bluuebunny/crossref_metadata_2025 huggingface dataset:
SAFETY AND EFFECTIVENESS OF THE BNT162B2 MRNA COVID-19 VACCINE IN A NATIONWIDE COHORT OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Khan Muhammad , Mushtaq Kamran , Saddique Muhammad , Alghizzawi Mohd , Yasir Muhammad , Younis Hafiz , Rashid Farah , AlSoub Deema , Yakoob Rafie , AlKaabi Saad , Al-Ejji Khalid
Published: January 2022

BACKGROUND & AIMS

The effectiveness of currently available SARS-CoV-2 vaccines in patients with inflammatory bowel disease (IBD) remains unknown. We aimed to determine the effectiveness of the Pfizer-BNT162b2 mRNA vaccine in a nationwide cohort of patients with IBD in Qatar.

METHODS

Using a cohort design, we compared 476 IBD patients vaccinated identified between January 1, 2021, and March 31, 2021, with 476 matched unvaccinated controls (matched on age and date of SARS-CoV-2 testing). Study outcomes included documented SARS-CoV-2 infection, symptomatic COVID-19, and COVID-19 related hospitalization. We also studied the side effects of the vaccination, including the effect on IBD exacerbation and hospitalizations related to adverse events.

RESULTS

Total follow-up was 23,289 person-days for the vaccinated and 23,653 person-days for the unvaccinated group. Vaccine effectiveness >14 days [AAB1] after the second dose was 85.1% (95% CI: 65.2, 93.6) for confirmed infection, and 87.1% (95% CI: 63.6, 95.4)[AAB2] for symptomatic infection. No patient required hospitalization >14 days after the second vaccine dose. Estimated vaccine effectiveness between 22 to 35 days after the first dose was 14.8% (95% CI: -151.5, 71.2) [AAB3] for any documented infection, and 59.8% (95% CI: -106.1, 92.2) for symptomatic COVID-19 disease. For patients taking biologics with or without immunomodulators, vaccine effectiveness >14 days after the second dose was 94% (95% CI: 53.1, 99.2), and 92.7% (95% CI: 45.1, 99.0) for any documented infection and symptomatic COVID-19 respectively. Vaccine effectiveness was 87.4% (95% CI: 46.0, 97.1) for any documented infection and 91.7% (95% CI: 37.2, 98.9) for symptomatic COVID-19 during the same period for patients taking immunomodulators alone. None of the vaccinated patients required intensive care unit admission or died. No patient had IBD exacerbation or required hospitalization for vaccination-related adverse events.

CONCLUSION

In a nationwide cohort of IBD patients, the BNT162b2 mRNA vaccine was safe and highly effective.
MIRIKIZUMAB IMPROVES PATIENT ASSESSMENT OF DISEASE SEVERITY AND CHANGE IN DISEASE ACTIVITY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE
Authors: Rubin David , Pollack Paul , Hunter Theresa , Shan Mingyang , Chan Lai-Shan , Deckard Deanilee
Published: January 2022

BACKGROUND

Mirikizumab (miri), an anti-IL-23p19 inhibitor, has demonstrated efficacy in patients with ulcerative colitis and moderately to severely active Crohn’s disease (CD) in a Phase 2, randomised, double-blind, placebo-controlled study (NCT02891226). This analysis evaluated the effect of miri on patient perception of symptom severity as well as disease activity over 12-week (W) induction and 40W maintenance periods.

METHODS

During induction, patients were randomised 2:1:1:2 to placebo (PBO), 200mg, 600mg, or 1000mg miri administered intravenously (IV) every four weeks (Q4W). Patients who received miri during induction and achieved ≥1 point improvement in Simple Endoscopic Score for Crohn’s Disease (SES-CD) at W12 were randomised 1:1 to continue induction treatment (IV 200mg, 600mg, 1000mg miri Q4W) or receive 300mg miri Q4W administered subcutaneously (SC) for 40W (maintenance). Because of small patient numbers, the randomised maintenance groups results were combined for those who continued IV induction treatment (All IV-C) and those who received SC treatment (All SC). SES-CD non-improvers and patients who received PBO during induction received 1000mg miri IV Q4W during maintenance. The 6-point Patient’s Global Rating of Severity (PGRS) scale (1=none to 6=very severe) was recorded daily on an electronic diary, and the 7-point Patient’s Global Rating of Change (PGRC) scale (1=very much better to 7=very much worse) was recorded at W4, 12 and 52. Weekly average score for PGRS was calculated and the change from baseline in miri compared to PBO using a mixed model for repeated measures (MMRM) for induction period. Observed PGRC values at W4, 12 and 52 are presented.

RESULTS

Significant reduction in PGRS compared to PBO was observed as early as W4 in patients treated with 600mg miri (least square mean (LSM) difference ± standard error [95% confidence internal]: -0.44 ± 0.2 [-0.84, -0.04], p=0.031), and in all miri treated patients by W12: 200mg (-0.58 ± 0.2 [-1.05, -0.12], p=0.014), 600mg (-0.86 ± 0.2 [-1.31, -0.40], p<0.001) and 1000mg (-0.52 ± 0.2 [-0.89, -0.15], p=0.007) (Table 1). Patients treated with 600mg miri and 1000mg reported greatest numerical improvement in PGRC at W12 (2.6 ± 1.0 and2.5 ± 0.9, respectively) (Table 1). Continued numeric reductions in PGRS and PGRC were observed at W52 in all miri dosing groups (Table 1). Patients treated with PBO/1000mg IV reported similar reductions in PGRS and PGRC at W52 to patients treated with miri from W0–52 (Table 1).

