Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

California's 2023 snow deluge: Contextualizing an extreme snow year against future climate change.

The increasing prevalence of low snow conditions in a warming climate has attracted substantial attention in recent years, but a focus exclusively on low snow leaves high snow years relatively underexplored. However, these large snow years are hydrologically and economically important in regions where snow is critical for water resources. Here, we introduce the term "snow deluge" and use anomalously high snowpack in California's Sierra Nevada during the 2023 water year as a case study. Snow monitoring sites across the state had a median 41 y return interval for April 1 snow water equivalent (SWE). Similarly, a process-based snow model showed a 54 y return interval for statewide April 1 SWE (90% CI: 38 to 109 y). While snow droughts can result from either warm or dry conditions, snow deluges require both cool and wet conditions. Relative to the last century, cool-season temperature and precipitation during California's 2023 snow deluge were both moderately anomalous, while temperature was highly anomalous relative to recent climatology. Downscaled climate models in the Shared Socioeconomic Pathway-370 scenario indicate that California snow deluges-which we define as the 20 y April 1 SWE event-are projected to decline with climate change (58% decline by late century), although less so than median snow years (73% decline by late century). This pattern occurs across the western United States. Changes to snow deluge, and discrepancies between snow deluge and median snow year changes, could impact water resources and ecosystems. Understanding these changes is therefore critical to appropriate climate adaptation.

Localizing unmapped sequences with families to validate the Telomere-to-Telomere assembly and identify new hotspots for genetic diversity.

Although it is ubiquitous in genomics, the current human reference genome (GRCh38) is incomplete: It is missing large sections of heterochromatic sequence, and as a singular, linear reference genome, it does not represent the full spectrum of human genetic diversity. To characterize gaps in GRCh38 and human genetic diversity, we developed an algorithm for sequence location approximation using nuclear families (ASLAN) to identify the region of origin of reads that do not align to GRCh38. Using unmapped reads and variant calls from whole-genome sequences (WGSs), ASLAN uses a maximum likelihood model to identify the most likely region of the genome that a subsequence belongs to given the distribution of the subsequence in the unmapped reads and phasings of families. Validating ASLAN on synthetic data and on reads from the alternative haplotypes in the decoy genome, ASLAN localizes >90% of 100-bp sequences with >92% accuracy and ∼1 Mb of resolution. We then ran ASLAN on 100-mers from unmapped reads from WGS from more than 700 families, and compared ASLAN localizations to alignment of the 100-mers to the recently released T2T-CHM13 assembly. We found that many unmapped reads in GRCh38 originate from telomeres and centromeres that are gaps in GRCh38. ASLAN localizations are in high concordance with T2T-CHM13 alignments, except in the centromeres of the acrocentric chromosomes. Comparing ASLAN localizations and T2T-CHM13 alignments, we identified sequences missing from T2T-CHM13 or sequences with high divergence from their aligned region in T2T-CHM13, highlighting new hotspots for genetic diversity.

Identifying crossovers and shared genetic material in whole genome sequencing data from families.

Large, whole-genome sequencing (WGS) data sets containing families provide an important opportunity to identify crossovers and shared genetic material in siblings. However, the high variant calling error rates of WGS in some areas of the genome can result in spurious crossover calls, and the special inheritance status of the X Chromosome presents challenges. We have developed a hidden Markov model that addresses these issues by modeling the inheritance of variants in families in the presence of error-prone regions and inherited deletions. We call our method PhasingFamilies. We validate PhasingFamilies using the platinum genome family NA1281 (precision: 0.81; recall: 0.97), as well as simulated genomes with known crossover positions (precision: 0.93; recall: 0.92). Using 1925 quads from the Simons Simplex Collection, we found that PhasingFamilies resolves crossovers to a median resolution of 3527.5 bp. These crossovers recapitulate existing recombination rate maps, including for the X Chromosome; produce sibling pair IBD that matches expected distributions; and are validated by the haplotype estimation tool SHAPEIT. We provide an efficient, open-source implementation of PhasingFamilies that can be used to identify crossovers from family sequencing data.

The contributions of rare inherited and polygenic risk to ASD in multiplex families.

Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.

Growing impact of wildfire on western US water supply.

