Days out of role and somatic, anxious-depressive, hypo-manic, and psychotic-like symptom dimensions in a community sample of young adults.

Transl Psychiatry 2021 05 13;11(1):285. Epub 2021 May 13.

Youth Mental Health & Technology Team, Brain and Mind Centre, University of Sydney, Sydney, Australia.

Improving our understanding of the causes of functional impairment in young people is a major global challenge. Here, we investigated the relationships between self-reported days out of role and the total quantity and different patterns of self-reported somatic, anxious-depressive, psychotic-like, and hypomanic symptoms in a community-based cohort of young adults. We examined self-ratings of 23 symptoms ranging across the four dimensions and days out of role in >1900 young adult twins and non-twin siblings participating in the "19Up" wave of the Brisbane Longitudinal Twin Study. Adjusted prevalence ratios (APR) and 95% confidence intervals (95% CI) quantified associations between impairment and different symptom patterns. Three individual symptoms showed significant associations with days out of role, with the largest association for impaired concentration. When impairment was assessed according to each symptom dimension, there was a clear stepwise relationship between the total number of somatic symptoms and the likelihood of impairment, while individuals reporting ≥4 anxious-depressive symptoms or five hypomanic symptoms had greater likelihood of reporting days out of role. Furthermore, there was a stepwise relationship between the total number of undifferentiated symptoms and the likelihood of reporting days out of role. There was some suggestion of differences in the magnitude and significance of associations when the cohort was stratified according to sex, but not for age or twin status. Our findings reinforce the development of early intervention mental health frameworks and, if confirmed, support the need to consider interventions for subthreshold and/or undifferentiated syndromes for reducing disability among young people.
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http://dx.doi.org/10.1038/s41398-021-01390-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119948PMC
May 2021

The Eating Disorders Genetics Initiative (EDGI): study protocol.

BMC Psychiatry 2021 05 4;21(1):234. Epub 2021 May 4.

QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Herston, QLD, 4029, Australia.

Background: The Eating Disorders Genetics Initiative (EDGI) is an international investigation exploring the role of genes and environment in anorexia nervosa, bulimia nervosa, and binge-eating disorder.

Methods: A total of 14,500 individuals with eating disorders and 1500 controls will be included from the United States (US), Australia (AU), New Zealand (NZ), and Denmark (DK). In the US, AU, and NZ, participants will complete comprehensive online phenotyping and will submit a saliva sample for genotyping. In DK, individuals with eating disorders will be identified by the National Patient Register, and genotyping will occur using bloodspots archived from birth. A genome-wide association study will be conducted within EDGI and via meta-analysis with other data from the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED).

Discussion: EDGI represents the largest genetic study of eating disorders ever to be conducted and is designed to rapidly advance the study of the genetics of the three major eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorder). We will explicate the genetic architecture of eating disorders relative to each other and to other psychiatric and metabolic disorders and traits. Our goal is for EDGI to deliver "actionable" findings that can be transformed into clinically meaningful insights.

Trial Registration: EDGI is a registered clinical trial: clinicaltrials.gov NCT04378101 .
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http://dx.doi.org/10.1186/s12888-021-03212-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097919PMC
May 2021

HIV prevention among gay and other men who have sex with men: public policy and social movements in Brazil, 1983-2019.

Cult Health Sex 2021 May 3:1-14. Epub 2021 May 3.

Institute for the Study of Collective Health, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.

This article revisits the history of HIV prevention for gay and other men who have sex with men in relation to public health policy and the role of LGBT and AIDS-related social movements in Brazil. An interpretive study was undertaken informed by philosophical and phenomenological hermeneutics. It included interviews with policymakers, researchers and activists involved in HIV and AIDS, especially HIV prevention among gay and other men who have sex with men. Prevention initiatives were analysed with a focus on the social and programmatic aspects of vulnerability to HIV, and advances and setbacks in the Brazilian response to the epidemic. The recent crisis in HIV prevention triggered by a growing conservatism in Brazilian politics and the current government's LGBT-phobia pose barriers that compromise issues of profound importance with regards to policy on HIV and AIDS: namely, engagement with human rights and social participation.
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http://dx.doi.org/10.1080/13691058.2021.1884292DOI Listing
May 2021

The contested global politics of pleasure and danger: Sexuality, gender, health and human rights.