CONCLUSION

Mirikizumab treatment improved both patients’ self-assessment of disease severity and disease activity as early as week 4 and these improvements were sustained through 52 weeks in patients with moderately to severely active Crohn’s disease.
INCIDENCE AND PREVALENCE OF PRIMARY SCLEROSING CHOLANGITIS: A META-ANALYSIS OF POPULATION-BASED STUDIES
Authors: Cooper Jared , Markovinovic Ante , Coward Stephanie , Shaheen Aziz , Swain Mark , Panaccione Remo , Ma Christopher , Novak Kerri , Kaplan Gilaad
Published: January 2022

BACKGROUND

Primary sclerosing cholangitis (PSC) is a chronic liver disease associated with significant morbidity, mortality and healthcare utilization—with nearly 80% of PSC patients having inflammatory bowel disease (IBD). Understanding the incidence of PSC is important in defining the burden of disease and planning for allocation of healthcare resources.

AIM

To conduct a systematic review and meta-analysis of population-based studies of the incidence and prevalence of PSC in the general population and in IBD.

METHODS

Medline and Embase (from inception to May 10, 2021) were systematically searched to identify studies via the following inclusion criteria: 1) original articles, 2) population-based study of defined geographic area, 3) reported the incidence or prevalence of PSC in the general population. Studies that assessed specific populations (e.g., pediatric-only) were excluded. Abstracts and full texts were reviewed for inclusion and data was extracted independently in duplicate by two individuals (JC, AM). Meta-analyses, using random-effects, were performed to calculate overall and country-specific incidence and prevalence rates (per 100,000 persons) with 95% confidence intervals (CI). Meta-analysis pooled the Average Annual Percentage Change (AAPC) in the incidence of PSC in the general population.

RESULTS

The initial search returned 3,958 abstracts. After duplicates were removed, abstracts (3,443) were screened, and full texts were reviewed (317), 17 studies met the criteria for inclusion for incidence and 19 for prevalence in the general population. Studies originated from 13 countries from North America, Asia, Europe, and Oceania (Figure 1). In the general population, incidence rates and prevalence of PSC was 0.75 (95% CI: 0.542, 1.05) and 11.16 (95%CI: 7.78, 16.02) per 100,000 persons, respectively (Figure 1). Incidence rates of PSC were significantly increasing overtime (AAPC: 4.56%; 95% CI: 0.45, 8.68).

DISCUSSION

The incidence of PSC is low at 0.75 per 100,000 but has been significantly increasing over time. The prevalence of PSC is low at 11.16 per 100,000 in the general population. Future studies on the incidence and prevalence of PSC in the general should be directed at Asia, Africa of Latin America to allow for a more robust assessment of the global epidemiology of PSC.
METHYLTRANSFERASE SMYD2 MODULATES THERAPEUTIC EFFECTS OF EPIDERMAL GROWTH FACTOR IN INFLAMMATORY BOWEL DISEASE
Authors: Guan Xiaoqing , Hou Yuning , Sharma Shaligram , Li Chunying
Published: January 2022

BACKGROUND

Inflammatory bowel disease (IBD) is a chronic and remitting inflammatory disorder of the gastrointestinal tract. A prior clinical trial demonstrated the ability of epidermal growth factor receptor (EGFR) ligand EGF to induce and maintain remission in ulcerative colitis. As a protein lysine methyltransferase, SET and MYND domain-containing protein 2 (SMYD2) regulates various cellular functions, including chromatin remodeling and tumorigenesis. A bioinformatic study has shown that EGFR might be a candidate for SMYD2-mediated methylation. In this research, we aimed to investigate whether SMYD2 depletion could synergize with EGFR-activating treatment to promote intestinal goblet cell regeneration in IBD.

METHODS

SMYD2 flox C57BL/6 (SMYD2fl/fl) and intestine epithelial cell-specific conditional knockout of SMYD2 (SMYD2ΔIEC) male mice (8 to10-week old) were given 3 cycles of DSS treatment, each cycle including 5 days of 2% DSS in drinking water followed by 16 days of normal drinking water. EGF (50 μg/kg/day) was administered via intraperitoneal injection once per day for 6 days during the third cycle of DSS treatment (from day 42 to 47 along with DSS administration). The disease activity index (DAI), including body weight loss, stool consistency and colorectal bleeding, was monitored and calculated daily. Histologic scoring was used to evaluate the extent of histopathologic change in middle colon tissue. Goblet cell differentiation and maturation was analyzed via Alcian Blue/periodic acid-Schiff (AB/PAS) staining and immunostaining.

RESULTS

EGF treatment significantly increased the number of goblet cells (AB/PAS staining positive cells) in both SMYD2fl/fl and SMYD2ΔIEC mice. However, in SMYD2ΔIEC mice, more mature goblet cells were observed. In contrast, in SMYD2fl/fl mice, most goblet cells were accumulated at the lower half of colon crypts with small mucin particles. As compared with SMYD2fl/fl mice receiving EGF treatment, SMYD2 depletion combined with EGF injection (6 days) failed to significantly improve body weight loss and DAI scoring during DSS treatment, as well as histologic scoring (including inflammatory cell infiltration and epithelial tissue damage). Immunostaining of goblet cell differentiation markers (including ATOH1, SPDEF and KLF4) revealed no significant difference between SMYD2fl/fl and SMYD2ΔIEC mice.

