Frail but Resilient: Frailty in Autologous Breast Reconstruction is Associated with Worse Surgical Outcomes but Equivalent Long-Term Patient-Reported Outcomes.

BACKGROUND: Frailty is associated with higher risk of complications following breast reconstruction, but its impact on long-term surgical and patient-reported outcomes has not been investigated. We examined the association of the five-item modified frailty index (MFI) score with long-term surgical and patient-reported outcomes in autologous breast reconstruction. PATIENTS AND METHODS: We conducted a retrospective cohort study of consecutive patients who underwent mastectomy and autologous breast reconstruction between January 2016 and April 2022. Primary outcome was any flap-related complication. Secondary outcomes were patient-reported outcomes and predictors of complications in the frail cohort. RESULTS: We identified 1640 reconstructions (mean follow-up 24.2 ± 19.2 months). In patients with MFI ≥ 2, the odds of surgical [odds ratio (OR) 2.13, p = 0.023] and medical (OR 17.02, p < 0.001) complications were higher than in nonfrail patients. We found no significant difference in satisfaction with the breast (p = 0.287), psychosocial well-being (p = 0.119), or sexual well-being (p = 0.314) according to MFI score. Chronic obstructive pulmonary disease was an independent predictor of infection (OR 3.70, p = 0.002). Tobacco use (OR 7.13, p = 0.002) and contralateral prophylactic mastectomy (OR 2.36, p = 0.014) were independent predictors of wound dehiscence. Dependent functional status (OR 2.36, p = 0.007) and immediate reconstruction (compared with delayed reconstruction; OR 3.16, p = 0.026) were independent predictors of skin flap necrosis. Dependent functional status was also independently associated with higher odds of reoperation (OR 2.64, p = 0.011). CONCLUSION: Frailty is associated with higher risk of complications in breast reconstruction, but there is no significant difference in long-term patient-reported outcomes. MFI should be considered in breast reconstruction to improve outcomes in high-risk frail patients.

Extended genome-wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry.

INTRODUCTION: Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts. METHODS: Genome-wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within-dataset results were meta-analyzed, followed by functional genomics analyses. RESULTS: A novel AD-risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, P = 3.68×10-9). Two additional novel common and nine rare loci were identified with suggestive associations (P < 9×10-7). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that this association is modulated by regional origin of local African ancestry. DISCUSSION: These analyses identified novel AD-associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects. HIGHLIGHTS: Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies. The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa. Single variant meta-analysis identified a novel genome-wide significant AD-risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome-wide significance at P < 9×10-7. Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus. These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry-informed genetic screening tools and therapeutic interventions.

Long-term Surgical and Patient-Reported Outcomes Comparing Skin-Preserving, Staged Versus Delayed Microvascular Breast Reconstruction.

BACKGROUND: Skin-preserving, staged, microvascular, breast reconstruction often is preferred in patients requiring postmastectomy radiotherapy (PMRT) but may lead to complications. We compared the long-term surgical and patient-reported outcomes between skin-preserving and delayed microvascular breast reconstruction with and without PMRT. METHODS: We conducted a retrospective, cohort study of consecutive patients who underwent mastectomy and microvascular breast reconstruction between January 2016 and April 2022. The primary outcome was any flap-related complication. The secondary outcomes were patient-reported outcomes and tissue-expander complications. RESULTS: We identified 1002 reconstructions (672 delayed; 330 skin-preserving) in 812 patients. Mean follow-up was 24.2 ± 19.3 months. PMRT was required in 564 reconstructions (56.3%). In the non-PMRT group, skin-preserving reconstruction was independently associated with shorter hospital stay (ß - 0.32, p = 0.045) and lower odds of 30-days readmission (odds ratio [OR] 0.44, p = 0.042), seroma (OR 0.42, p = 0.036), and hematoma (OR 0.24, p = 0.011) compared with delayed reconstruction. In the PMRT group, skin-preserving reconstruction was independently associated with shorter hospital stay (ß - 1.15, p < 0.001) and operative time (ß - 97.0, p < 0.001) and lower odds of 30-days readmission (OR 0.29, p = 0.005) and infection (OR 0.33, p = 0.023) compared with delayed reconstruction. Skin-preserving reconstruction had a 10.6% tissue expander loss rate and did not differ from delayed reconstruction in terms of patient-reported satisfaction with breast, psychosocial well-being, or sexual well-being. CONCLUSIONS: Skin-preserving, staged, microvascular, breast reconstruction is safe regardless of the need for PMRT, with an acceptable tissue expander loss rate, and is associated with improved flap outcomes and similar patient-reported quality of life to that of delayed reconstruction.