Glob Public Health 2021 May;16(5):651-663

Institute for the Study of Collective Health, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

This special issue of brings together papers examining how sexuality, gender, health and human rights have become increasing visible and highly contested within global health. The papers included here question and explore the often contradictory processes through which global equity-seeking populations negotiate pleasure and danger across multiple arenas (including HIV and AIDS, LGBTQ+ health and rights, intersex rights, sex worker rights, realities of refugee and displaced persons, and gender-based violence) and in diverse geographic contexts (Afghanistan, Bangladesh, Canada, Ghana, Haiti, Kenya, Mauritania, Nigeria, Peru, Rwanda, and the USA). These papers examine emerging questions about the gaps and limits in current legal structures that do not legitimize sexual rights as fundamental human rights, the role of agency (and of bounded agency) needed to navigate constrained contexts, ways in which community-based solidarity efforts shape access to sexual rights, and how sexual pleasure and consent are experienced and negotiated in rights-constrained contexts. The interdisciplinary authors included in this collection showcase how the ranging definitions of sexual rights, their enactment, and expressions of pleasure and danger are inextricably entangled with local contexts and cultural systems that underpin not only people's lived experience but simultaneously become central topics for global health research, policy and practice.
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http://dx.doi.org/10.1080/17441692.2021.1893373DOI Listing
May 2021

A two-arm parallel-group individually randomised prison pilot study of a male remand alcohol intervention for self-efficacy enhancement: the APPRAISE study protocol.

BMJ Open 2021 04 2;11(4):e040636. Epub 2021 Apr 2.

School of Social Sciences, Humanities & Law, Teesside University, Middlesbrough, UK.

Introduction: The prevalence of at-risk drinking is far higher among those in contact with the criminal justice system (73%) than the general population (35%). However, there is little evidence on the effectiveness of alcohol brief interventions (ABIs) in reducing risky drinking among those in the criminal justice system, including the prison system and, in particular, those on remand. Building on earlier work, A two-arm parallel group individually randomised Prison Pilot study of a male Remand Alcohol Intervention for Self-efficacy Enhancement (APPRAISE) is a pilot study designed to assess the feasibility and acceptability of an ABI, delivered to male prisoners on remand. The findings of APPRAISE should provide the information required to design a future definitive randomised controlled trial (RCT).

Methods And Analysis: APPRAISE will use mixed methods, with two linked phases, across two prisons in the UK, recruiting 180 adult men on remand: 90 from Scotland and 90 from England. Phase I will involve a two-arm, parallel-group, individually randomised pilot study. The pilot evaluation will provide data on the likely impact of A two-arm parallel group individually randomised Prison Pilot study of a male Remand Alcohol Intervention for Self-efficacy Enhancement (APPRAISE), which will be used to inform a future definitive multicentre RCT. Phase II will be a process evaluation assessing how the ABI has been implemented to explore the change mechanisms underpinning the ABI (figure 1) and to assess the context within which the ABI is delivered.

Ethics And Dissemination: The APPRAISE protocol has been approved by the East of Scotland Research Ethics Committee (19/ES/0068), National Offender Management System (2019-240), Health Board Research and Development (2019/0268), Scottish Prison Service research and ethics committee, and by the University of Edinburgh's internal ethics department. The findings will be disseminated via peer-reviewed journal publications, presentations at local, national and international conferences, infographics and shared with relevant stakeholders through meetings and events.

Trial Registration Number: ISRCTN27417180.
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http://dx.doi.org/10.1136/bmjopen-2020-040636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023744PMC
April 2021

Framing HIV and AIDS: how leaders of black religious institutions in New York City interpret and address sex and sexuality in their HIV interventions.

Cult Health Sex 2021 Apr 2:1-31. Epub 2021 Apr 2.

Sociomedical Sciences, Columbia University, New York, NY, USA.

This study explored how leaders of Black churches active in the fight against HIV conceptualised sex and sexuality when describing HIV interventions within their institutions. We analysed interviews with pastors and identified three frames through which leaders understood and communicated about sex and sexuality: (1) an , in which participants avoided discussing behaviours and populations that have historically been disparaged within the church by emphasising involuntary risk exposure; (2) an , which recognised sexual behaviour that differed from heteronormative conduct; and, (3) a , which allowed individuals to maintain their own beliefs about appropriate sexual conduct. Participants used frames to engage in a range of HIV interventions while upholding stigmatising beliefs about sexual behaviour and identity.
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http://dx.doi.org/10.1080/13691058.2021.1898676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486886PMC
April 2021

The Clinical Radiographic Incidence of Posttraumatic Osteoarthritis 10 Years After Anterior Cruciate Ligament Reconstruction: Data From the MOON Nested Cohort.

