The vicious cycle of psychopathology and stressful life events: A meta-analytic review testing the stress generation model.

Stress generation theory initially posited that depression elevates risk for some stressful events (i.e., dependent events) but not others (i.e., independent events). This preregistered meta-analytic review examined whether stress generation occurs transdiagnostically by examining 95 longitudinal studies with 38,228 participants (537 total effect sizes) from over 30 years of research. Our multilevel meta-analyses found evidence of stress generation across a broad range of psychopathology, as evidenced by significantly larger prospective effects for dependent (overall psychopathology: r = .23) than independent (overall psychopathology: r = .10) stress. We also identified unique patterns of effects across specific types of psychopathology. For example, effects were larger for depression than anxiety. Furthermore, effects were sometimes larger in studies with younger participants, shorter time lags between assessments, checklist measures of stress, and for interpersonal stressors. Finally, a multilevel meta-analytic structural equation model suggested that dependent stress exacerbates psychopathology symptoms over time (ß = .04), possibly contributing to chronicity. Interventions targeting the prevention of stress generation may mitigate chronic psychopathology. Conclusions of this study are limited by the predominance of depression effect sizes in the literature and our review of only English language articles. On the other hand, the findings are strengthened by rigorous inclusion criteria, lack of publication bias, and absence of moderating effects by publication year. The latter underscores the replicability of the stress generation effect over the last 30 years. Taken together, the review provides robust evidence that stress generation is a cross-diagnostic phenomenon that contributes to a vicious cycle of increasing stress and psychopathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Risk and protective factors for stress generation: A meta-analytic review.

The stress generation hypothesis suggests that some individuals contribute more than others to the occurrence of dependent (self-generated), but not independent (fateful), stressful life events. This phenomenon is commonly studied in relation to psychiatric disorders, but effects are also driven by underlying psychological processes that extend beyond the boundaries of DSM-defined entities. This meta-analytic review of modifiable risk and protective factors for stress generation synthesizes findings from 70 studies with 39,693 participants (483 total effect sizes) from over 30 years of research. Findings revealed a range of risk factors that prospectively predict dependent stress with small-to-moderate meta-analytic effects (rs = 0.10-0.26). Negligible to small effects were found for independent stress (rs = 0.03-0.12), and, in a critical test for stress generation, most effects were significantly stronger for dependent compared to independent stress (ßs = 0.04-0.15). Moderation analyses suggest effects of maladaptive interpersonal emotion regulation behaviors and repetitive negative thinking are stronger for interpersonal (versus non-interpersonal) stress; effects of repetitive negative thinking and excessive standards for self may be inflated by overreliance on self-report measures that fail to isolate psychological distress from objective experience. Findings have key implications for advancing stress generation theory and informing targets for intervention.

Validation and calibration of the Eating Assessment in Toddlers FFQ (EAT FFQ) for children, used in the Growing Up Milk - Lite (GUMLi) randomised controlled trial.

The Eating Assessment in Toddlers FFQ (EAT FFQ) has been shown to have good reliability and comparative validity for ranking nutrient intakes in young children. With the addition of food items (n 4), we aimed to re-assess the validity of the EAT FFQ and estimate calibration factors in a sub-sample of children (n 97) participating in the Growing Up Milk - Lite (GUMLi) randomised control trial (2015-2017). Participants completed the ninety-nine-item GUMLi EAT FFQ and record-assisted 24-h recalls (24HR) on two occasions. Energy and nutrient intakes were assessed at months 9 and 12 post-randomisation and calibration factors calculated to determine predicted estimates from the GUMLi EAT FFQ. Validity was assessed using Pearson correlation coefficients, weighted kappa (κ) and exact quartile categorisation. Calibration was calculated using linear regression models on 24HR, adjusted for sex and treatment group. Nutrient intakes were significantly correlated between the GUMLi EAT FFQ and 24HR at both time points. Energy-adjusted, de-attenuated Pearson correlations ranged from 0·3 (fibre) to 0·8 (Fe) at 9 months and from 0·3 (Ca) to 0·7 (Fe) at 12 months. Weighted κ for the quartiles ranged from 0·2 (Zn) to 0·6 (Fe) at 9 months and from 0·1 (total fat) to 0·5 (Fe) at 12 months. Exact agreement ranged from 30 to 74 %. Calibration factors predicted up to 56 % of the variation in the 24HR at 9 months and 44 % at 12 months. The GUMLi EAT FFQ remained a useful tool for ranking nutrient intakes with similar estimated validity compared with other FFQ used in children under 2 years.