The Early-Onset Alzheimer's Disease Whole-Genome Sequencing Project: Study design and methodology.

INTRODUCTION: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations, resulting in a lack of understanding of its molecular etiology. METHODS: Whole-genome sequencing and harmonization of clinical, neuropathological, and biomarker data of over 5000 EOAD cases of diverse ancestries. RESULTS: A publicly available genomics resource for EOAD with extensive harmonized phenotypes. Primary analysis will (1) identify novel EOAD risk loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. DISCUSSION: This novel resource complements over 50,000 control and late-onset AD samples generated through the Alzheimer's Disease Sequencing Project (ADSP). The harmonized EOAD/ADSP joint call will be available through upcoming ADSP data releases and will allow for additional analyses across the full onset range. HIGHLIGHTS: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations. This results in a significant lack of understanding of the molecular etiology of this devastating form of the disease. The Early-Onset Alzheimer's Disease Whole-genome Sequencing Project is a collaborative initiative to generate a large-scale genomics resource for early-onset Alzheimer's disease with extensive harmonized phenotype data. Primary analyses are designed to (1) identify novel EOAD risk and protective loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. The harmonized genomic and phenotypic data from this initiative will be available through NIAGADS.

Shifts in predator behaviour following climate induced disturbance on coral reefs.

Coral reefs are increasingly ecologically destabilized across the globe due to climate change. Behavioural plasticity in corallivore behaviour and short-term trophic ecology in response to bleaching events may influence the extent and severity of coral bleaching and subsequent recovery potential, yet our understanding of these interactions in situ remains unclear. Here, we investigated interactions between corallivory and coral bleaching during a severe high thermal event (10.3-degree heating weeks) in Belize. We found that parrotfish changed their grazing behaviour in response to bleaching by selectively avoiding bleached Orbicella spp. colonies regardless of bleaching severity or coral size. For bleached corals, we hypothesize that this short-term respite from corallivory may temporarily buffer coral energy budgets by not redirecting energetic resources to wound healing, and may therefore enable compensatory nutrient acquisition. However, colonies that had previously been heavily grazed were also more susceptible to bleaching, which is likely to increase mortality risk. Thus, short-term respite from corallivory during bleaching may not be sufficient to functionally rescue corals during prolonged bleaching. Such pairwise interactions and behavioural shifts in response to disturbance may appear small scale and short term, but have the potential to fundamentally alter ecological outcomes, especially in already-degraded ecosystems that are vulnerable and sensitive to change.

Negligible Greenhouse Gas Release from Sediments in Oyster Habitats.

After centuries of decline, oyster populations are now on the rise in coastal systems globally following aquaculture development and restoration efforts. Oysters regulate the biogeochemistry of coastal systems in part by promoting sediment nutrient recycling and removing excess nitrogen via denitrification. Less clear is how oysters alter sediment greenhouse gas (GHG) fluxes-an important consideration as oyster populations grow. Here, we show that sediments in oyster habitats produce carbon dioxide (CO2), with highest rates in spring (2396.91 ± 381.98 µmol CO2 m-2 h-1) following deposition of seasonal diatom blooms and in summer (2795.20 ± 307.55 µmol CO2 m-2 h-1) when temperatures are high. Sediments in oyster habitats also consistently released methane to the water column (725.94 ± 150.34 nmol CH4 m-2 h-1) with no seasonal pattern. Generally, oyster habitat sediments were a sink for nitrous oxide (N2O; -36.11 ± 7.24 nmol N2O m-2 h-1), only occasionally releasing N2O in spring. N2O release corresponded to high organic matter and dissolved nitrogen availability, suggesting denitrification as the production pathway. Despite potential CO2 production increases under aquaculture in some locations, we conclude that in temperate regions oysters have an overall negligible impact on sediment GHG cycling.

Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927.

Phenolic groups are responsible for the high clearance and low oral bioavailability of the estrogen receptor alpha (ERα) clinical candidate GDC-0927. An exhaustive search for a backup molecule with improved pharmacokinetic (PK) properties identified several metabolically stable analogs, although in general at the expense of the desired potency and degradation efficiency. C-8 hydroxychromene 30 is the first example of a phenol-containing chromene that not only maintained excellent potency but also exhibited 10-fold higher oral exposure in rats. The improved in vivo clearance in rat was hypothesized to be the result of C-8 hydroxy group being sterically protected from glucuronide conjugation. The excellent potency underscores the possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the chromene core. Co-crystal structures were obtained to highlight the change in key interactions and rationalize the retained potency.

Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.

Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).

Low Greenhouse Gas Emissions from Oyster Aquaculture.

Production of animal protein is associated with high greenhouse gas (GHG) emissions. Globally, oyster aquaculture is increasing as a way to meet growing demands for protein, yet its associated GHG-emissions are largely unknown. We quantified oyster aquaculture GHG-emissions from the three main constituents of GHG-release associated with terrestrial livestock production: fermentation in the animal gut, manure management, and fodder production. We found that oysters release no methane (CH4) and only negligible amounts of nitrous oxide (0.00012 ± 0.00004 µmol N2O gDW-1 hr-1) and carbon dioxide (3.556 ± 0.471 µmol CO2 gDW-1 hr-1). Further, sediment fluxes of N2O and CH4 were unchanged in the presence of oyster aquaculture, regardless of the length of time it had been in place. Sediment CO2 release was slightly stimulated between 4 and 6 years of aquaculture presence and then returned to baseline levels but was not significantly different between aquaculture and a control site when all ages of culture were pooled. There is no GHG-release from oyster fodder production. Considering the main drivers of GHG-release in terrestrial livestock systems, oyster aquaculture has less than 0.5% of the GHG-cost of beef, small ruminants, pork, and poultry in terms of CO2-equivalents per kg protein, suggesting that shellfish aquaculture may provide a a low GHG alternative for future animal protein production compared to land based sources. We estimate that if 10% of the protein from beef consumption in the United States was replaced with protein from oysters, the GHG savings would be equivalent to 10.8 million fewer cars on the road.

Deamidation of N76 in human γS-crystallin promotes dimer formation.

BACKGROUND: Cataract formation is often attributed to the build-up of post-translational modifications in the crystallin proteins of the eye lens. One such modification, the deamidation of N76 in human γS-crystallin to D76, is highly correlated with age-related cataract (Hooi et al. Invest. Ophthalmol. Vis. Sci. 53 (2012) 3554-3561). In the current work, this modification has been extensively characterised in vitro. METHODS: Biophysical characterisation was performed on wild type and N76D γS-crystallins using turbidity measurements to monitor aggregation, intrinsic fluorescence and circular dichroism spectroscopy to determine the folded state and NMR spectroscopy for identifying local changes in structure. Protein mass was determined using SEC-MALLS and analytical ultracentrifugation methods. RESULTS: Relative to the wild type protein, deamidation at N76 in γS-crystallin causes an increase in the thermal stability and resistance to thermally induced aggregation alongside a decrease in stability to denaturants, a propensity to aggregate rapidly once destabilised and a tendency to form a dimer. We ascribe the apparent increase in thermal stability upon deamidation to the formation of dimer which prevents the unfolding of the inherently less stable monomer. CONCLUSIONS: Deamidation causes a decrease in stability of γS-crystallin but this is offset by an increased tendency for dimer formation. GENERAL SIGNIFICANCE: Deamidation at N76 in human γS-crystallin likely has a combinatorial effect with other post-translational crystallin modifications to induce age-related cataract. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.

