Social Needs and Happiness:A Life Course Perspective

Both the fulfilment of affection, status, and behavioral confirmation needs and their role in happiness may differ along the adult lifespan. We examined age-graded differences in (a) the fulfilment of the need for affection, status, and behavioral confirmation, (b) disharmonious profiles of need fulfillment (e.g., high affection but low status), and (c) the associations between these needs and happiness. Data from 11,406 Dutch respondents (age range 18–87 (M = 44.82, SD = 14.62), 67% female) were collected via hoegekis.nl and categorized over six age groups (early, young, middle-aged and late adults, young-old and oldest-old). Age-graded differences in social need fulfilment and their link to happiness were examined using regression analyses. Need fulfillment profiles were identified with LCA cluster analyses. Age-graded differences in social need fulfilment were virtually absent (Cohen’s d = 0.20 or smaller) and their link with happiness was stable across the age groups. Social need fulfilment profiles were harmonious as people reported either low, middle, or high need fulfilment in general, irrespective of age. The idea that different social needs are more important in different phases of adult life received only weak support in our data. No strategic investment in specific social needs was observed (no substitution-effects).People typically differed in their capacities to fulfil their affection, status, and behavioral confirmation needs in general, regardless of age. The implications of these results for the social production function theory of wellbeing and socioemotional selectivity theory are outlined in the discussion

Primary Exposure to SARS-CoV-2 via Infection or Vaccination Determines Mucosal Antibody-Dependent ACE2 Binding Inhibition

Background: Mucosal antibodies play a critical role in preventing SARS-CoV-2 infections or reinfections by blocking the interaction of the receptor-binding domain (RBD) with the angiotensin-converting enzyme 2 (ACE2) receptor on the cell surface. In this study, we investigated the difference between the mucosal antibody response after primary infection and vaccination. Methods: We assessed longitudinal changes in the quantity and capacity of nasal antibodies to neutralize the interaction of RBD with the ACE2 receptor using the spike protein and RBD from ancestral SARS-CoV-2 (Wuhan-Hu-1), as well as the RBD from the Delta and Omicron variants. Results: Significantly higher mucosal IgA concentrations were detected postinfection vs postvaccination, while vaccination induced higher IgG concentrations. However, ACE2-inhibiting activity did not differ between the cohorts. Regarding whether IgA or IgG drove ACE2 inhibition, infection-induced binding inhibition was driven by both isotypes, while postvaccination binding inhibition was mainly driven by IgG. Conclusions: Our study provides new insights into the relationship between antibody isotypes and neutralization by using a sensitive and high-Throughput ACE2 binding inhibition assay. Key differences are highlighted between vaccination and infection at the mucosal level, showing that despite differences in the response quantity, postinfection and postvaccination ACE2 binding inhibition capacity did not differ.</p

Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent

Scope: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter‐individual variability in associations between body weight and dairy consumption. Methods and results: A genome‐wide interaction study to discover genetic variants that account for variation in BMI in the context of low‐fat, high‐fat and total dairy intake in cross‐sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta‐analyzed. Twenty‐six genetic variants reached the selected significance threshold (p‐interaction \u3c10−7), and six independent variants (LINC01512‐rs7751666, PALM2/AKAP2‐rs914359, ACTA2‐rs1388, PPP1R12A‐rs7961195, LINC00333‐rs9635058, AC098847.1‐rs1791355) were evaluated meta‐analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3’ of LINC00333) was replicated (p‐interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p‐interaction = 7.36 × 10−8) such that each serving of low‐fat dairy was associated with 0.225 kg m−2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2‐rs1388) approached interaction replication significance for low‐fat dairy exposure. Conclusion: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight

Pharmacokinetics and tissue distribution of PGG–paclitaxel, a novel macromolecular formulation of paclitaxel, in nu/nu mice bearing NCI-460 lung cancer xenografts