Effects of heavy rainfall on waterborne disease hospitalizations among young children in wet and dry areas of New Zealand.

Heavy rainfall is associated with increased risk of waterborne disease. However, it is not known whether the risk increment differs between wet and dry regions. We examined this question in New Zealand, which has a wide geographical variation of annual rainfall totals (10th-90th percentile difference ≥3000 mm). We conducted a nested case-crossover study within a prospective child cohort (born in 2009-2010) for assessing transient health effects when modified by longitudinal exposures to rainfall. Short-term heavy rainfall effects on hospitalizations due to enteric bacterial and viral infectious causes at lag of 0-14 days were assessed using a Cox regression model adjusted for daily temperature, relative humidity and evapotranspiration. We derived quantiles of time-weighted long-term rainfall levels at the children's homes and these were added as an interaction term to the short-term effect model. Hospitalization risks were higher two days after heavy rainfall days (hazard ratio [95% confidence interval]: 1.73 [1.10-2.70]). The lowest-observable-adverse-effect-level was detected at the 94th percentile of daily rainfall total. Hospital admissions 1-2 days after heavy rainfall increased most in locations with the lowest and highest long-term rainfall. An interaction of this kind between short-term weather and long-term climate has not been reported previously. It is relevant to climate change risk assessments given global projections of increasing intensity of precipitation, against a background of more severe, and possibly more frequent, droughts and flooding.

A comparison of the effect of a Growing Up Milk - Lite (GUMLi) v. cows' milk on longitudinal dietary patterns and nutrient intakes in children aged 12-23 months: the GUMLi randomised controlled trial.

The second year of life is a period of nutritional vulnerability. We aimed to investigate the dietary patterns and nutrient intakes from 1 to 2 years of age during the 12-month follow-up period of the Growing Up Milk - Lite (GUMLi) trial. The GUMLi trial was a multi-centre, double-blinded, randomised controlled trial of 160 healthy 1-year-old children in Auckland, New Zealand and Brisbane, Australia. Dietary intakes were collected at baseline, 3, 6, 9 and 12 months post-randomisation, using a validated FFQ. Dietary patterns were identified using principal component analysis of the frequency of food item consumption per d. The effect of the intervention on dietary patterns and intake of eleven nutrients over the duration of the trial were investigated using random effects mixed models. A total of three dietary patterns were identified at baseline: 'junk/snack foods', 'healthy/guideline foods' and 'breast milk/formula'. A significant group difference was observed in 'breast milk/formula' dietary pattern z scores at 12 months post-randomisation, where those in the GUMLi group loaded more positively on this pattern, suggesting more frequent consumption of breast milk. No difference was seen in the other two dietary patterns. Significant intervention effects were seen on nutrient intake between the GUMLi (intervention) and cows' milk (control) groups, with lower protein and vitamin B12, and higher Fe, vitamin D, vitamin C and Zn intake in the GUMLi (intervention) group. The consumption of GUMLi did not affect dietary patterns, however, GUMLi participants had lower protein intake and higher Fe, vitamins D and C and Zn intake at 2 years of age.

A multicenter, double-blind, randomized, placebo-controlled trial to evaluate the effect of consuming Growing Up Milk "Lite" on body composition in children aged 12-23 mo.