Streamflow often increases after fire, but the persistence of this effect and its importance to present and future regional water resources are unclear. This paper addresses these knowledge gaps for the western United States (WUS), where annual forest fire area increased by more than 1,100% during 1984 to 2020. Among 72 forested basins across the WUS that burned between 1984 and 2019, the multibasin mean streamflow was significantly elevated by 0.19 SDs (P < 0.01) for an average of 6 water years postfire, compared to the range of results expected from climate alone. Significance is assessed by comparing prefire and postfire streamflow responses to climate and also to streamflow among 107 control basins that experienced little to no wildfire during the study period. The streamflow response scales with fire extent: among the 29 basins where >20% of forest area burned in a year, streamflow over the first 6 water years postfire increased by a multibasin average of 0.38 SDs, or 30%. Postfire streamflow increases were significant in all four seasons. Historical fire-climate relationships combined with climate model projections suggest that 2021 to 2050 will see repeated years when climate is more fire-conducive than in 2020, the year currently holding the modern record for WUS forest area burned. These findings center on relatively small, minimally managed basins, but our results suggest that burned areas will grow enough over the next 3 decades to enhance streamflow at regional scales. Wildfire is an emerging driver of runoff change that will increasingly alter climate impacts on water supplies and runoff-related risks.

The long-term intercorrelation between post-burn pain, anxiety, and depression: a post hoc analysis of the "RE-ENERGIZE" double-blind, randomized, multicenter placebo-controlled trial.

BACKGROUND: Despite the growing prevalence of burn survivors, a gap persists in our understanding of the correlation between acute burn trauma and the long-term impact on psychosocial health. This study set out to investigate the prevalence of long-term pain and symptoms of anxiety and depression in survivors of extensive burns, comparing this to the general population, and identify injury and demographic-related factors predisposing individuals to psychosocial compromise. METHODS: RE-ENERGIZE was an international, double-blinded, randomized-controlled trial that enrolled 1200 patients with partial- or full-thickness burns that required surgical treatment. For the post hoc analysis, we excluded participants who did not complete the Short Form Health Survey (SF-36) questionnaire. Normative data were taken from the 2021 National Health Interview Survey dataset. Propensity score matching was performed using the nearest-neighbor 1-to-1 method, and the two cohorts were compared in terms of chronic pain, and symptoms of anxiety and depression. A multivariable analysis was performed on the burns cohort to identify factors predicting post-discharge pain and symptoms of anxiety and depression. RESULTS: A total of 600 burn patients and 26,666 general population adults were included in this study. Following propensity score matching, both groups comprised 478 participants each, who were predominately male, white, overweight and between 20 and 60 years old. Compared to the general population, burn patients were significantly more likely to report the presence of moderate and a lot of pain (p = 0.002). Symptoms of anxiety were significantly higher in the burn population in two of four levels (most of the time; some of the time; p < 0.0001 for both). Responders in the burn population were significantly less likely to report the absence of depressive symptoms (p < 0.0001). Burn patients were also significantly more likely to report that their mental health affects their social life. TBSA, history of depression, and female sex were identified as independently associated factors for pain, anxiety, and depressive symptoms. The presence of chronic pain and anxiety symptoms independently predicted for symptoms of depression. CONCLUSIONS: Analyzing the largest multicenter cohort of patients with extensive burns, we find that burn injury is associated with chronic pain, and symptoms of anxiety and depression. In addition, TBSA-burned and history of depression directly correlate with the prevalence of chronic pain, and symptoms of anxiety and depression. Finally, pain, and symptoms of anxiety and depression are interrelated and may have interactive effects on the process of recovery following burn injury. Burn patients would, therefore, benefit from a multidisciplinary team approach with early mobilization of pain and mental health experts, in order to promptly prevent the development of psychosocial challenges and their consequences.

Conversion of a Validated Melanoma Risk Stratification Tool Into a Tablet-Based Patient Questionnaire for Targeted Melanoma Screening in Primary Care Settings: A Pilot Study.

