In a Perspective, Julie Garon and Walter Orenstein discuss Lessler and colleagues' modeling study on measles vaccination and the implications for triggered and routine immunization programs.
Research in molecular genetics has generally focused on genome-wide association studies (GWAS) and exploratory candidate gene and candidate gene–environment (G × E) studies. In this article it is proposed that hypothesis-driven and biologically informed research provides a complementary approach to GWAS to advance pressing research questions about G × E relations that are of public health relevance. Prior research studies and developmental and evolutionary theory were used to guide hypothesis testing of G × E relationships in this study. The study investigated whether the oxytocin polymorphism, rs53576, moderated the relationship between parental divorce during adolescence and depression symptoms in young adulthood. Oxytocin is a neuropeptide that has been related to the regulation of complex social cognition and behaviors such as empathy, attachment, and nurturance. We hypothesized that the GG polymorphism would be associated with more depressive symptoms following parental divorce, and that this effect would be stronger in females than males. The sample consisted of 340 individuals who participated in a longitudinal study with data used both from adolescence and young adulthood. Findings using prospective follow-up and autoregressive change models supported the hypothesized relationships. Young adult females who had experienced parental divorce during adolescence and had the GG oxytocin genotype reported almost twice as many depressive symptoms relative to young adult females who also experienced parental divorce during adolescence but had the AA or AG genotype. This pattern was not indicated among males. Findings were discussed with regard to how molecular genetic factors in combination with environmental stressors, such parental divorce, framed within a developmental framework may facilitate the future study of G × E relationships in the parental divorce-child adjustment literature and contribute to a prevention science perspective.
by
Yugo Ando;
Guo-Xiang Yang;
Masanobu Tsuda;
Kazuhito Kawata;
Weici Zhang;
Takahiko Nakajima;
Koichi Tsuneyama;
Patrick Leung;
Zhe-Xiong Lian;
Kazuichi Okazaki;
William M. Ridgway;
Gary L. Norman;
Aftab A Ansari;
Xiao-Song He;
Ross L. Coppel;
M. Eric Gershwin
dnTGFβRII mice, expressing a dominant negative form of TGFβ receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis . We previously observed that deficiency in IL-12p40 led to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL-12p40 mediated protection acted via the IL-12 or IL-23 pathways, we generated an IL-23p19−/− dnTGFβRII strain deficient in IL-23 but not in IL-12; mice were longitudinally followed for changes in the natural history of disease and immune responses. Interestingly, IL-23p19−/− mice demonstrate dramatic improvement in their colitis but no changes in biliary pathology; mice also manifest reduced Th17 cell populations and unchanged IFN-γ levels. We submit that the IL-12/Th1 pathway is essential for biliary disease pathogenesis, while the IL-23/Th17 pathway mediates colitis. To further assess the mechanism of the IL-23 mediated protection from colitis, we generated an IL-17A−/− dnTGFβRII strain deficient in IL-17, a major effector cytokine produced by IL-23-dependent Th17 cells. Deletion of the IL-17A gene did not affect the severity of either cholangitis or colitis, suggesting that the IL-23/Th17 pathway contributes to the colon disease in an IL-17-independent manner. These results affirm that the IL-12/Th1 pathway is critical to biliary pathology in dnTGFβRII mice while the colitis is caused by a direct effect of IL-23.
Background:
Anterior cruciate ligament (ACL) tears are frequently associated with meniscal injury. Risk factors for concomitant meniscal injuries have been studied in the adult population but less so in pediatric patients.
Purpose:
To evaluate the relationship between age and body mass index (BMI) and the presence of a concomitant meniscal tear at the time of ACL reconstruction (ACLR) in pediatric patients.
Study Design:
Case-control study; Level of evidence, 3.
Methods:
A single-institution retrospective review was performed of patients aged <19 years who underwent primary ACLR over a 3.5-year period. Revision ACLR and multiligament knee reconstructions were excluded. Logistic regression was used to identify risk factors associated with having a meniscal tear at the time of surgery. Subgroup analysis was performed for medial and lateral meniscal tears.