BACKGROUND: Growing Up Milk (GUM) was developed to assist young children in meeting their nutritional requirements during the second year of life. However, there is limited evidence that GUM improves nutritional status and growth in young children. OBJECTIVES: To evaluate the effect of consuming Growing Up Milk "Lite" (GUMLi) (reduced protein with synbiotics and micronutrients added) compared with standard cow milk as part of a whole diet for 1 y on body composition at 2 y of age. METHODS: GUMLi Trial was a multicenter, double-blind, randomized placebo-controlled trial conducted in Auckland and Brisbane. Healthy 1-y-olds were recruited and randomly assigned to receive either GUMLi or standard cow milk for 12 mo as part of a whole diet. The primary outcome was percentage body fat at 2 y of age measured by bioelectrical impedance. All regression models adjusted for baseline outcome and study center. RESULTS: 160 children (80 per arm) were randomly assigned, and 134 (67 per arm) were included in the modified intention-to-treat analyses. The mean percentage body fat at 12 mo was 23.3% (SD 7.9) in the GUMLi group and 25.7% (SD 7.2) in the cow milk group. After adjusting for baseline outcome and study location, the estimated mean difference in percentage body fat between the intervention and control at 12 mo was -2.19% (95% CI: -4.24, -0.15; P = 0.036). Per-protocol analysis showed a similar effect (mean difference: -2.09%; 95% CI: -4.16, -0.03; P = 0.047). Both fat mass and the fat mass index were significantly lower in the GUMLi group at 12 mo than in the cow milk group. CONCLUSIONS: At 2 y of age, children who consumed a GUM with a lower protein content than cow milk over 12 mo had a lower percentage of body fat. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12614000918628.

Evaluation of the Effect of a Growing up Milk Lite vs. Cow's Milk on Diet Quality and Dietary Intakes in Early Childhood: The Growing up Milk Lite (GUMLi) Randomised Controlled Trial.

scores provide an alternative approach to measuring dietary quality. The Growing Up Milk-Lite (GUMLi) Trial was a multi-centre, double-blinded, randomised controlled trial of children randomised to receive a reduced protein GUM (GUMLi) or unfortified cow's milk (CM). In a secondary analysis of the GUMLi Trial, we used the Probability of Adequate Nutrient Intake (PANDiet) to determine the nutritional adequacy of the diets of participating children living in Auckland. The PANDiet was adapted to the New Zealand Nutrient Reference Values and data from four 24 h Recalls (24HR) collected at months 7, 8, 10, and 11 post-randomisation were used. Differences between randomised groups (GUMLi vs. CM) of the PANDiet and its components were made. Eighty-three Auckland participants were included in the study (GUMLi n = 41 vs. CM n = 42). Total PANDiet scores were significantly higher in the GUMLi group (p < 0.001), indicating better overall nutrient adequacy and diet quality. Dietary intakes of children in both groups met the recommendations for fat, total carbohydrates and most micronutrients; however, protein intakes exceeded recommendations. Consumption of GUMLi was associated with higher nutritional adequacy, with an increased likelihood of meeting nutrient requirements; however, the impact of the family diet and GUMLi on dietary diversity requires further evaluation.

Compared with Cow Milk, a Growing-Up Milk Increases Vitamin D and Iron Status in Healthy Children at 2 Years of Age: The Growing-Up Milk-Lite (GUMLi) Randomized Controlled Trial.

Background: Iron deficiency (ID) and vitamin D deficiency (VDD) are significant pediatric health issues in New Zealand and Australia and remain prevalent micronutrient deficiencies in young children globally. Objective: We aimed to investigate the effect of a micronutrient-fortified, reduced-energy growing-up milk (GUMLi) compared with cow milk (CM) consumed for 1 y on dietary iron and vitamin D intakes and the status of New Zealand and Australian children at 2 y of age. Methods: The GUMLi Trial was a multicenter, double-blind, randomized controlled trial in 160 healthy 1-y-old New Zealand and Australian children conducted in 2015-2017. Participants were randomly assigned 1:1 to receive GUMLi (1.7 mg Fe/100 mL; 1.3 µg cholecalciferol/100 mL) or CM (0.02 mg Fe/100 mL; 0.06 µg cholecalciferol/100 mL) for 12 mo. Secondary outcomes, reported here, included change in dietary iron and vitamin D intakes, iron status, and 25-hydroxyvitamin D [25(OH)D] concentrations from blood samples at age 2 y. All regression models were adjusted for baseline outcome and study center. Results: GUMLi was a large contributor to dietary intakes of iron and vitamin D after 12 mo when compared with intakes from food and CM. The adjusted mean difference between groups for serum ferritin concentrations was 17.8 µg/L (95% CI: 13.6, 22.0 µg/L; P < 0.0001), and for 25(OH)D it was 16.6 nmol/L (95% CI: 9.9, 23.3 nmol/L; P < 0.0001). After 12 mo, ID was present in 16 (24%) participants in the CM group and 5 (7%) participants in the GUMLi group (P = 0.009), and the prevalence of VDD in the CM group increased to 14% (n = 10) and decreased to 3% (n = 2) (P = 0.03) in the GUMLi group. Conclusion: In comparison with CM, GUMLi significantly improved dietary iron and vitamin D intakes and the iron and vitamin D status of healthy children at 2 y of age. This trial was registered with the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12614000918628.

Computed tomographic pneumocolonography in normal dogs.

Objectives of this prospective study were to describe effects of varying technical components that may contribute to an optimal protocol for computed tomographic pneumocolonography (CTP) in dogs, and to develop a standardized methodology for CTP as a future potential diagnostic tool in canine clinical patients with large bowel disease. Eight purpose-bred intact male hound cross-research dogs were enrolled and randomized to groups based on variables of pressure/body position (n = 4) and insufflation time (n = 4). For each segment of large bowel (rectum, colorectal junction, descending colon, transverse colon, ascending colon), the adequacy of bowel preparation, % of bowel lumen filled with fecal material, and bowel tortuosity or folding were assessed. Measurements of bowel wall thickness (cm), cross-sectional bowel lumen diameter (cm), and cross-sectional bowel luminal area (cm(2) ) were obtained at standardized locations within the large bowel. False discovery rates (FDR) were calculated to adjust for multiple testing. Values of FDR < 0.05 were considered significant. Differences in mean cross-sectional area and diameter and bowel wall thickness under increasing pressure were not significant after adjusting for multiple testing; some had raw p values <0.05. Ascending colon diameter and ascending colon area significantly increased with insufflation time (FDR < 0.05). No other response variables showed a significant change with insufflation time. The optimal insufflation pressure for maintaining pneumocolon in this study was determined to be 20 mmHg. CTP is a feasible technique to provide consistent distension for imaging of the large bowel and further study on application of CTP in clinical patients is warranted.

Ultrasonographic thickening of the muscularis propria in feline small intestinal small cell T-cell lymphoma and inflammatory bowel disease.

Gastrointestinal lymphoma is the most common form of lymphoma in the cat. More recently, an ultrasonographic pattern associated with feline small cell T-cell gastrointestinal lymphoma has been recognized as a diffuse thickening of the muscularis propria of the small intestine. This pattern is also described with feline inflammatory bowel disease. To evaluate the similarities between the diseases, we quantified the thickness of the muscularis propria layer in the duodenum, jejunum and ileum of 14 cats affected by small cell T-cell lymphoma and inflammatory bowel disease (IBD) and 19 healthy cats. We found a significantly increased thickness of the muscularis propria in cats with lymphoma and IBD compared with healthy cats. The mean thickness of the muscularis propria in cats with lymphoma or IBD was twice the thickness of that of healthy cats, and was the major contributor to significant overall bowel wall thickening in the duodenum and jejunum. A muscularis to submucosa ratio >1 is indicative of an abnormal bowel segment. Colic lymph nodes in cats with lymphoma were increased in size compared with healthy cats. In cats with gastrointestinal lymphoma and histologic transmural infiltration of the small intestines, colic or jejunal lymph nodes were rounded, increased in size and hypoechoic.

The quality of pediatric orthopaedic information on the internet.