A structural and functional study of Gln147 deamidation in αA-crystallin, a site of modification in human cataract.

Deamidation of Glu147 in human αA-crystallin is common in aged cataractous lenses (Hains and Truscott, Invest. Ophthalmol. Vis. Sci. 2010, 51, 3107). Accordingly, this modification may have a causative effect in cataract. αA-crystallin is a small heat-shock molecular chaperone protein that prevents aggregation of proteins and is the principal defence against crystallin unfolding and aggregation in the ageing lens. Deamidated Q147E αA-crystallin was structurally characterised using a variety of spectroscopic and biophysical methods, including NMR, circular dichroism and fluorescence spectroscopy and dynamic light scattering. The effect of Glu147 deamidation on αA-crystallin in vitro chaperone ability was determined for a variety of aggregating proteins. Compared to the wild type protein, Q147E αA-crystallin generally exhibited slightly reduced chaperone ability and a small loss of overall structure in its central α-crystallin domain while also showing significantly enhanced thermal stability and a tendency to form slightly larger oligomers. As αA-crystallin is the major lens protein, even a small loss of function could combine with other sources of age-related damage to the crystallins to contribute to lens opacification.

The Effects of Computerized Cognitive Training in Older Adults' Cognitive Performance and Biomarkers of Structural Brain Aging.

OBJECTIVES: Cognitive training (CT) has been investigated as a means of delaying age-related cognitive decline in older adults. However, its impact on biomarkers of age-related structural brain atrophy has rarely been investigated, leading to a gap in our understanding of the linkage between improvements in cognition and brain plasticity. This study aimed to explore the impact of CT on cognitive performance and brain structure in older adults. METHODS: One hundred twenty-four cognitively normal older adults recruited from 2 study sites were randomly assigned to either an adaptive CT (n = 60) or a casual game training (active control, AC, n = 64). RESULTS: After 10 weeks of training, CT participants showed greater improvements in the overall cognitive composite score (Cohen's d = 0.66, p < .01) with nonsignificant benefits after 6 months from the completion of training (Cohen's d = 0.36, p = .094). The CT group showed significant maintenance of the caudate volume as well as significant maintained fractional anisotropy in the left internal capsule and in left superior longitudinal fasciculus compared to the AC group. The AC group displayed an age-related decrease in these metrics of brain structure. DISCUSSION: Results from this multisite clinical trial demonstrate that the CT intervention improves cognitive performance and helps maintain caudate volume and integrity of white matter regions that are associated with cognitive control, adding to our understanding of the changes in brain structure contributing to changes in cognitive performance from adaptive CT. CLINICAL TRIAL REGISTRATION: NCT03197454.

Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways.

Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Using data from EOAD cases and controls, we performed a genome-wide association study (GWAS) and trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) and East Asians (NCase=375, NControl=838 CO). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, eQTL, pQTL and functional annotations, we nominate four novel genes that are involved in microglia activation, glutamate production, and signaling pathways. These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.

The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD.

A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.

Oyster aquaculture enhances sediment microbial diversity- Insights from a multi-omics study.

The global aquaculture industry has grown substantially, with consequences for coastal ecology and biogeochemistry. Oyster aquaculture can alter the availability of resources for microbes that live in sediments as oysters move large quantities of organic material to the sediments via filter feeding, possibly leading to changes in the structure and function of sediment microbial communities. Here, we use a chronosequence approach to investigate the impacts of oyster farming on sediment microbial communities over 7 years of aquaculture activity in a temperate coastal system. We detected shifts in bacterial composition (16S rRNA amplicon sequencing), changes in gene expression (meta-transcriptomics), and variations in sediment elemental concentrations (sediment geochemistry) across different durations of oyster farming. Our results indicate that both the structure and function of bacterial communities vary between control (no oysters) and farm sites, with an overall increase in diversity and a shift towards anoxic tolerance in farm sites. However, little to no variation was observed in either structure or function with respect to farming duration suggesting these sediment microbial communities are resilient to change. We also did not find any significant impact of farming on heavy metal accumulation in the sediments. The minimal influence of long-term oyster farming on sediment bacterial function and biogeochemical processes as observed here can bear important consequences for establishing best practices for sustainable farming in these areas. Importance: Sediment microbial communities drive a range of important ecosystem processes such as nutrient recycling and filtration. Oysters are well-known ecological engineers, and their presence is increasing as aquaculture expands in coastal waters globally. Determining how oyster aquaculture impacts sediment microbial processes is key to understanding current and future estuarine biogeochemical processes. Here, we use a multi-omics approach to study the effect of different durations of oyster farming on the structure and function of bacteria and elemental accumulation in the farm sediments. Our results indicate an increase in the diversity of bacterial communities in the farm sites with no such increases observed for elemental concentrations. Further, these effects persist across multiple years of farming with an increase of anoxic tolerant bacteria at farm sites. The multi-omics approach used in this study can serve as a valuable tool to facilitate understanding of the environmental impacts of oyster aquaculture.