Results:
Included in this study were 453 patients (230 males, 223 females; median age, 15 years). Of these, 265 patients (58%) had a meniscal tear, including 150 isolated lateral meniscal tears, 53 isolated medial meniscal tears, and 62 patients with both lateral and medial meniscal tears. Median time from injury to surgery was 48 days. For every 1-year increase in age, there was a 16% increase in the adjusted odds of having any meniscal tear (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.05-1.27; P = .002), with a 20% increase in the odds of having a medial meniscal tear (OR, 1.20; 95% CI, 1.07-1.35; P = .002) and a 16% increase in the odds of having a lateral meniscal tear (OR, 1.16; 95% CI, 1.05-1.27; P = .003). For every 2-point increase in BMI, there was a 12% increase in the odds of having any meniscal tear (OR, 1.12; 95% CI, 1.02-1.22; P = .016) and a 10% increase in the odds of having a lateral meniscal tear (OR, 1.10; 95% CI, 1.01-1.19; P = .028).
Conclusion:
Pediatric patients undergoing ACLR had a 58% incidence of concomitant meniscal pathology. Increasing age and BMI were independent risk factors for these injuries, while no association was found between time to surgery and meniscal pathology.
Abstract
Hospital readmissions are receiving more attention because of the implications on cost and quality of care. Many researchers and clinicians believe that a substantial number of readmissions are preventable as evidenced by the significant reductions achieved after the Hospital Readmission Reduction Program mandated by the Affordable Care Act. While sickle cell disease is not currently one of the diseases designated for inclusion in the Hospital Readmission Reduction Program, some of the lessons learned addressing hospital structural characteristics and processes of care can be applied to this population.
Acute worsening of chronic pain is the predominant clinical presentation of patients with sickle cell disease to the hospital. Pain and the measurement of pain is subjective and there are no clearly defined objective clinical criteria or biomarkers to validate or refute the presence of acute sickle cell pain crisis. The current epidemic of nonmedical opioid use and medical opioid abuse combined with racial unrest and governmental oversight in the US worsens a wellknown atmosphere of mistrust on the part of both clinicians and patients with sickle cell disease. These dynamics force the need for a paradigm change in management of these patients.
Deubiquitinating enzymes (DUBs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin (or ubiquitin-like protein), and remodel polyubiquitin (or ubiquitin-like) chains on target proteins. The human genome encodes nearly 100 DUBs with specificity for ubiquitin in five families: the UCH, USP, OTU, Josephin, and JAMM families. Four families are cysteine proteases, while the later is a family of metalloproteases. Most DUB activity is cryptic and active site rearrangements often occur during the binding of ubiquitin and/or scaffold proteins. DUBs with specificity for ubiquitin contain multiple domains with insertions and extensions modulating DUB substrate specificity, protein-protein interactions, and cellular localization. Binding partners and multi-protein complexes with which DUBs associate modulate DUB activity and substrate specificity. Quantitative studies of activity and protein-protein interactions, together with genetic studies and the advent of RNAi, have lead to new insights into the function of yeast and human DUBs. This review will discuss ubiquitin-specific DUBs, some of the generalizations emerging from recent studies of the regulation of DUB activity, and their roles in various cellular processes. Specific examples are drawn from studies of protein degradation, DNA repair, chromatin remodeling, cell cycle regulation, endocytosis, and modulation of signaling kinases.
by
Jonathan Beitler;
Qiang Zhang;
Karen K Fu;
Andy Trotti;
Sharon A Spencer;
Christopher U Jones;
Adam S Garden;
George Shenouda;
Jonathan Harris;
Kian K Ang
Purpose To test whether altered radiation fractionation schemes (hyperfractionation [HFX], accelerated fractionation, continuous [AFX-C], and accelerated fractionation with split [AFX-S]) improved local-regional control (LRC) rates for patients with squamous cell cancers (SCC) of the head and neck when compared with standard fractionation (SFX) of 70 Gy. Methods and Materials Patients with stage III or IV (or stage II base of tongue) SCC (n=1076) were randomized to 4 treatment arms: (1) SFX, 70 Gy/35 daily fractions/7 weeks; (2) HFX, 81.6 Gy/68 twice-daily fractions/7 weeks; (3) AFX-S, 67.2 Gy/42 fractions/6 weeks with a 2-week rest after 38.4 Gy; and (4) AFX-C, 72 Gy/42 fractions/6 weeks. The 3 experimental arms were to be compared with SFX. Results With patients censored for LRC at 5 years, only the comparison of HFX with SFX was significantly different: HFX, hazard ratio (HR) 0.79 (95% confidence interval 0.62-1.00), P=.05; AFX-C, 0.82 (95% confidence interval 0.65-1.05), P=.11. With patients censored at 5 years, HFX improved overall survival (HR 0.81, P=.05). Prevalence of any grade 3, 4, or 5 toxicity at 5 years; any feeding tube use after 180 days; or feeding tube use at 1 year did not differ significantly when the experimental arms were compared with SFX. When 7-week treatments were compared with 6-week treatments, accelerated fractionation appeared to increase grade 3, 4 or 5 toxicity at 5 years (P=.06). When the worst toxicity per patient was considered by treatment only, the AFX-C arm seemed to trend worse than the SFX arm when grade 0-2 was compared with grade 3-5 toxicity (P=.09). Conclusions At 5 years, only HFX improved LRC and overall survival for patients with locally advanced SCC without increasing late toxicity.
In their article, “Immunomodulation as treatment for severe COVID-19: a systematic review of current modalities and future directions,” Meyerowitz and colleagues provide a straightforward source of information for the clinician [1]. In a time when we are flooded with preprints and publications of varying quality, one of the most critical challenges is to separate the grain from the chaff. The authors have done this for us by reviewing hundreds of references and carefully selecting the most appropriate sources of information. Their article helps us forge our conclusions not only for the use of the different immunomodulatory treatments available but importantly also on the rationale of their use.
by
Jesmin Pervin;
Allisyn Moran;
Monjur Rahman;
Abdur Razzaque;
Lynn Sibley;
Peter K. Streatfield;
Laura J. Reichenbach;
Marge Koblinsky;
Daniel Hruschka;
Anisur Rahman
Background: Antenatal Care (ANC) during pregnancy can play an important role in the uptake of evidence-based services vital to the health of women and their infants. Studies report positive effects of ANC on use of facility-based delivery and perinatal mortality. However, most existing studies are limited to cross-sectional surveys with long recall periods, and generally do not include population-based samples.
Methods: This study was conducted within the Health and Demographic Surveillance System (HDSS) of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) in Matlab, Bangladesh. The HDSS area is divided into an icddr,b service area (SA) where women and children receive care from icddr,b health facilities, and a government SA where people receive care from government facilities. In 2007, a new Maternal, Neonatal, and Child Health (MNCH) program was initiated in the icddr,b SA that strengthened the ongoing maternal and child health services including ANC. We estimated the association of ANC with facility delivery and perinatal mortality using prospectively collected data from 2005 to 2009. Using a before-after study design, we also determined the role of ANC services on reduction of perinatal mortality between the periods before (2005 - 2006) and after (2008-2009) implementation of the MNCH program.
Results: Antenatal care visits were associated with increased facility-based delivery in the icddr,b and government SAs. In the icddr,b SA, the adjusted odds of perinatal mortality was about 2-times higher (odds ratio (OR) 1.91; 95% confidence intervals (CI): 1.50, 2.42) among women who received ≤1 ANC compared to women who received ≥3 ANC visits. No such association was observed in the government SA. Controlling for ANC visits substantially reduced the observed effect of the intervention on perinatal mortality (OR 0.64; 95% CI: 0.52, 0.78) to non-significance (OR 0.81; 95% CI: 0.65, 1.01), when comparing cohorts before and after the MNCH program initiation (Sobel test of mediation P < 0.001).
Conclusions: ANC visits are associated with increased uptake of facility-based delivery and improved perinatal survival in the icddr,b SA. Further testing of the icddr,b approach to simultaneously improving quality of ANC and facility delivery care is needed in the existing health system in Bangladesh and in other low-income countries to maximize health benefits to mothers and newborns.