BACKGROUND: Risk stratification can identify individuals in primary care settings who are at increased risk of developing melanoma. OBJECTIVE: Converting and implementing a validated risk stratification tool as a patient self-administered tablet-based survey. METHODS: Mackie risk stratification tool was transformed into a patient questionnaire. The questionnaire was completed in academic dermatologist practices by patients and dermatologists and revised to optimize sensitivity and specificity using physician assessment as gold standard. The optimized survey was administered before routine primary care visits during 2019 to 2021. High-risk patients were referred to dermatology. The number needed to screen (NNS), sensitivity, specificity, positive predictive value, and negative predictive value to identify a melanoma were calculated. RESULTS: Of the 7,893 respondents, 5,842 (74%) and 2,051 (26%) patients were categorized as low-risk and high-risk population, respectively. The NNS to identify 1 melanoma was 64 in the high-risk population. CONCLUSION: Incorporating self-administered patient-risk stratification tools in primary care settings can identify high-risk individuals for targeted melanoma screening. Further studies are needed to optimize specificity and sensitivity in more targeted populations.

Associations among drug acquisition and use behaviors, psychosocial attributes, and opioid-involved overdoses.

AIMS: This study sought to develop and assess an exploratory model of how demographic and psychosocial attributes, and drug use or acquisition behaviors interact to affect opioid-involved overdoses. DESIGN: We conducted exploratory and confirmatory factor analysis (EFA/CFA) to identify a factor structure for ten drug acquisition and use behaviors. We then evaluated alternative structural equation models incorporating the identified factors, adding demographic and psychosocial attributes as predictors of past-year opioid overdose. SETTING AND PARTICIPANTS: We used interview data collected for two studies recruiting opioid-misusing participants receiving services from a community-based syringe services program. The first investigated current attitudes toward drug-checking (N = 150). The second was an RCT assessing a telehealth versus in-person medical appointment for opioid use disorder treatment referral (N = 270). MEASUREMENTS: Demographics included gender, age, race/ethnicity, education, and socioeconomic status. Psychosocial measures were homelessness, psychological distress, and trauma. Self-reported drug-related risk behaviors included using alone, having a new supplier, using opioids with benzodiazepines/alcohol, and preferring fentanyl. Past-year opioid-involved overdoses were dichotomized into experiencing none or any. FINDINGS: The EFA/CFA revealed a two-factor structure with one factor reflecting drug acquisition and the second drug use behaviors. The selected model (CFI = .984, TLI = .981, RMSEA = .024) accounted for 13.1% of overdose probability variance. A latent variable representing psychosocial attributes was indirectly associated with an increase in past-year overdose probability (ß = .234, p = .001), as mediated by the EFA/CFA identified latent variables: drug acquisition (ß = .683, p < .001) and drug use (ß = .567, p = .001). Drug use behaviors (ß = .287, p = .04) but not drug acquisition (ß = .105, p = .461) also had a significant, positive direct effect on past-year overdose. No demographic attributes were significant direct or indirect overdose predictors. CONCLUSIONS: Psychosocial attributes, particularly homelessness, increase the probability of an overdose through associations with risky drug acquisition and drug-using behaviors. Further research is needed to replicate these findings with populations at high-risk of an opioid-related overdose to assess generalizability and refine the metrics used to assess psychosocial characteristics.

The combined risk predictive power of frailty and hypoalbuminemia in free tissue flap reconstruction: A cohort study of 34,571 patients from the NSQIP database.