Am J Sports Med 2021 04;49(5):1251-1261

Investigation performed at the Cleveland Clinic, Cleveland, Ohio, USA.

Background: The incidence of posttraumatic osteoarthritis (PTOA) based on clinical radiographic grading criteria at 10 years after anterior cruciate ligament (ACL) reconstruction (ACLR) has not been well-defined in a prospective cohort of young athletic patients.

Hypothesis: Among young athletic patients, there is a high incidence of clinical radiographic PTOA at 10 years after ACLR. Additionally, there is a significant difference in clinical radiographic osteoarthritis (OA) changes (joint space narrowing and osteophyte formation) between ACL-reconstructed and contralateral knees at 10 years.

Study Design: Case series; Level of evidence, 4.

Methods: The first 146 patients in an ongoing nested cohort study of the Multicenter Orthopaedic Outcomes Network (MOON) prospective cohort presented for a minimum 10-year follow-up. Included patients had a sports-related ACL injury, were aged <33 years at the time of ACLR, had no history of ipsilateral or contralateral knee surgery, and did not undergo revision ACLR before follow-up. Bilateral knee metatarsophalangeal view radiographs were obtained and graded according to International Knee Documentation Committee (IKDC), Osteoarthritis Research Society International (OARSI), and modified Kellgren-Lawrence (KL) criteria by 2 blinded reviewers. The incidence and severity of ipsilateral and contralateral radiographic OA were determined among patients without a contralateral ACL injury before 10-year follow-up (N = 133).

Results: Interrater reliability was substantial for the IKDC (Gwet Agreement Coefficient [AC] 1 = 0.71), moderate for the KL (0.48), and almost perfect for the OARSI (0.84) grading systems. Among patients with a contralateral radiographically normal knee, the 10-year incidence of clinical radiographic PTOA after ACLR was 37% as defined by osteophytes and 23% as defined by joint space narrowing. The maximum side-to-side difference in the OARSI osteophyte grade in the medial or lateral compartment was 0 in 65% of patients, 1 in 20%, and ≥2 in 15%. The maximum side-to-side difference in the OARSI joint space narrowing grade was 0 in 77% of patients, 1 in 19%, and ≥2 in 4%.

Conclusion: In young active patients, the 10-year incidence of clinical radiographic PTOA after ACLR was 37% as defined by osteophytes and 23% as defined by joint space narrowing. The mean difference in the degree of osteophyte formation (≤1 grade in 85%) and joint space narrowing (≤1 grade in 96%) between the ACL-reconstructed and contralateral knees was small.

Registration: NCT02717559 (ClinicalTrials.gov identifier).
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http://dx.doi.org/10.1177/0363546521995182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375261PMC
April 2021

High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial.

Circulation 2021 Jun 23;143(23):2214-2224. Epub 2021 Mar 23.

BHF Centre for Cardiovascular Science (A.A., K.K.L., A.R.C., A.V.F., P.D.A., F.E.S., K.A.A.F., D.E.N., A.S.V.S., N.L.M.), University of Edinburgh, United Kingdom.s.

Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the safety and efficacy of this approach is uncertain. We investigated whether an early rule-out pathway is safe and effective for patients with suspected acute coronary syndrome.

Methods: We performed a stepped-wedge cluster randomized controlled trial in the emergency departments of 7 acute care hospitals in Scotland. Consecutive patients presenting with suspected acute coronary syndrome between December 2014 and December 2016 were included. Sites were randomized to implement an early rule-out pathway where myocardial infarction was excluded if high-sensitivity cardiac troponin I concentrations were <5 ng/L at presentation. During a previous validation phase, myocardial infarction was ruled out when troponin concentrations were <99th percentile at 6 to 12 hours after symptom onset. The coprimary outcome was length of stay (efficacy) and myocardial infarction or cardiac death after discharge at 30 days (safety). Patients were followed for 1 year to evaluate safety and other secondary outcomes.