CONCLUSION

SMYD2 depletion combined with EGF treatment could promote goblet cell expansion and maturation in mouse DSS-induced chronic colitis. However, the mechanism by which SMYD2 depletion facilitates goblet cell maturation needs further investigation.
OXPHOS DRIVES CRYPT FISSIONING REQUIRED FOR HEALING OF IBD ULCERS
Authors: Abomhya Ahmed , Goretsky Tatiana , Kapur Neeraj , Perry Courtney , Avdiushko Margarita , Bradford Emily , Barrett Terrence
Published: January 2022

INTRODUCTION

The failure of ulcers healing is a characteristic feature of IBD. Mitochondrial dysfunction in intestinal epithelial cells (IEC) occurs in IBD and is linked to worse clinical outcomes in pediatric Crohn’s and ulcerative colitis (Kugrathasan et al Lancet 2017, Haberman et al Nat Comm 2019). Cellular polarization and maintenance of cell polarity are energy-dependent and highly regulated by mitochondrial biogenesis (Hardie DG et al Genes Dev 2011). Yet, it is unclear how mitochondria participate in mucosal repair.

METHODS

To model mitochondrial deficiency, TFAM, a transcriptional factor needed for mitochondrial DNA (mtDNA)-encoded genes was silenced in human colonoids (shTFAM) and VilCre/mTmG/TFAMfl/fl (IEC-TFAM-/-) mice. Levels of crypt branching and intestinal stem cell (ISC) and mitochondrial gene mRNA levels were assessed in colonoids cultured in Wnt-containing (WENR) media. Effects on IEC mitochondrial complex levels and oxygen consumption rates (OCR) were assessed in control IEC-TFAM-/- mice and effects on disease activity and ulcer healing assessed in DSS colitis IEC-TFAM-/- mice (fed DSS x 7d, peak ulcer healing-D13-15). Dual florescence confocal microscopy examined crypt fissioning and IHC in WT (Tom+) and Tfamfl/fl (GFP+) crypts during windows of peak ulcer healing.

RESULTS

shTFAM-treated colonoids expressed 55-92% lower mitochondrial gene mRNA (Cox6A1, mt-CO1, ATP5A1) levels (p<0.01) {A} and displayed reduced size (35%) and budding (86%) compared to WT cells (p<0.005) {B}. Studies on IEC from IEC-TFAM-/- mice revealed lower mitochondrial complex protein levels {C i-iv}, and >65% lower mtDNA (p<0.01) {D} compared to controls that correlated with 43 and 65% lower IEC OCR (using Oroboros). In DSS mice, levels of ulceration were greater in IEC-TFAM-/- mice (25%) compared to WT (7.5%) (P<0.005). More importantly, levels of crypt fissioning were 85% lower in TFAM-deficient (GFP+) compared to WT (Tom+) crypts {E}. WT fissioning crypt stained for SOX9 {F} and nuclear pβCat552 {G}.

CONCLUSION

Together, these results suggest that IEC mitochondrial deficiency as seen in IBD patients, impairs crypt fissioning during ulcer healing through a process that impairs cooperation between Wnt and PI3K signaling pathways. The data argue that therapeutic improvement of mitochondrial function may enhance mucosal repair in IBD by promoting crypt fissioning needed to re-establish barrier function.
A NOVEL MICROBIALLY-DERIVED PROTEIN CAN BE EXPRESSED INLACTOCOCCUS LACTIS AND DELIVERED ORALLY TO IMPROVE GUT BARRIER FUNCTION AND PREVENT FIBROGENESIS BY INTERACTING WITH THE EXTRACELLULAR MATRIX DURING GI INJURY
Authors: La Chat Chip La , Nigatu Eskedar , Messner Elisabeth , Raja Bernat Baeza , Desnoyer Jill , Johnson Amy Jo , Willcoxon Michi , Banas Stefanie , Han Andrew , DeSantis Todd , Dabbagh Karim , Shilova Irina , Yamamoto Lynn
Published: January 2022

Intestinal barrier dysfunction or the loss of the epithelial integrity allowing the permeation of microorganisms, dietary antigens and other particles into the gastrointestinal (GI) mucosa results in the activation of the immune system and drives inflammation during IBD. Ongoing inflammation in the GI tract and loss of the mucosal barrier are key features of active disease and predict relapse and serious complications. Existing drugs approved in IBD have limited effects on endoscopic remission and improvement in mucosal healing, driving a critical need for therapies which lead directly to mucosal healing. We have identified a microbial protein, SG-2-0776, that directly improves barrier function and reduces fibrogenesis in vitro and in vivo with potential to become a driver of mucosal healing. SG-2-0776 was identified through a novel algorithm, multi-technology meta-analysis (MTMA), using mucosal biopsies from UC patients and control subjects. Two bacterial strains, Eubacterium eligens and Roseburia hominis were significantly reduced in UC samples. Screening of proteins predicted to be secreted from these strains using in vitro transepithelial/endothelial electrical resistance (TEER) and wound healing assays, identified SG-2-0776, a novel protein, which significantly improved epithelial barrier integrity and reduced fibrogenesis. Administration of recombinant SG-2-0776 protein showed improvement in intestinal barrier function, reduced inflammation and fibrosis in rodent models of colitis. Moreover, SG-2-0776 was expressed in Lactococcus lactis as a delivery vehicle and administered orally to act locally for therapeutic effects in these models of colitis. Mechanism of action studies demonstrated that SG-2-0776 interacts with extracellular matrix proteins regulating myofibroblasts differentiation, leading to reduced fibrogenic phenotypes. Altogether, these results demonstrate SG-2-0776 has the potential, as a standalone or adjunct therapy to existing treatments, to ameliorate mucosal barrier function and prevent fibrogenesis in IBD patients.
THE MICROBIAL LANDSCAPE OF ULCERATIVE COLITIS IN ENDOSCOPIC REMISSION
Authors: Jangi Sushrut , Robison Glenn , Sebastiani Paola , Crott Jimmy , Weinstock Joel , Singh Siddharth , Michaud Dominique
Published: January 2022

BACKGROUND

Achieving endoscopic remission (Mayo endoscopic score of 1 or 0) appears to be the optimal clinical target in ulcerative colitis, reducing risk of relapse, hospitalizations, complications, and need for surgery. While attaining complete endoscopic remission (MES 0) appears to reduce these risks further over mild endoscopic activity (MES 1), the etiologic factors for why MES 0 might be the superior target is poorly understood. Given the putative role of the gut microbiome in driving underlying endoscopic activity and subsequent relapse risk, we sought to define the microbial landscape of UC among patients who achieve either MES 0 vs MES 1 endoscopic remission, especially since the colonic microbial constituents of UC in remission remain uncharacterized.

