Forum on Public Policy Rotten Outcomes: How Impoverished Neighborhoods Influence the Life Trajectories of Children in the United States

Abstract To use Lisbeth Schorr's term, children who are at risk for "rotten outcomes" are not randomly scattered throughout the society but are, rather, concentrated in impoverished neighborhoods. In recent decades, government policy and public opinion in the U.S. has reflected the belief that children who experience rotten outcomes are, at least in large part, somehow responsible for their own problems. I assert that the social influences which the child experiences in their neighborhood of residence also influence their life outcomes in both direct and indirect ways. Neighborhoods are social environments where children experience life: presenting risks and opportunities, offering or withholding resources necessary for success, creating experiences with and beliefs about social institutions and their representatives, and providing the ecology in which children develop into adults. This article summarizes contemporary scholarly perspectives and unpublished research that describe how neighborhoods influence life outcomes for children. It adopts a social capital perspective in addressing the influence of neighborhood's residents, places, and institutions on the child's safety, health, and education, distinguishing between compositional and contextual neighborhood effects. It concludes that the life outcomes of children, be they successful or rotten, are influenced by their access to the resources of immediate family and peer social networks (bonding capital), connections to other residents and their networks (bridging capital), and relations with representatives of broader social institutions as manifested in their neighborhood (linking capital)

Evaluation of the AGDISP ground boom spray drift model

AGDISP is a well-established spray drift model that has been validated for aerial spraying of forests. Recently a prototypical ground boom option has been added to AGDISP. This was evaluated in the current study by collecting data from spray trials over a grass sward using a ground boom sprayer and representative application parameters. Spray solutions were made up of water, sticker adjuvant and a metal cation, which was changed for each spray application. Deposition from spray drift was measured by analyses of the cation deposits on artificial targets (plastic tapes) placed on the grass surface. Measured deposition was compared with profiles calculated using AGDISP. AGDISP overpredicted deposition from spray drift by a factor of 3.5-100 outside the spray block. Possible reasons for these discrepancies are given. Options are to improve measured deposition and the algorithms for the deposition on the downwind swath of the spray block and evaporation of droplets

Quantitative data on red cell measures of iron status and their relation to the magnitude of the systemic inflammatory response and survival in patients with colorectal cancer

Background: Inflammation is recognised to be associated with perturbation of serum measures of iron status. However, the impact of colorectal cancer associated host inflammation on red cell measures of iron status has not been previously quantified. Methods: Patients undergoing elective surgery with curative intent, for colorectal cancer, at a single centre between 2008 and 2017 were included (n = 824). Blood samples taken for C-reactive protein (CRP), albumin, and full blood count (FBC) allowed patients to be grouped by modified Glasgow Prognostic Score (mGPS), and anaemia subtype (haemoglobin (Hb) M < 130 mg/L and F < 120 mg/L, with microcytic anaemia being mean corpuscular volume (MCV) < 80 f/L, and normocytic anaemia with MCV 80–100 f/L). Relationships between these groupings and red cell measures iron status including Hb, MCV, mean corpuscular haemoglobin (MCH) and red cell distribution width (RDW) were examined. Results: The combination of increasing T stage and increasing mGPS was associated with lower Hb, lower MCV, lower MCH, higher RDW, and higher prevalence of both microcytic and normocytic anaemia (all p < 0.001). The combination of CRP >10 mg/L and albumin <35  g/L was associated with lower Hb, lower MCV, lower MCH, higher RDW, and higher prevalence of both microcytic and normocytic anaemia (all p < 0.010). At multivariate Cox regression only Hb remained significantly associated with cancer specific (HR 0.98, 95% CI 0.97–0.99, p < 0.001), and overall survival (HR 0.98, 95% CI 0.97–0.99, p = 0.001). Conclusions: The presence of a host systemic inflammatory response to colorectal cancer was associated with significant perturbation of red cell measure of iron status

Perioperative blood transfusion is associated with the postoperative systemic inflammatory response and poorer outcomes following surgery for colorectal cancer

Background: The present study investigated relationships between perioperative blood transfusion, postoperative systemic inflammatory response, and outcomes following surgery for colorectal cancer. Methods: Data were recorded for patients (n = 544) undergoing potentially curative, elective surgery for colorectal cancer at a single center between 2012 and 2017. Transfusion history was obtained retrospectively from electronic records. Associations between blood transfusion, postoperative C-reactive protein (CRP), albumin, hemoglobin, complications, cancer-specific survival and overall survival (OS) were assessed using propensity score matching (n =116). Results: Of 544 patients, the majority were male (n =294, 54%), over 65 years of age (n =350, 64%), and with colonic (n =347, 64%) node-negative disease (n =353, 65%). Eighty-six patients (16%) required perioperative blood transfusion. In the unmatched cohort, blood transfusion was associated with higher median postoperative day (POD) 3 CRP {143 [interquartile range (IQR) 96–221 mg/L] vs. 120 (IQR 72–188 mg/L); p = 0.004}, lower median POD 3 albumin [24 (IQR 20–26 g/L) vs. 27 (IQR 24–30 g/L); p < 0.001], more postoperative complications [odds ratio (OR) 3.28, 95% confidence interval (CI) 2.03–5.29] and poorer OS [hazard ratio (HR) 3.18, 95% CI 2.08–4.84]. In the propensity score matched cohort, blood transfusion was similarly associated with higher median POD 3 CRP [130 (IQR 93–196 mg/L) vs. 113 (IQR 66–173 mg/L); p = 0.046], lower median POD 3 albumin [24 (IQR 20–26 g/L) vs. 26 (IQR 24–30 g/L); p < 0.001], more postoperative complications (OR 2.91, 95% CI 1.36–6.20) and poorer OS (HR 2.38, 95% CI 0.99–5.73). Conclusions: Perioperative blood transfusion was associated with postoperative inflammation, complications, and poorer survival in patients undergoing colorectal cancer surgery, with and without propensity score techniques