Results: We enrolled 31 492 patients (59±17 years of age [mean±SD]; 45% women) with troponin concentrations <99th percentile at presentation. Length of stay was reduced from 10.1±4.1 to 6.8±3.9 hours (adjusted geometric mean ratio, 0.78 [95% CI, 0.73-0.83]; <0.001) after implementation and the proportion of patients discharged increased from 50% to 71% (adjusted odds ratio, 1.59 [95% CI, 1.45-1.75]). Noninferiority was not demonstrated for the 30-day safety outcome (upper limit of 1-sided 95% CI for adjusted risk difference, 0.70% [noninferiority margin 0.50%]; =0.068), but the observed differences favored the early rule-out pathway (0.4% [57/14 700] versus 0.3% [56/16 792]). At 1 year, the safety outcome occurred in 2.7% (396/14 700) and 1.8% (307/16 792) of patients before and after implementation (adjusted odds ratio, 1.02 [95% CI, 0.74-1.40]; =0.894), and there were no differences in hospital reattendance or all-cause mortality.

Conclusions: Implementation of an early rule-out pathway for myocardial infarction reduced length of stay and hospital admission. Although noninferiority for the safety outcome was not demonstrated at 30 days, there was no increase in cardiac events at 1 year. Adoption of this pathway would have major benefits for patients and health care providers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03005158.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177493PMC
June 2021

Can network analysis of self-reported psychopathology shed light on the core phenomenology of bipolar disorders in adolescents and young adults?

Bipolar Disord 2021 Sep 8;23(6):584-594. Epub 2021 Mar 8.

Brain and Mind Centre, The University of Sydney, Sydney, Australia.

Objectives: Network analysis is increasingly applied to psychopathology research. We used it to examine the core phenomenology of emerging bipolar disorder (BD I and II) and 'at risk' presentations (major depression with a family history of BD).

Methodology: The study sample comprised a community cohort of 1867 twin and nontwin siblings (57% female; mean age ~26) who had completed self-report ratings of (i) depression-like, hypomanic-like and psychotic-like experiences; (ii) family history of BD; and (iii) were assessed for mood and psychotic syndromes using the Composite International Diagnostic Interview (CIDI). Symptom networks were compared for recent onset BD versus other cohort members and then for individuals at risk of BD (depression with/without a family history of BD).

Results: The four key symptoms that differentiated recent onset BD from other cohort members were: anergia, psychomotor speed, hypersomnia and (less) loss of confidence. The four key symptoms that differentiated individuals at high risk of BD from unipolar depression were anergia, psychomotor speed, impaired concentration and hopelessness. However, the latter network was less stable and more error prone.

Conclusions: We are encouraged by the overlaps between our findings and those from two recent publications reporting network analyses of BD psychopathology, especially as the studies recruited from different populations and employed different network models. However, the advantages of applying network analysis to youth mental health cohorts (which include many individuals with multimorbidity) must be weighed against the disadvantages including basic issues such as judgements regarding the selection of items for inclusion in network models.
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http://dx.doi.org/10.1111/bdi.13067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387492PMC
September 2021

Examining the effectiveness of telemonitoring with routinely acquired blood pressure data in primary care: challenges in the statistical analysis.

BMC Med Res Methodol 2021 02 10;21(1):31. Epub 2021 Feb 10.

Usher Institute, University of Edinburgh, Edinburgh, UK.

Background: Scale-up BP was a quasi-experimental implementation study, following a successful randomised controlled trial of the roll-out of telemonitoring in primary care across Lothian, Scotland. Our primary objective was to assess the effect of telemonitoring on blood pressure (BP) control using routinely collected data. Telemonitored systolic and diastolic BP were compared with surgery BP measurements from patients not using telemonitoring (comparator patients). The statistical analysis and interpretation of findings was challenging due to the broad range of biases potentially influencing the results, including differences in the frequency of readings, 'white coat effect', end digit preference, and missing data.

Methods: Four different statistical methods were employed in order to minimise the impact of these biases on the comparison between telemonitoring and comparator groups. These methods were "standardisation with stratification", "standardisation with matching", "regression adjustment for propensity score" and "random coefficient modelling". The first three methods standardised the groups so that all participants provided exactly two measurements at baseline and 6-12 months follow-up prior to analysis. The fourth analysis used linear mixed modelling based on all available data.

Results: The standardisation with stratification analysis showed a significantly lower systolic BP in telemonitoring patients at 6-12 months follow-up (-4.06, 95% CI -6.30 to -1.82, p < 0.001) for patients with systolic BP below 135 at baseline. For the standardisation with matching and regression adjustment for propensity score analyses, systolic BP was significantly lower overall (- 5.96, 95% CI -8.36 to - 3.55 , p < 0.001) and (- 3.73, 95% CI- 5.34 to - 2.13, p < 0.001) respectively, even after assuming that - 5 of the difference was due to 'white coat effect'. For the random coefficient modelling, the improvement in systolic BP was estimated to be -3.37 (95% CI -5.41 to -1.33 , p < 0.001) after 1 year.

Conclusions: The four analyses provide additional evidence for the effectiveness of telemonitoring in controlling BP in routine primary care. The random coefficient analysis is particularly recommended due to its ability to utilise all available data. However, adjusting for the complex array of biases was difficult. Researchers should appreciate the potential for bias in implementation studies and seek to acquire a detailed understanding of the study context in order to design appropriate analytical approaches.
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http://dx.doi.org/10.1186/s12874-021-01219-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877114PMC
February 2021

Trajectory of Serum Bilirubin Predicts Spontaneous Recovery in a Real-World Cohort of Patients With Alcoholic Hepatitis.

Clin Gastroenterol Hepatol 2021 Jan 28. Epub 2021 Jan 28.

Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Background And Aims: Alcoholic hepatitis (AH) is a severe condition with poor short-term prognosis. Specific treatment with corticosteroids slightly improves short-term survival but is associated with infection and is not used in many centers. A reliable method to identify patients who will recover spontaneously will minimise the numbers of patients who experience side effects of available treatments.

Methods: We analysed the trajectory of serum bilirubin concentration over the course of hospital admissions in patients with AH to predict spontaneous survival and the need for treatment.

Results: data from 426 patients were analysed. Based on bilirubin trajectory, patients were categorized into three groups: 'fast fallers' (bilirubin <0.8 x admission value at day 7), 'static' (bilirubin of >0.9 - <1.2 x admission value) and 'rapid risers' (bilirubin of ≥1.2 x admission bilirubin). Fast fallers had significantly better 90-day survival compared to other groups (log rank p < .001), and showed no benefit of corticosteroid therapy (OR for survival at 28 days of treatment, 0.94, 95% CI 0.06 - 8.41). These findings remained even amongst patients with severe disease based on initial DF, GAHS or MELD scores.

Conclusions: We present an intuitive method of classifying patients with AH based on the trajectory of bilirubin over the first week of admission. It is complimentary to existing scores that identify candidates for corticosteroid treatment or assess response to treatment. This method identifies a group of patients with AH who recover spontaneously and can avoid corticosteroid therapy.
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http://dx.doi.org/10.1016/j.cgh.2021.01.042DOI Listing
January 2021

The birth environment of planetary systems.

Authors:
Richard J Parker

R Soc Open Sci 2020 Nov 25;7(11):201271. Epub 2020 Nov 25.

Royal Society Dorothy Hodgkin Fellow, Department of Physics and Astronomy, The University of Sheffield, Hicks Building, Hounsfield Road, Sheffield S3 7RH, UK.

Star and planet formation are inextricably linked. In the earliest phases of the collapse of a protostar, a disc forms around the young star and such discs are observed for the first several million years of a star's life. It is within these circumstellar, or protoplanetary, discs that the first stages of planet formation occur. Recent observations from the Atacama large millimetre array (ALMA) suggest that planet formation may already be underway after only 1 Myr of a star's life. However, stars do not form in isolation; they form from the collapse and fragmentation of giant molecular clouds several parsecs in size. This results in young stars forming in groups-often referred to as 'clusters'. In these star-forming regions, the stellar density is much higher than the location of the Sun and other stars in the Galactic disc that host exoplanets. As such, the environment where stars form has the potential to influence the planet formation process. In star-forming regions, protoplanetary discs can be truncated or destroyed by interactions with passing stars, as well as photoevaporation from the radiation fields of very massive stars. Once formed, the planets themselves can have their orbits altered by dynamical encounters-either directly from passing stars or through secondary effects such as the Kozai-Lidov mechanism. In this contribution, I review the different processes that can affect planet formation and stability in star-forming regions. I discuss each process in light of the typical range of stellar densities observed for star-forming regions. I finish by discussing these effects in the context of theories for the birth environment of the Solar System.
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http://dx.doi.org/10.1098/rsos.201271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735350PMC
November 2020

Fibrosis progression rate in a systematic review of placebo-treated nonalcoholic steatohepatitis.