METHODS

We performed a retrospective cohort study, utilizing data from The Study of a Prospective Adult Research Cohort with IBD (SPARC IBD), part of the IBD Plexus network established by the Crohn’s and Colitis Foundation. SPARC IBD is a national, multi-center, longitudinal cohort study enrolling eligible (>= 18 years) patients with IBD that includes demographic and disease specific clinical data, endoscopic scores, and stool metagenomics. To examine the microbiome, we evaluated beta-diversity (Bray-curtis dissimilarity), and phylum and genera-level differential taxal abundance, utilizing linear models (limma), between patients with UC in either MES 1 vs MES 0 endoscopic remission. Statistical analysis was performed using phyloseq and limma packages in R (ver 4.1).

RESULTS

Within the SPARC cohort, we identified 77 patients in endoscopic remission (48 with MES 0, 29 with MES 1), of which 52% were female and 91% white, with median age of 48. Patients in MES 0 or MES 1 had no significant differences in exposure to anti-TNF therapy (50% vs 50%), vedolizumab (25% vs 19%) or mesalamine (69% vs 72%). Beta-diversity was similar between MES 0 and MES 1 remission [Figure 1]. Both MES 1 and MES 0 remission were dominated by Bacteroidetes and Firmicutes, and were specifically abundant for Bacteroides uniformis, unclassified Subdoligranulum, and Akkermansia mucuniphila. Compared to MES 1 remission, patients with MES 0 remission had increased abundance of Bacteroidetes, Firmicutes, and Actinobacteria, but reduced levels of Proteobacteria and Verrucomicrobia, although after adjusting for multiple comparisons, differential abundance at the phylum and taxa-level between both groups were comparable [Figure 2].

CONCLUSIONS

The microbial landscape of ulcerative colitis in MES 1 vs MES 0 endoscopic remission is comparable with respect to beta-diversity, phylum and genera-level differential taxal abundance. Further investigation will include comparison of UC in remission to healthy controls, and whether the presence of specific microbial groups in remission can predict subsequent relapse.
PREVALENCE AND IMPACTS OF POST-TRAUMATIC STRESS SYMPTOMS IN IBD PATIENTS FROM UNDER-REPRESENTED MINORY GROUPS
Authors: McGarva Josie , Taft Tiffany
Published: January 2022

INTRODUCTION

Post Traumatic Stress (PTS) is a chronic psychological condition that occurs in response to a traumatic event, and includes symptoms of re-experiencing, avoidance behaviors, changes in mood, and hyperarousal. Left untreated, PTS is associated with poor outcomes and significant impairments in quality of life (HRQoL). Recent studies find 20-30% of IBD patients report significant PTS symptoms due to IBD experiences. The majority of participants in these studies are white, non-Hispanic making results difficult to generalize to other populations. As such, we aim to characterize IBD related PTS in under-represented minority (URM) patients.

METHODS

Adult patients 18+ who identify as a URM (Latino/a, African American, Asian, Middle Eastern, Native American or Native Pacific Islander) 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 (fatigue, sleep disturbance, social isolation, pain interreference), and PTSD Checklist-5 (PCL5) with >30 = suggested IBD-PTS, with subscale scores. Independent samples t-Test, Pearson’s correlation, and hierarchical linear regression statistics were used.

RESULTS

67 participants: 46% UC, 79% female, 73% South/Southeast Asian, 6% Hispanic, Age (Mean±SD) = 35.42±9.79 years. 55% had active IBD (HBI/SCCAI > 4; 5.57±4.51). 43% scored >30 on PCL5. Specifically, 55.2% reported re-experiencing trauma, 59.7% avoiding trauma triggers, 62.7% mood changes/irritability, and 67.2% autonomic hyperarousal. Patients with active IBD reported higher IBD-PTS (p=.001) as well as more fatigue, sleep disturbance, pain interference, and social isolation (all p<.001); no differences by IBD diagnosis, gender, or age. When controlling for HBI/SCCAI score, IBD-PTS severity was a significant predictor, but smaller than disease severity, of fatigue (β=.223, p=.025) and pain interference (β=.254, p=.006), and a larger predictor of sleep disturbance (β=.424, p<.001) and social isolation (β= -.417, p<.001). Only the PTS symptoms of hyperarousal and mood contributed to these relationships.

CONCLUSION

43% of URM met criteria for PTS, and scored above 50% in each symptom category of the PCL-5, suggesting URM patients are at even higher risk for IBD-related PTS. Despite disease severity, IBD-PTS severity predicted fatigue, pain interference, sleep disturbance, and social isolation domains of HRQoL; mood changes or hyperarousal presence appear to be the most important symptoms to address. IBD-PTS could have a greater influence on HRQoL than disease activity and should be assessed in patients with both active and inactive disease. More research is necessary to evaluate this relationship and the prevalence of IBD-PTS in URM.
‘Adaptation science’ is needed to inform the sustainable management of the world's oceans in the face of climate change
Authors: Hidalgo Manuel , Bartolino Valerio , Coll Marta , Hunsicker Mary E , Travers-Trolet Morgane , Browman Howard I
Published: January 2022