Ensuring Safety While Achieving Beauty: An Evidence-Based Approach to Optimizing Mastectomy and Autologous Breast Reconstruction Outcomes in Patients with Obesity.

BACKGROUND: Although obesity has previously been associated with poor outcomes after mastectomy and breast reconstruction, its impact across the WHO obesity classification spectrum and the differential effects of various optimization strategies on patient outcomes have yet to be delineated. We sought to examine the impact of WHO obesity classification on intraoperative surgical and medical complications, postoperative surgical and patient-reported outcomes of mastectomy and autologous breast reconstruction, and delineate outcomes optimization strategies for obese patients. STUDY DESIGN: This is a review of consecutive patients who underwent mastectomy and autologous breast reconstruction from 2016 to 2022. Primary outcomes were complication rates. Secondary outcomes were patient-reported outcomes and optimal management strategies. RESULTS: We identified 1,640 mastectomies and reconstructions in 1,240 patients with mean follow-up of 24.2 ± 19.2 months. Patients with class II/III obesity had higher adjusted risk of wound dehiscence (odds ratio [OR] 3.20; p < 0.001), skin flap necrosis (OR 2.60; p < 0.001), deep venous thrombosis (OR 3.90; p < 0.033), and pulmonary embolism (OR 15.3; p = 0.001) than nonobese patients. Obese patients demonstrated significantly lower satisfaction with breasts (67.3 ± 27.7 vs 73.7 ± 24.0; p = 0.043) and psychological well-being (72.4 ± 27.0 vs 82.0 ± 20.8; p = 0.001) than nonobese patients. Unilateral delayed reconstructions were associated with independently shorter hospital stay (ß -0.65; p = 0.002) and lower adjusted risk of 30-day readmission (OR 0.45; p = 0.031), skin flap necrosis (OR 0.14; p = 0.031), and pulmonary embolism (OR 0.07; p = 0.021). CONCLUSIONS: Obese women should be closely monitored for adverse events and lower quality of life, offered measures to optimize thromboembolic prophylaxis, and advised on the risks and benefits of unilateral delayed reconstruction.

Extended genome-wide association study employing the African Genome Resources Panel identifies novel susceptibility loci for Alzheimer's Disease in individuals of African ancestry.

INTRODUCTION: Despite a two-fold increased risk, individuals of African ancestry have been significantly underrepresented in Alzheimer's Disease (AD) genomics efforts. METHODS: GWAS of 2,903 AD cases and 6,265 cognitive controls of African ancestry. Within-dataset results were meta-analyzed, followed by gene-based and pathway analyses, and analysis of RNAseq and whole-genome sequencing data. RESULTS: A novel AD risk locus was identified in MPDZ on chromosome 9p23 (rs141610415, MAF=.002, P =3.68×10 -9 ). Two additional novel common and nine novel rare loci approached genome-wide significance at P <9×10 -7 . Comparison of association and LD patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 ( ASCL1 ), suggesting that the association is modulated by regional origin of local African ancestry. DISCUSSION: Increased sample sizes and sample sets from Africa covering as much African genetic diversity as possible will be critical to identify additional disease-associated loci and improve deconvolution of local genetic ancestry effects.