Liver Int 2021 05 23;41(5):982-995. Epub 2020 Dec 23.

Leeds Liver Unit, St James's University Hospital, Leeds, UK.

Background & Aims: Liver fibrosis is the critical determinant of liver-related outcomes in persons with nonalcoholic fatty liver disease. The rate that fibrosis develops determines the time taken to reach cirrhosis and consequent clinical outcomes. Estimates of the fibrosis progression rate (FPR) are uncertain having been defined in small observational series that rely largely on nonstandardised repeat biopsy in selected patients. The aim of this study was to evaluate the FPR in placebo-treated participants with nonalcoholic steatohepatitis (NASH) in randomised controlled trials (RCTs).

Methods: Systematic review and meta-analysis of RCTs in NASH with data on fibrosis change extracted. Calculated fibrosis progression rates were pooled in meta-analysis. The pooled estimate was then used to model the proportion of hypothetical cohorts starting with no fibrosis at the age of 30 who develop cirrhosis.

Results: A total of 35 trials including 1419 placebo-treated participants who underwent repeat liver biopsy were evaluated. Considering all trials, the overall FPR was 0.00 stages per year, increasing to 0.03 stages per year in both trials at low risk of bias and trials including >50 placebo-treated participants. This estimate was markedly lower than the value derived from previously pooled analyses of observational data. Using a FPR of 0.03 resulted in a substantial reduction in the proportion of patients developing cirrhosis compared with the FPR derived from observational studies (13% vs 28%).

Conclusions: The FPR in placebo-treated participants in RCTs is lower than that described from observational data. Slower fibrosis progression predicts fewer persons with NASH will progress to cirrhosis than previously estimated.
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http://dx.doi.org/10.1111/liv.14749DOI Listing
May 2021

Commentary on Willan & Thabane: Bayesian methods are valuable in pilot trials but the choice of prior needs careful consideration.

Authors:
Richard A Parker

Clin Trials 2021 02 24;18(1):130-131. Epub 2020 Nov 24.

Edinburgh Clinical Trials Unit, Usher Institute, The University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1177/1740774520974976DOI Listing
February 2021

High rates of ineligibility for participation in trials of new therapies in non-alcoholic steatohepatitis: a systematic review.

Eur J Gastroenterol Hepatol 2020 08;32(8):1023-1029

Leeds Liver Unit, St James's University Hospital.

Background And Aims: Non-alcoholic fatty liver disease is common and there are a number of treatments in development. Patients with non-alcoholic steatohepatitis (NASH) and significant fibrosis are thought to be the population most in need of treatment. Identification of this group requires liver biopsy. The aim of this study was to identify the proportion of patients screened for phase 2 randomised controlled trials who subsequently entered these studies.

Methods: Large, multicentre, phase 2 randomised controlled trials of pharmacological therapies for NASH were identified by systematic review. The pooled proportion of potential participants who entered the trials was estimated by meta-analysis. The reasons for trial ineligibility were separately extracted and analysed.

Results: Thirteen reports of 14 trials were included. Overall, there were 4014 screened individuals included in the quantitative analyses and 53% were subsequently enrolled in a trial. Considering trials in which the entry criteria matched the current paradigm for treatment, that is, the presence of NASH and significant fibrosis, only 35% of screened individuals were eligible for trial entry. More than half of ineligible individuals were excluded on the basis of liver histology most often due to insufficient disease activity with or without insufficient fibrosis.

Conclusion: The majority of patients considered at risk of NASH and fibrosis sufficient for treatment in randomised controlled trials are ineligible for trial entry. Most often, this is due to ineligible liver histology. These findings have implications for the design of future trials in NASH and for the applicability of treatments after licensing.
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http://dx.doi.org/10.1097/MEG.0000000000001614DOI Listing
August 2020
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