The global response to the challenge of increasingly rapid and severe climate change is shifting from a focus on mitigation and remediation of impacts to a pragmatic adaptation framework. Innovative adaptive solutions that transform the way in which we manage the world's oceans and, particularly, the harvesting of marine resources in a sustainable manner, are urgently needed. In that context, ICES Journal of Marine Science solicited contributions to the themed article set (TS), “Exploring adaptation capacity of the world's oceans and marine resources to climate change”. We summarize the contributions included in this TS that provide examples of emerging climate change impacts, assess system risks at subnational and international scales, prove and evaluate different adaptation options and approaches, and explore societal and stakeholder perceptions. We also provide some “food for thought" on possible future developments in a transdisciplinary “adaptation science” working at the interface between ecology, socio-economics, and policy-governance, and that will have to provide concrete solutions to the challenges represented by climate-change and anthropogenic activity. Success will depend on the extent to which new knowledge and approaches can be integrated into the decision-making process to support evidence-based climate policy and ecosystem-based management. This includes testing their effectiveness in real systems, but also consider how social acceptance of adaptive measures will/will not support their full implementation.
Weight Gain After Smoking Cessation and Cancer Risk in 3 Prospective Cohorts in the United States
Authors: Hu Yang , Zong Geng , Sun Qi , Giovannucci Edward , Song Mingyang
Published: January 2022

Background

It remains unknown how cancer risks vary by duration of smoking cessation and whether the benefit is attenuated by postcessation weight gain.

Methods

We prospectively followed 198 565 persons from the Nurses’ Health Study (1978-2016), Nurses’ Health Study II (1991-2017), and Health Professionals Follow-up Study (1988-2016) who were free of cancer at baseline. We used proportional hazard Cox models to compare cancer risk between current smokers and former smokers with different durations of smoking cessation and postcessation weight gains.

Results

During 4 718 199 person-years of follow-up, we identified 32 456 cases of total cancer. Compared with current smokers, the risks for total and smoking-related cancer in past smokers were reduced to the level similar to never smokers after abstaining smoking for more than 26 years, with the hazard ratio of 0.69 (95% confidence interval [CI] = 0.63 to 0.76) for total cancer and 0.31 (95% CI = 0.26 to 0.37) for smoking-related cancer, whereas no risk reduction was found for obesity-related cancer. Comparing former smokers with current smokers, the multivariable-adjusted hazard ratios for postcessation weight gain of 0-4.9 kg, 5-9.9 kg, and 10 kg or higher were 0.85 (95% CI = 0.81 to 0.89), 0.88 (95% CI = 0.83 to 0.93), and 0.93 (95% CI = 0.88 to 1.00) for total cancer and 0.62 (95% CI = 0.58 to 0.67), 0.65 (95% CI = 0.60 to 0.71), and 0.71 (95% CI = 0.65 to 0.78) for total smoking-related cancer. In contrast, higher weight gain following smoking cessation was associated with a modest increased obesity-related cancer risk.

Conclusion

Smoking cessation overall has a strong net association with lower risk of total cancer irrespective of weight gain. However, this inverse association may be attenuated by substantial postcessation weight gain, largely because of an increased risk of obesity-related cancers.
Overexpression mutants reveal a role for a chloroplast MPD protein in regulation of reactive oxygen species during chilling in Arabidopsis
Authors: Lunn Daniel , Smith Gracen A , Wallis James G , Browse John
Published: January 2022

Reactive oxygen species (ROS) contribute to cellular damage in several different contexts, but their role during chilling damage is poorly defined. Chilling sensitivity both limits the distribution of plant species and causes devastating crop losses worldwide. Our screen of chilling-tolerant Arabidopsis (Arabidopsis thaliana) for mutants that suffer chilling damage identified a gene (At4g03410) encoding a chloroplast Mpv17_PMP22 protein, MPD1, with no previous connection to chilling. The chilling-sensitive mpd1-1 mutant is an overexpression allele that we successfully phenocopied by creating transgenic lines with a similar level of MPD1 overexpression. In mammals and yeast, MPD1 homologs are associated with ROS management. In chilling conditions, Arabidopsis overexpressing MPD1 accumulated H2O2 to higher levels than wild-type controls and exhibited stronger induction of ROS response genes. Paraquat application exacerbated chilling damage, confirming that the phenotype occurs due to ROS dysregulation. We conclude that at low temperature increased MPD1 expression results in increased ROS production, causing chilling damage. Our discovery of the effect of MPD1 overexpression on ROS production under chilling stress implies that investigation of the nine other members of the Mpv17_PMP22 family in Arabidopsis may lead to new discoveries regarding ROS signaling and management in plants.
H-band temperature and metallicity indicators for cool giants empirical relations in bayesian framework
Authors: Ghosh Supriyo , Ninan J P , Ojha D K
Published: January 2022

We explored here the near-infrared H-band atmospheric window aiming to provide quantitative diagnostic tools for deriving stellar parameters, for instance, effective temperature (Teff) and metallicity ([Fe/H]), of cool giants (Teff < 5000 K) using low-resolution spectra. We obtained 177 cool giants from the X-shooter spectral library covering a wider metallicity range (−2.35 dex < [Fe/H] < 0.5 dex) than in earlier works. Degrading the spectral resolution to R ∼ 1200, we estimated equivalent widths of several important spectral features, and the behaviour of spectral features with stellar parameters are studied. Also, the empirical relations for deriving Teff and [Fe/H] are established in the Bayesian framework. We found that 12CO at 1.56 and 1.62 $\mu$m, and 12CO + MgI at 1.71 $\mu$m are the best threeTeff indicators with a typical accuracy of 153, 123, and 107 K, respectively. The cubic Bayesian model provides the best metallicity estimator with a typical accuracy of 0.22, 0.28, and 0.24 dex for FeH at 1.62 $\mu$m, 12CO at 1.64 $\mu$m, and Fe I at 1.66 $\mu$m, respectively. We also showed a detailed quantitative metallicity dependence ofTeff–EWs correlations defining three metallicity groups, supersolar ([Fe/H] > 0.0 dex), solar (−0.3 dex < [Fe/H] < 0.3 dex), and subsolar ([Fe/H] <−0.3 dex), from Hierarchical Bayesian modelling. The difference between the solar and subsolar relationship is statistically significant, but such difference is not evident between the solar and supersolar groups.
Out of one, many: distinguishing time delays from lensed supernovae
Authors: Denissenya Mikhail , Bag Satadru , Kim Alex G , Linder Eric V , Shafieloo Arman
Published: January 2022

Gravitationally lensed Type Ia supernovae are an emerging probe with great potential for constraining dark energy, spatial curvature, and the Hubble constant. The multiple images and their time delayed and magnified fluxes may be unresolved, however, blended into a single light curve. We demonstrate methods without a fixed source template matching for extracting the individual images, determining whether there are one (no lensing) or two or four (lensed) images, and measuring the time delays between them that are valuable cosmological probes. We find 100 per cent success for determining the number of images for time delays greater than ∼10 d.
Deuterium chemistry and D/H ratios in Class 0/I proto-brown dwarfs
Authors: Riaz B , Thi W-F
Published: January 2022

We have conducted the first extensive observational survey of several deuterated species in 16 Class 0/I proto-brown dwarfs (proto-BDs) and 4 Class Flat/Class II brown dwarfs. Observations were obtained with the IRAM 30m telescope in the DCO+ (3–2), DCN (3–2), DNC (3–2), and N2D+ (3–2) lines. The DCO+/H13CO+, DCN/H13CN, and DNC/HN13C ratios are comparatively higher and show a narrower range than the DCO+/HCO+, DCN/HCN, and DNC/HNC ratios, respectively. The mean D/H ratios for the proto-BDs derived from these molecules are in the range of ∼0.02–3. Both low-temperature gas-phase ion-molecule deuteron transfer and grain surface reactions are required to explain the enhanced deuterium fractionation. The very dense and cold ($n_{H_{2}} \ge 10^{6}$ cm−3, T ≤10 K) interior of the proto-BDs provide the suitable conditions for efficient deuterium fractionation in these cores. There is no correlation between the D/H ratios and the CO depletion factor, with the exception of the DCN/HCN ratios that show a strong anti-correlation possibly due to the difference in the peak emitting regions of the DCN and HCN molecules. Over a wide range in the bolometric luminosities spanning ∼0.002–40 L⊙, we find a trend of higher DCO+/HCO+ and DCN/HCN ratios, nearly constant DNC/HNC and DNC/HN13C ratios, and lower N2D+/N2H+ ratios in the proto-BDs compared to protostars. Only one Class II brown dwarf shows emission in the DCO+ (3–2) line. No correlation is seen between the D/H ratios and the evolutionary stage.
A principal component analysis of polycyclic aromatic hydrocarbon emission in NGC 7023
Authors: Sidhu Ameek , Bazely Josh , Peeters Els , Cami Jan
Published: January 2022

We carried out a principal component analysis (PCA) of the fluxes of five polycyclic aromatic hydrocarbon (PAH) bands at 6.2, 7.7, 8.6, 11.0, and 11.2 µm in the reflection nebula NGC 7023 comprising of the photodissociation region (PDR) and a cavity. We find that only two principal components (PCs) are required to explain the majority of the observed variance in PAH fluxes ( 98 per cent). The first PC ( PC1), which is the primary driver of the variance, represents the total PAH emission. The second PC (PC2) is related to the ionization state of PAHs across the nebula. This is consistent with the results of a similar analysis of the PAH emission in NGC 2023. The biplots and the correlations of PCs with the various PAH ratios show that there are two subsets of ionic bands with the 6.2 and 7.7 µm bands forming one subset and the 8.6 and 11.0 µm bands the other. However, the distinction between these subsets is only present in the PDR. We have also carried out a separate PCA analysis of the PAH fluxes, this time only considering variations in the cavity. This shows that in the cavity, PC2 is not related to the charge state of PAHs but possibly to structural molecular changes.
The DRAKE mission: finding the frequency of life in the Cosmos
Authors: Sarkar Subhajit
Published: January 2022

In the search for life in the Universe, exoplanets represent numerous natural experiments in planet formation, evolution, and the emergence of life. This raises the fascinating prospect of evaluating cosmic life on a statistical basis. One key statistic is the occurrence rate of life-bearing worlds, fL, the ‘frequency of life’ term in the famous Drake Equation. Measuring fL would give profound insight into how common life is and may help us to constrain origin-of-life theories. I propose fL as the goal for the DRAKE mission (Dedicated Research for Advancing Knowledge of Exobiology): a transit spectroscopy survey of M-dwarf habitable zone terrestrial planets. I investigate how the uncertainty on the observed value of fL scales with sample size. I determine that sampling error dominates over observational error and that the uncertainty is a function of the observed fL value. I show that even small sample sizes can provide significant constraints on fL, boding well for the transit spectroscopy approach. I perform a feasibility study of the DRAKE mission using a nominal instrument design and mission plan. Due to low observing efficiencies, DRAKE may need to be incorporated into a wider-ranging deep-space or lunar observatory. A 50-planet survey could constrain fL to ≤ 0.06 (at 95 per cent confidence) if the sample fL  = 0, or 0.03–0.2 if the sample fL  = 0.1. This can be achieved (on average) in 10 yr using a 17-m telescope with an unrestricted field-of-regard. DRAKE is a viable approach to attempting the first experimental measurement of fL.
A Fourier method for the determination of focus for telescopes with stars
Authors: Tan C Y , Schulz B
Published: January 2022