PGG–PTX is a water-soluble formulation of paclitaxel (PTX), made by conjugating PTX to poly(l-γ-glutamylglutamine) acid (PGG) via ester bonds, that spontaneously forms a nanoparticle in aqueous environments. The purpose of this study was to compare the pharmacokinetics and tissue distribution of PTX following injection of either free PTX or PGG–PTX in mice. Both [3H]PTX and PGG–[3H]PTX were administered as an IV bolus injection to mice bearing SC NCI-H460 lung cancer xenografts at a dose of 40-mg PTX equivalents/kg. Plasma, tumor, major organs, urine, and feces were collected at intervals out to 340 h. Total taxanes, taxane extractable into ethyl acetate, and native PTX were quantified by liquid scintillation counting and HPLC. Conjugation of PTX to the PGG polymer increased plasma and tumor C max, prolonged plasma half-life and the period of accumulation in tumor, and reduced washout from tumor. In plasma injection of PGG–PTX increased total taxane AUC0–340 by 23-fold above that attained with PTX. In tumors, it increased the total taxane by a factor of 7.7, extractable taxane by 5.7, and native PTX by a factor of 3.5-fold. Conjugation delayed and reduced total urinary and fecal excretion of total taxanes. Incorporation of PTX into the PGG–PTX polymer significantly prolonged the half-life of total taxanes, extractable taxane, and native PTX in both the plasma and tumor compartments. This resulted in a large increase in the amount of active PTX delivered to the tumor. PGG–PTX is an attractive candidate for further development

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm&lt; 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

A non-randomized risk-adjusted comparison of lenalidomide + R-CHOP versus R-CHOP for MYC-rearranged DLBCL patients

Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission rates as more intensive chemotherapy regimens in literature. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed MYC-R DLBCL patients in the Netherlands. Eligible patients from the observational cohort that were not included in the interventional trial served as control group in the present risk-adjusted comparison. R2CHOP treated patients from the interventional trial (n = 77) were younger than patients in the R-CHOP control cohort (n = 56) (median age 63 versus 70 years, p = 0.018) and they were more likely to have a lower WHO performance score (p = 0.013). We adjusted for differences at baseline using 1:1 matching, multivariable analysis, and weighting using the propensity score to reduce treatment-selection bias. These analyses consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.51, and 0.59, respectively, for OS, and 0.53, 0.59, and 0.60 for PFS. Thus, this non-randomized risk-adjusted comparison supports R2CHOP as an additional treatment option for MYC-R DLBCL patients. [Figure not available: see fulltext.

Pollutant effects on genotoxic parameters and tumor-associated protein levels in adults: a cross sectional study

<p>Abstract</p> <p>Background</p> <p>This study intended to investigate whether residence in areas polluted by heavy industry, waste incineration, a high density of traffic and housing or intensive use of pesticides, could contribute to the high incidence of cancer observed in Flanders.</p> <p>Methods</p> <p>Subjects were 1583 residents aged 50–65 from 9 areas with different types of pollution. Cadmium, lead, p,p'-DDE, hexachlorobenzene, PCBs and dioxin-like activity (Calux test) were measured in blood, and cadmium, t,t'-muconic acid and 1-hydroxypyrene in urine. Effect biomarkers were prostate specific antigen, carcinoembryonic antigen and p53 protein serum levels, number of micronuclei per 1000 binucleated peripheral blood cells, DNA damage (comet assay) in peripheral blood cells and 8-hydroxy-deoxyguanosine in urine. Confounding factors were taken into account.</p> <p>Results</p> <p>Overall significant differences between areas were found for carcinoembryonic antigen, micronuclei, 8-hydroxy-deoxyguanosine and DNA damage. Compared to a rural area with mainly fruit production, effect biomarkers were often significantly elevated around waste incinerators, in the cities of Antwerp and Ghent, in industrial areas and also in other rural areas. Within an industrial area DNA strand break levels were almost three times higher close to industrial installations than 5 kilometres upwind of the main industrial installations (p < 0.0001). Positive exposure-effect relationships were found for carcinoembryonic antigen (urinary cadmium, t,t'-muconic acid, 1-hydroxypyrene and blood lead), micronuclei (PCB118), DNA damage (PCB118) and 8-hydroxy-deoxyguanosine (t,t'-muconic acid, 1-hydroxypyrene). Also, we found significant associations between values of PSA above the p90 and higher values of urinary cadmium, between values of p53 above the p90 and higher serum levels of p,p'-DDE, hexachlorobenzene and marker PCBs (PCB 138, 153 and 180) and between serum levels of p,p'-DDE above the p90 and higher serum values of carcinoembryonic antigen. Significant associations were also found between effect biomarkers and occupational or lifestyle parameters.</p> <p>Conclusion</p> <p>Levels of internal exposure, and residence near waste incinerators, in cities, or close to important industries, but not in areas with intensive use of pesticides, showed positive correlations with biomarkers associated with carcinogenesis and thus probably contribute to risk of cancer. In some rural areas, the levels of these biomarkers were not lower than in the rest of Flanders.</p

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p&lt;0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p&lt;0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data