BACKGROUND: Many patients use the Internet for health information. However, there are few guarantees to the reliability and accuracy of this information. This study examined the quality and content of the Internet Web pages for 10 common pediatric orthopaedic diagnoses. METHODS: We identified 10 common diagnoses in pediatric orthopaedics: brachial plexus injury, cerebral palsy, clubfoot, developmental dysplasia of the hip, leg length discrepancy, osteochondroma, polydactyly, scoliosis, spina bifida, and syndactyly. We used 2 of the most popular search engines to identify the top 10 Web sites for each disease. We evaluated the Web sites utilizing both the quality-based Health On the Net (HON) Foundation criteria and our own content-based grading sheets. The custom grading sheets focused on essential information about disease summary, pathogenesis, diagnosis, treatment, and prognosis. RESULTS: Three orthopaedic surgeons graded 98 academic, commercial, nonprofit, and physicians' Web sites for 10 diseases. Academic Web sites scored the highest in content (mean, 60.8% ± 15.5%), whereas commercial Web sites scored the lowest (mean, 46.7% ± 22.2%). Among the diagnoses, osteochondroma Web sites had the highest content scores (mean, 75.8% ± 11.8%), whereas polydactyly Web sites had the lowest content scores (mean, 39.3% ± 15.7%). In contrast, Web sites about developmental dysplasia of the hip had the highest HON scores (65.0 ± 11.1), whereas those about brachial plexus birth palsy scored the lowest (42.6% ± 16.9%). Among the content subgroups, scores were generally higher for disease summary and diagnostics and lower for prognosis. CONCLUSIONS: The Internet Web sites reviewed demonstrated a wide range of content and information. We found that nonprofit and academic Web sites were the most reliable sources, whereas commercial and, surprisingly, physician-run Web sites were the least reliable. We advise physicians to talk to their patients about the information they get on the Internet and how it dictates their expectations. We hope this study, combined with further understanding of how our patients use this information, can help improve the Internet content. CLINICAL RELEVANCE: Physicians should know that their patients may be receiving misleading information from the Internet and be able to discuss this with their patients.

CD25 preselective anti-HIV vectors for improved HIV gene therapy.

As HIV continues to be a global public health problem with no effective vaccine available, new and innovative therapies, including HIV gene therapies, need to be developed. Due to low transduction efficiencies that lead to low in vivo gene marking, therapeutically relevant efficacy of HIV gene therapy has been difficult to achieve in a clinical setting. Methods to improve the transplantation of enriched populations of anti-HIV vector-transduced cells may greatly increase the in vivo efficacy of HIV gene therapies. Here we describe the development of preselective anti-HIV lentiviral vectors that allow for the purification of vector-transduced cells to achieve an enriched population of HIV-resistant cells. A selectable protein, human CD25, not normally found on CD34+ hematopoietic progenitor cells (HPCs), was incorporated into a triple combination anti-HIV lentiviral vector. Upon purification of cells transduced with the preselective anti-HIV vector, safety was demonstrated in CD34+ HPCs and in HPC-derived macrophages in vitro. Upon challenge with HIV-1, improved efficacy was observed in purified preselective anti-HIV vector-transduced macrophages compared to unpurified cells. These proof-of-concept results highlight the potential use of this method to improve HIV stem cell gene therapy for future clinical applications.

Generation of an HIV-1-resistant immune system with CD34(+) hematopoietic stem cells transduced with a triple-combination anti-HIV lentiviral vector.

HIV gene therapy has the potential to offer an alternative to the use of current small-molecule antiretroviral drugs as a treatment strategy for HIV-infected individuals. Therapies designed to administer HIV-resistant stem cells to an infected patient may also provide a functional cure, as observed in a bone marrow transplant performed with hematopoietic stem cells (HSCs) homozygous for the CCR5-Δ32-bp allele. In our current studies, preclinical evaluation of a combination anti-HIV lentiviral vector was performed, in vivo, in humanized NOD-RAG1(-/-) IL2rγ(-/-) knockout mice. This combination vector, which displays strong preintegration inhibition of HIV-1 infection in vitro, contains a human/rhesus macaque TRIM5α isoform, a CCR5 short hairpin RNA (shRNA), and a TAR decoy. Multilineage hematopoiesis from anti-HIV lentiviral vector-transduced human CD34(+) HSCs was observed in the peripheral blood and in various lymphoid organs, including the thymus, spleen, and bone marrow, of engrafted mice. Anti-HIV vector-transduced CD34(+) cells displayed normal development of immune cells, including T cells, B cells, and macrophages. The anti-HIV vector-transduced cells also displayed knockdown of cell surface CCR5 due to the expression of the CCR5 shRNA. After in vivo challenge with either an R5-tropic BaL-1 or X4-tropic NL4-3 strain of HIV-1, maintenance of human CD4(+) cell levels and a selective survival advantage of anti-HIV gene-modified cells were observed in engrafted mice. The data provided from our study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validates its potential application in future clinical trials.