We introduce a Fourier method (Fm) for the determination of best focus for telescopes with stars. Our method fits a power function, that we will derive in this paper, to a set of images taken as a function of focuser position. The best focus position is where the power is maximum. Fm was first tested with small refractor and Schmidt–Cassegrain telescopes. After the successful small telescope tests, we then tested Fm with a 2 m Ritchey–Chrétien–Coudé. Our tests show that Fm is immune to the problems inherent in the popular half-flux diameter method.
A compact symmetric radio source born at one-tenth the current age of the Universe
Authors: An Tao , Wang Ailing , Zhang Yingkang , Aditya J N H S , Hong Xiaoyu , Cui Lang
Published: January 2022

Studies of high-redshift radio galaxies can shed light on the activity of active galactic nuclei (AGNs) in massive elliptical galaxies, and on the assembly and evolution of galaxy clusters in the Universe. J1606+3124 has been tentatively identified as a radio galaxy at a redshift of 4.56, at an era of one-tenth of the current age of the Universe. Very long baseline interferometry (VLBI) images show a compact triple structure with a size of 68 pc. The radio properties of J1606+3124, including the edge-brightening morphology, peaked GHz radio spectrum, slow variability, and low jet speed, consistently indicate that it is a compact symmetric object (CSO). The radio source size and expansion rate of the hotspots suggest that J1606+3124 is a young (kinematic age of ∼3600 yr) radio source. Infrared observations reveal a gas- and dust-rich host galaxy environment, which may hinder the growth of the jet; however, the ultra-high jet power of J1606+3124 gives it an excellent chance to grow into a large-scale double-lobe radio galaxy. If its redshift and galaxy classification can be confirmed by further optical spectroscopic observations, J1606+3124 will be the highest redshift CSO galaxy known to date.
Is 2021 PH27 an active asteroid with a meteor shower detectable on Venus?
Authors: Carbognani Albino , Tanga Paolo , Bernardi Fabrizio
Published: January 2022

The recently discovered near-Earth asteroid 2021 PH27 has the shortest orbital period of all known asteroids. It cannot be excluded that 2021 PH27 is also an active asteroid, as (3200) Phaethon. We intend to estimate the consequences of this hypothesis, although testing is difficult with ground-based observations during perihelion passages, due to low solar elongation. Assuming a surface activity similar to that of Phaethon, an increase in brightness of about 1.4 mag can be estimated. Since it is an asteroid with a minimum orbit intersection distance of 0.014660 ± 0.000034 au with Venus, 2021 PH27 could be the equivalent of Phaethon for the Earth and be the progenitor body of a Venusian meteor shower. A good opportunity to observe the hypothetical fireballs in Venus’s atmosphere will take place on the days around 2023 June 7, when Venus will pass at the minimum distance from the nominal orbit of 2021 PH27. Another favourable date will be 2026 July 5. Finally, on 2022 March 28, the asteroid will also be at the maximum Sun elongation of about 52${_{.}^{\circ}}$3 and at the aphelion of its orbit, the most favourable configuration to characterize it from the physical point of view with photometric, polarimetric, and spectroscopic observations.
Analysis of epigenetic features characteristic of L1 loci expressed in human cells
Authors: Freeman Benjamin , White Travis , Kaul Tiffany , Stow Emily C , Baddoo Melody , Ungerleider Nathan , Morales Maria , Yang Hanlin , Deharo Dawn , Deininger Prescott , Belancio Victoria P
Published: January 2022

Only a select few L1 loci in the human genome are expressed in any given cell line or organ, likely to minimize damage done to the genome. The epigenetic features and requirements of expressed L1 loci are currently unknown. Using human cells and comprehensive epigenetic analysis of individual expressed and unexpressed L1 loci, we determined that endogenous L1 transcription depends on a combination of epigenetic factors, including open chromatin, activating histone modifications, and hypomethylation at the L1 promoter. We demonstrate that the L1 promoter seems to require interaction with enhancer elements for optimal function. We utilize epigenetic context to predict the expression status of L1Hs loci that are poorly mappable with RNA-Seq. Our analysis identified a population of ‘transitional’ L1 loci that likely have greater potential to be activated during the epigenetic dysregulation seen in tumors and during aging because they are the most responsive to targeted CRISPR-mediated delivery of trans-activating domains. We demonstrate that an engineered increase in endogenous L1 mRNA expression increases Alu mobilization. Overall, our findings present the first global and comprehensive analysis of epigenetic status of individual L1 loci based on their expression status and demonstrate the importance of epigenetic context for L1 expression heterogeneity.
Acid–base homeostasis: a historical inquiry of its origins and conceptual evolution
Authors: Eknoyan Garabed
Published: January 2022