Isotopic ordering in atmospheric O2 as a tracer of ozone photochemistry and the tropical atmosphere

The distribution of isotopes within O2 molecules can be rapidly altered when they react with atomic oxygen. This mechanism is globally important: while other contributions to the global budget of O2 impart isotopic signatures, the O(3P) + O2 reaction resets all such signatures in the atmosphere on subdecadal timescales. Consequently, the isotopic distribution within O2 is determined by O3 photochemistry and the circulation patterns that control where that photochemistry occurs. The variability of isotopic ordering in O2 has not been established, however. We present new measurements of 18O18O in air (reported as Δ36 values) from the surface to 33 km altitude. They confirm the basic features of the clumped-isotope budget of O2: Stratospheric air has higher Δ36 values than tropospheric air (i.e., more 18O18O), reflecting colder temperatures and fast photochemical cycling of O3. Lower Δ36 values in the troposphere arise from photochemistry at warmer temperatures balanced by the influx of high-Δ36 air from the stratosphere. These observations agree with predictions derived from the GEOS-Chem chemical transport model, which provides additional insight. We find a link between tropical circulation patterns and regions where Δ36 values are reset in the troposphere. The dynamics of these regions influences lapse rates, vertical and horizontal patterns of O2 reordering, and thus the isotopic distribution toward which O2 is driven in the troposphere. Temporal variations in Δ36 values at the surface should therefore reflect changes in tropospheric temperatures, photochemistry, and circulation. Our results suggest that the tropospheric O3 burden has remained within a ±10% range since 1978

Loss of Hsp70 Exacerbates Pathogenesis But Not Levels of Fibrillar Aggregates in a Mouse Model of Huntington's Disease

Endogenous protein quality control machinery has long been suspected of influencing the onset and progression of neurodegenerative diseases characterized by accumulation of misfolded proteins. Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of a polyglutamine (polyQ) tract in the protein huntingtin (htt), which leads to its aggregation and accumulation in inclusion bodies. Here, we demonstrate in a mouse model of HD that deletion of the molecular chaperones Hsp70.1 and Hsp70.3 significantly exacerbated numerous physical, behavioral and neuropathological outcome measures, including survival, body weight, tremor, limb clasping and open field activities. Deletion of Hsp70.1 and Hsp70.3 significantly increased the size of inclusion bodies formed by mutant htt exon 1, but surprisingly did not affect the levels of fibrillar aggregates. Moreover, the lack of Hsp70s significantly decreased levels of the calcium regulated protein c-Fos, a marker for neuronal activity. In contrast, deletion of Hsp70s did not accelerate disease in a mouse model of infectious prion-mediated neurodegeneration, ruling out the possibility that the Hsp70.1/70.3 mice are nonspecifically sensitized to all protein misfolding disorders. Thus, endogenous Hsp70s are a critical component of the cellular defense against the toxic effects of misfolded htt protein in neurons, but buffer toxicity by mechanisms independent of the deposition of fibrillar aggregates

A five-year quasi-experimental study to evaluate the impact of empiric antibiotic order sets on antibiotic use metrics among hospitalized adult patients

Objective: Evaluation of adult antibiotic order sets (AOSs) on antibiotic stewardship metrics has been limited. The primary outcome was to evaluate the standardized antimicrobial administration ratio (SAAR). Secondary outcomes included antibiotic days of therapy (DOT) per 1,000 patient days (PD); selected antibiotic use; AOS utilization; Clostridioides difficile infection (CDI) cases; and clinicians’ perceptions of the AOS via a survey following the final study phase. Design: This 5-year, single-center, quasi-experimental study comprised 5 phases from 2017 to 2022 over 10-month periods between August 1 and May 31. Setting: The study was conducted in a 752-bed tertiary care, academic medical center. Intervention: Our institution implemented AOSs in the electronic medical record (EMR) for common infections among hospitalized adults. Results: For the primary outcome, a statistically significant decreases in SAAR were detected from phase 1 to phase 5 (1.0 vs 0.90; P \u3c .001). A statistically significant decreases were detected in DOT per 1,000 PD (4,884 vs 3,939; P = .001), fluoroquinolone orders (407 vs 175;P \u3c .001), carbapenem orders (147 vs 106; P = .024), and clindamycin orders (113 vs 73; P = .01). No statistically significant change in mean vancomycin orders was detected (991 vs 902; P = .221). A statistically significant decrease in CDI cases was also detected (7.8, vs 2.4; P = .002) but may have been attributable to changes in CDI case diagnosis. Clinicians indicated that the AOSs were easy to use overall and that they helped them select the appropriate antibiotics. Conclusions: Implementing AOS into the EMR was associated with a statistically significant reduction in SAAR, antibiotic DOT per 1,000 PD, selected antibiotic orders, and CDI cases

Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions1–5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7–9. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer10. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA