Hepatitis C virus (HCV) infection is common and can accelerate chronic kidney disease (CKD) progression. Direct-acting antiviral (DAA) therapies against hepatitis C have consistently shown rates of ...sustained viral remission. However, the effect on kidney function is unknown. In a retrospective observational cohort study of HCV-infected patients receiving DAA therapies from 2013 to 2017, the slopes of estimated glomerular filtration rate (eGFR) decline were compared in the three years before DAA therapy to the slope after therapy. Pre- and post-treatment albuminuria values were also compared. In all, 1,178 patients were included; mean age of 56, 64% male, 71% white, 21% were diabetic, and 42% with cirrhosis. In patients with eGFR less than 60ml/min per 1.73m2, the annual decline in eGFR in the three years prior to treatment was -5.98 ml/min per year (95% confidence interval -7.30 to -4.67) and improved to -1.32 ml/min per year (95% confidence interval -4.50 to 1.88) after DAA therapy. In patients with eGFR greater than 60ml/min per 1.73m2 the annual decline in eGFR in the three years prior to treatment was -1.43 ml/min per year (95% confidence interval -1.78 to -1.08) and after DAA therapy was -2.32 ml/min per year (95% confidence interval -3.36 to -1.03). Albuminuria improved significantly in patients without diabetes, but not in those with diabetes. Predictors of eGFR improvement included having CKD at baseline and being non-diabetic. Events of acute kidney injury were rare, occurring in 29 patients, and unrelated to antiviral therapy in 76% of cases. Thus, DAA therapy for HCVs infection may slow CKD progression.
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Previous research illustrated that infants' temperamental traits shape parents' behaviors, but parents' behaviors can also elicit or intensify infants' behaviors in ways that shape temperament. One ...understudied aspect of parenting that may exhibit bidirectional influences with temperament is parent technology use (e.g., use of mobile devices) within family contexts. To date, few studies have examined whether maternal technology use is associated with infant temperament and whether age-related differences in these associations exist. The present study was a secondary analysis of pooled data from three infant feeding studies. Mothers (
= 374) of young infants (age 16.2 ± 6.2 weeks) completed measures of maternal technology use during infant feeding and care interactions, infant temperament, and family demographics. Maternal technology use was positively associated with negative affectivity and negatively associated with orienting/regulatory capacity but was not associated with positive affectivity/surgency. The association between maternal technology use and negative affectivity was stronger for younger infants than older infants, while the association between maternal technology use and orienting/regulatory capacity was not significant for younger infants but was for older infants. Findings suggest maternal technology use is associated with infant negative affectivity and orienting/regulatory capacity, but the strength of these associations may change with infant age. Further longitudinal research is needed to verify this interpretation and understand mechanisms underlying these associations.
Speech motor processes and phonological forms influence one another because speech and language are acquired and used together. This hypothesis underpins the Computational Core (CC) model, which ...provides a framework for understanding the limitations of perceptually-driven changes to production. The model assumes a lexicon of motor and perceptual wordforms linked to concepts and whole-word production based on these forms. Motor wordforms are built up with speech practice. Perceptual wordforms encode ambient language patterns in detail. Speech production is the integration of the two forms. Integration results in an output trajectory through perceptual-motor space that guides articulation. Assuming successful communication of the intended concept, the output trajectory is incorporated into the existing motor wordform for that concept. Novel word production exploits existing motor wordforms to define a perceptually-acceptable path through motor space that is further modified by the perceptual wordform during integration. Simulation results show that, by preserving a distinction between motor and perceptual wordforms in the lexicon, the CC model can account for practice-based changes in the production of known words and for the effect of expressive vocabulary size on production accuracy of novel words.
Intelligible speakers achieve specific vocal tract constrictions in rapid sequence. These constrictions are associated in theory with speech motor goals. Adult-focused models of speech production ...assume that discrete phonological representations, sequenced into word-length plans for output, define these goals. This assumption introduces a serial order problem for speech. It is also at odds with children's speech. In particular, child phonology and timing control suggest holistic speech plans, and so the hypothesis of whole word production. This hypothesis solves the serial order problem by avoiding it. When the same solution is applied to adult speech the problem becomes how to explain the development of highly intelligible speech. This is the problem addressed here. A modeling approach is used to demonstrate how perceptual-motor units of production emerge over developmental time with the perceptual-motor integration of holistic speech plans that are also phonological representations; the specific argument is that perceptual-motor units are a product of trajectories (nearly) crossing in motor space. The model, which focuses on the integration process, defines the perceptual-motor map as a set of linked pairs of experienced perceptual and motor trajectories. The trajectories are time-based excursions through speaker-defined perceptual and motor spaces. By hypothesis, junctures appear where motor trajectories near or overlap one another in motor space when the shared (or extremely similar) articulatory configurations in these regions are exploited to combine perceptually-linked motor paths along different trajectories. Junctures form in clusters in motor space. These clusters, along with their corresponding (linked) perceptual points, represent perceptual-motor units of production, albeit at the level of speech motor control only. The units serve as pivots in motor space during speaking; they are points of transition from one motor trajectory to another along perceptually-linked paths that are selected to produce best approximations of whole word targets.
Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte ...enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine.
Prevalence estimates for monoclonal gammopathy of undetermined significance (MGUS) are based on predominantly White study populations screened by serum protein electrophoresis supplemented with ...immunofixation electrophoresis. A prevalence of 3% is reported for MGUS in the general population of European ancestry aged 50 years or older. MGUS prevalence is two times higher in individuals of African descent or with a family history of conditions related to multiple myeloma. We aimed to evaluate the prevalence and clinical implications of monoclonal gammopathies in a high-risk US population screened by quantitative mass spectrometry.
We used quantitative matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) mass spectrometry and EXENT-iQ software to screen for and quantify monoclonal gammopathies in serum from 7622 individuals who consented to the PROMISE screening study between Feb 26, 2019, and Nov 4, 2021, and the Mass General Brigham Biobank (MGBB) between July 28, 2010, and July 1, 2021. M-protein concentrations at the monoclonal gammopathy of indeterminate potential (MGIP) level were confirmed by liquid chromatography mass spectrometry testing. 6305 (83%; 2211 from PROMISE, 4094 from MGBB) of 7622 participants in the cohorts were at high risk for developing a monoclonal gammopathy on the basis of Black race or a family history of haematological malignancies and fell within the eligible high-risk age range (30 years or older for PROMISE cohort and 18 years or older for MGBB cohort); those over 18 years were also eligible if they had two or more family members with a blood cancer (PROMISE cohort). Participants with a plasma cell malignancy diagnosed before screening were excluded. Longitudinal clinical data were available for MGBB participants with a median follow-up time from serum sample screening of 4·5 years (IQR 2·4-6·7). The PROMISE study is registered with ClinicalTrials.gov, NCT03689595.
The median age at time of screening was 56·0 years (IQR 46·8-64·1). 5013 (66%) of 7622 participants were female, 2570 (34%) male, and 39 (<1%) unknown. 2439 (32%) self-identified as Black, 4986 (65%) as White, 119 (2%) as other, and 78 (1%) unknown. Using serum protein electrophoresis with immunofixation electrophoresis, the MGUS prevalence was 6% (101 of 1714) in high-risk individuals aged 50 years or older. Using mass spectrometry, we observed a total prevalence of monoclonal gammopathies of 43% (1788 of 4207) in this group. We termed monoclonal gammopathies below the clinical immunofixation electrophoresis detection level (<0·2 g/L) MGIPs, to differentiate them from those with higher concentrations, termed mass-spectrometry MGUS, which had a 13% (592 of 4207) prevalence by mass spectrometry in high-risk individuals aged 50 years or older. MGIP was predominantly of immunoglobulin M isotype, and its prevalence increased with age (19% 488 of 2564 for individuals aged <50 years, 29% 1464 of 5058 for those aged ≥50 years, and 37% 347 of 946 for those aged ≥70 years). Mass-spectrometry MGUS prevalence increased with age (5% 127 of 2564 for individuals aged <50 years, 13% 678 of 5058 for those aged ≥50 years, and 18% 173 of 946 for those aged ≥70 years) and was higher in men (314 12% of 2570) compared with women (485 10% 5013; p=0·0002), whereas MGIP prevalence did not differ significantly by gender. In those aged 50 years or older, the prevalence of mass spectrometry was significantly higher in Black participants (224 17% of 1356) compared with the controls (p=0·0012) but not in those with family history (368 13% of 2851) compared with the controls (p=0·1008). Screen-detected monoclonal gammopathies correlated with increased all-cause mortality in MGBB participants (hazard ratio 1·55, 95% CI 1·16-2·08; p=0·0035). All monoclonal gammopathies were associated with an increased likelihood of comorbidities, including myocardial infarction (odds ratio 1·60, 95% CI 1·26-2·02; p=0·00016 for MGIP-high and 1·39, 1·07-1·80; p=0·015 for mass-spectrometry MGUS).
We detected a high prevalence of monoclonal gammopathies, including age-associated MGIP, and made more precise estimates of mass-spectrometry MGUS compared with conventional gel-based methods. The use of mass spectrometry also highlighted the potential hidden clinical significance of MGIP. Our study suggests the association of monoclonal gammopathies with a variety of clinical phenotypes and decreased overall survival.
Stand Up To Cancer Dream Team, the Multiple Myeloma Research Foundation, and National Institutes of Health.