To a great extent, the conceptual evolution of acid–base homeostasis has been shaped by progress in chemistry. It began with the theoretical consideration of matter by the natural philosophers of antiquity, progressed into an observational craft as chymistry during the Scientific Revolution, evolved into analytical chemistry in the Enlightenment when acid–alkali interactions began to be deciphered, then was clearly exposed in the organic chemistry of the 19th century and ultimately formulated in mathematical precision as the chemical equations of physical chemistry in the 20th century. Two principal transformational changes shaped their clinical application. The first, launched by the Chemical Revolution of Antoine Lavoisier, introduced quantitation, clarified the language and added experimental rigor to chemical studies, which Claude Bernard then introduced into physiology, formulated the concept of regulatory homeostasis, refined experimental medicine and explored the role of the kidney in acid–base balance. The second transformational change in their gradual clinical applicability began in electrochemical studies that revived the atomic composition of matter and introduced the notion of ions and electrolytes that were fundamental in formulating the concept of acid–base ionization by Svante Arrhenius in 1884 and their measurement from hydrogen ion concentration as pH by Søren Sørensen in 1909. Subsequent studies of Lawrence J. Henderson and Donald D. van Slyke introduced these laboratory-based conceptual advances to the bedside in the 20th century. Clinical studies of acidosis and alkalosis that followed over the past few decades have facilitated and refined the clinical recognition, interpretation and treatment of acid–base disorders.
Rates and predictors of methotrexate-related adverse events in patients with early rheumatoid arthritis: results from a nationwide UK study
Authors: Sherbini Ahmad A , Gwinnutt James M , Hyrich Kimme L ,   RAMS Co-Investigators, Adebajo Ade , Ahmed Khalid , Al-Ansari Atheer , Amarasena Roshan , Bukhari Marwan , Callan Margaret , Chelliah Easwaradhas G , Chinoy Hector , Cooper Annie , Dasgupta Bhaskar , Davis Martin , Galloway James , Gough Andrew , Green Michael , Gullick Nicola , Hamilton Jennifer , Hassan Waji , Hider Samantha , Hyrich Kimme , Kamath Sanjeet , Knight Susan , Lane Suzanne , Lee Martin , Levy Sarah , Macphie Lizzy , Marguerie Christopher , Marshall Tarnya , Mathews Catherine , McKenna Frank , Naz Sophia , Perry Mark , Pollard Louise , Quilty Brian , Robertson Lindsay , Roy Dipak , Sanders Paul , Saravanan Vadivelu , Scott David , Smith Gillian , Smith Richard , Symmons Deborah , Teh Lee-Suan , Viner Nick , Verstappen Suzanne M M
Published: January 2022

Objectives

To estimate prevalence rates and identify baseline predictors of adverse events (AEs) over the first year of treatment in patients with RA starting MTX.

Methods

Data came from the UK Rheumatoid Arthritis Medication Study (RAMS), a prospective cohort of patients with RA starting MTX. This analysis included patients aged ≥18 years with physician diagnosed RA and symptom duration ≤2 years, who were commencing MTX for the first time. AEs were recorded by interviewing patients at 6- and 12-month follow-up visits. The period prevalence rates of AEs are reported for 0–6 months, 6–12 months and 0–12 months of follow-up. The associations between baseline characteristics and AEs were assessed using multivariable logistic regression.

Results

A total of 1069 patients were included in the analysis. Overall, 77.5% experienced at least one AE. The most commonly reported AEs were: gastrointestinal (42.0%), neurological (28.6%), mucocutaneous (26.0%), pulmonary (20.9%), elevated alanine transaminase (18.0%) and haematological AEs (5.6%). Factors associated with increased odds of AEs were: women vs men (gastrointestinal, mucocutaneous, neurological) and alcohol consumption (nausea, alopecia, mucocutaneous). Older age, higher estimated glomerular filtration rate and alcohol consumption were associated with less reporting of haematological AEs.

Conclusions

AEs were common among patients over the first year of MTX, although most were not serious. Knowledge of the rates and factors associated with AE occurrence are valuable when communicating risks prior to commencing MTX. This can help patients make informed decisions whether to start MTX, potentially increasing adherence to treatment.
CDK12 Is Necessary to Promote Epidermal Differentiation Through Transcription Elongation
Authors: Li Jingting , Tiwari Manisha , Chen Yifang , Luanpitpong Sudjit , Sen George L
Published: January 2022

Proper differentiation of the epidermis is essential to prevent water loss and to protect the body from the outside environment. Perturbations in this process can lead to a variety of skin diseases that impacts 1 in 5 people. While transcription factors that control epidermal differentiation have been well characterized, other aspects of transcription control such as elongation are poorly understood. Here we show that of the two cyclin-dependent kinases (CDK12 and CDK13), that are known to regulate transcription elongation, only CDK12 is necessary for epidermal differentiation. Depletion of CDK12 led to loss of differentiation gene expression and absence of skin barrier formation in regenerated human epidermis. CDK12 binds to genes that code for differentiation promoting transcription factors (GRHL3, KLF4, and OVOL1) and is necessary for their elongation. CDK12 is necessary for elongation by promoting Ser2 phosphorylation on the C-terminal domain of RNA polymerase II and the stabilization of binding of the elongation factor SPT6 to target genes. Our results suggest that control of transcription elongation by CDK12 plays a prominent role in adult cell fate decisions.
Pathogenicity and Biological Characteristics of Septotinia populiperda Causing Leaf Blotch of Willow
Authors: Zhu Li-Hua , Xu Wu , Huang Lin , Ye Jian-Ren , Li De-Wei
Published: January 2022

Salix babylonica is an important landscape tree in China and has been widely planted. In this study, the pathogenicity of Septotinia populiperda causing leaf blotch of Sa. babylonica to four willow species (Sa. matsudana, Sa. chaeomoloides, Sa. matsudana f. tortuosa, and Sa. suchowensis) and Populus tomentosa (Chinese white poplar) was determined. Its sexual stage and biological characteristics were studied. Leaves from four willow species and P. tomentosa were inoculated with mycelial plugs. Typical leaf blotches with sporodochia were produced on all inoculated leaves. Among the isolates studied, some developed conidia but sclerotia were rare. The sclerotia developed apothecia after induction at 4°C for 3 months in an incubator and 2 more months outdoors from January to March. The biological characteristics of S. populiperda showed that mycelium grew better on complete medium than on potato dextrose agar, Czapek’s agar, and minimal medium. For mycelial growth, the optimal carbon source was dextrose and the optimal nitrogen source was yeast powder. Conidia germination rate was 59.4% at 24 h. The conidia germinated best in a 4% willow leaf extraction. The optimal temperature for conidia germination was 25°C, and the optimal pH was 4.