Abstract
Introduction: Social interactions shape the infant microbiome by providing opportunities for caregivers to spread bacteria through physical contact. With most research focused on the impact ...of maternal–infant contact on the infant gut microbiome, it is unclear how alloparents (i.e., caregivers other than the parents) influence the bacterial communities of infant body sites that are frequently contacted during bouts of caregiving, including the skin.
Methods: To begin to understand how allocare may influence the diversity of the infant microbiome, detailed questionnaire data on infant–alloparent relationships and specific allocare behaviors were coupled with skin and fecal microbiome samples (four body sites) from 48 infants living in Chicago, United States.
Results: Data from 16S
rRNA
gene amplicon sequencing indicated that infant skin and fecal bacterial diversity showed strong associations (positive and negative) to having female adult alloparents. Alloparental feeding and co‐sleeping displayed stronger associations to infant bacterial diversity compared to playing or holding. The associations with allocare behaviors differed in magnitude and direction across infant body sites. Bacterial relative abundances varied by infant–alloparent relationship and breastfeeding status.
Conclusion: This study provides some of the first evidence of an association between allocare and infant skin and fecal bacterial diversity. The results suggest that infants' exposure to bacteria from the social environment may vary based on infant–alloparent relationships and allocare behaviors. Since the microbiome influences immune system development, variation in allocare that impacts the diversity of infant bacterial communities may be an underexplored dimension of the social determinants of health in early life.
Antenatal anxiety has been linked to adverse obstetric outcomes, including miscarriage and preterm birth. However, most studies investigating anxiety during pregnancy, particularly during the ...COVID-19 pandemic, have focused on symptoms during the second and third trimester. This study aims to describe the prevalence of anxiety symptoms early in pregnancy and identify predictors of early pregnancy anxiety during the COVID-19 pandemic.
We assessed baseline moderate-to-severe anxiety symptoms after enrollment in the UCSF ASPIRE (Assessing the Safety of Pregnancy in the Coronavirus Pandemic) Prospective Cohort from May 2020 through February 2021. Pregnant persons < 10 weeks' gestation completed questions regarding sociodemographic characteristics, obstetric/medical history, and pandemic-related experiences. Univariate and multivariate hierarchical logistic regression analyses determined predictors of moderate or severe anxiety symptoms (Generalized Anxiety Disorder-7 questionnaire score ≥ 10). All analyses performed with Statistical Analysis Software (SAS®) version 9.4.
A total of 4,303 persons completed the questionnaire. The mean age of this nationwide sample was 33 years of age and 25.7% of participants received care through a fertility clinic. Over twelve percent of pregnant persons reported moderate-to-severe anxiety symptoms. In univariate analysis, less than a college education (p < 0.0001), a pre-existing history of anxiety (p < 0.0001), and a history of prior miscarriage (p = 0.0143) were strong predictors of moderate-to-severe anxiety symptoms. Conversely, having received care at a fertility center was protective (26.6% vs. 25.7%, p = 0.0009). COVID-19 related stressors including job loss, reduced work hours during the pandemic, inability to pay rent, very or extreme worry about COVID-19, and perceived stress were strongly predictive of anxiety in pregnancy (p < 0.0001). In the hierarchical logistic regression model, pre-existing history of anxiety remained associated with anxiety during pregnancy, while the significance of the effect of education was attenuated.
Pre-existing history of anxiety and socioeconomic factors likely exacerbated the impact of pandemic-related stressors on early pregnancy anxiety symptoms during the COVID-19 pandemic. Despite on-going limitations for in-person prenatal care administration, continued emotional health support should remain an important focus for providers, particularly when caring for less privileged pregnant persons or those with a pre-existing history of anxiety.
Hepatitis C virus (HCV) infection, a major cause of end‐stage liver disease, is a common comorbidity in patients on dialysis and causes increased morbidity and mortality. Historically HCV has been ...extremely difficult to cure with interferon and ribavirin‐based therapies, which are also associated with significant side effects, and few dialysis patients ever received HCV treatment. However, in the last 4 years, interferon‐free direct‐acting antiviral therapies have been approved, and several combinations have been studied in dialysis patients. A recently approved, pan‐genotypic, direct‐acting antiviral regimen, glecaprevir and pibrentasvir, may simplify prescribing. The simplicity of these new therapies, with few side effects, makes it possible for nephrologists to treat HCV infection in their patients on dialysis. We review the workflow and motivation behind nephrology‐led management of HCV infection. We highlight the importance of identifying which patients need referral to a hepatologist or HCV specialist prior to treatment and which can be managed by their nephrologist. Nephrologist involvement would lead to improved access to treatment and ensure that appropriate patients are referred for HCV treatment. In this paper, we review the background of HCV infection, its effect on dialysis patients, and impact on kidney transplantation. In addition, we outline the therapy options for each genotype of HCV, and we discuss the benefits and barriers to nephrology‐led HCV treatment.
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