INTRODUCTION: Significant morbidity and mortality are hallmarks of the functional decline seen in physically frail patients. The modified frailty index 5 (mFI-5) represents a risk predictor score that has been validated as a comorbidity-based scale in surgery. Serum albumin levels of <3.5 g/dL (hypoalbuminemia) have also been implicated with poor postoperative outcomes. However, the association between these two parameters remains to be investigated. We aimed to elucidate the interdependence of preoperative albumin levels and frailty, as evaluated by the mFI-5 score, and its reliability to prognosticate postoperative results in free flap reconstruction (FFR). METHODS: We conducted a multicenter, retrospective cohort study and accessed the ACS National Surgical Quality Improvement Program (ACS-NSQIP) from 2008 to 2021. We identified all adult patients (≥18 years of age) who underwent a FFR. We extracted perioperative data and lab values including albumin. Multivariable linear and logistic regression analyses were performed to identify independent risk predictors. Main outcomes involved mortality, length of hospital stay, reoperation, medical and surgical complications, and discharge destination within the 30-day postoperative period. RESULTS: A total of 34,571 patients were included in the study, with an average age of 53.9 years (standard deviation [SD] 12.2) and an average body mass index (BMI) of 28.8 (SD 6.1). Of these patients, 7484 were male (21.6%), whereas 22,363 (64.7%) had no frailty (mFI = 0). Additionally, 9466 patients had a frailty score of 1 (27.4%), 2505 had a score of 2 (7.2%), 226 had a score of 3 (0.7%), and 11 had a score of 4 or higher (0.0%). Albumin levels were available for 16,250 patients (47.0%), and among them, 1334 (8.2%) had hypoalbuminemia. Regression analyses showed that higher mFI scores were independent predictors of any, surgical, and medical complications, as well as increased rates of reoperations, unplanned readmissions, and prolonged hospital stays. Hypoalbuminemia independently predicted any, surgical, and medical complications, and higher mortality, reoperation, and longer hospital stay. When both frailty and albumin levels (mFI-5 and albumin) were considered together, this combined assessment was found to be a more accurate predictor of all major outcomes (any, medical and surgical complications, mortality, and reoperation). Further, our analysis identified a weak negative correlation between serum albumin levels and mFI scores (Spearman R: -.1; p < .0001). CONCLUSION: In conclusion, this cohort study highlights the association of hypoalbuminemia with adverse postoperative outcomes, including those not directly related to frailty. Simultaneously, higher mFI scores independently predicted outcomes not associated with hypoalbuminemia. Stemming from these findings, we recommend considering both serum albumin levels and frailty in patients receiving FFR. This perioperative algorithm may help provide more individualized planning including multidisciplinary care and pre and posthabilitation.

An ACS-NSQIP Data Analysis of 30-Day Outcomes Following Surgery for Bell's Palsy.

BACKGROUND: There exists a paucity of large-scale, multi-institutional studies that investigate the outcomes of surgery for Bell's palsy (BP). Here, we utilize a large, multi-institutional database to study the risk factors and early-stage outcomes following surgical procedures in BP. METHODS: We reviewed the American College of Surgeons National Surgical Quality Improvement Program database (2008-2019) to identify patients who underwent surgery for the diagnosis of BP. We extracted data on comorbidities and preoperative blood values, and 30-day postoperative outcomes. RESULTS: Two hundred fifty-seven patients who underwent surgery for BP symptoms over the 12-year review period were identified. Muscle grafts (n=50; 19%) and fascial grafts (n=48; 19%) accounted for the majority of procedures. The most common comorbidities were hypertension (n=89; 35%) and obesity (n=79; 31%). Complications occurred in 26 (10.1%) cases. Additionally, length of hospital stay was significantly associated with both surgical and medical complications (3.9±4.7 versus 1.5±2.0; P <0.01) and (3.2±3.8 versus 1.4±2.0; P <0.01), respectively. Preoperative creatinine, blood urea nitrogen, and alkaline phosphatase were identified as potential predictors of poor postoperative outcomes. CONCLUSION: Based on multi-institutional analysis, complication rates following surgery for BP were found to be overall low and seen to correlate with length of hospital stay. Reoperations and readmissions were the most frequent complications after surgery for BP. The preoperative evaluation of routine laboratory values may help refine patient eligibility and risk stratification. In addition, our findings call for future large-scale prospective studies in the field of facial palsy surgery to further improve the quality of care and optimize perioperative protocols.

Outcomes of Dermal Regeneration Templates in Irradiated and Nonirradiated Scalp Defects.

OBJECTIVES: Dermal regeneration templates (DRTs) are frequently used to treat scalp defects. The aim was to compare the time course of healing for DRTs in scalp defects with and without preoperative radiation. METHODS: The authors conducted a retrospective cohort study of DRT-based scalp reconstruction at 2 academic medical centers between 2013 and 2022. Information was collected on demographic variables, comorbidities, medication use, history of radiation, and DRT outcomes. The primary outcome was DRT loss, defined as exposed calvarium or DRT detachment based on postoperative follow-up documentation. Kaplan-Meier survival analysis and multivariable Cox proportional-hazard regressions were used to compare DRT loss in irradiated and nonirradiated defects. Multivariable logistic regressions were used to compare 30-day postoperative complications (infection, hematoma, or seroma) in irradiated and nonirradiated defects. RESULTS: In total, 158 cases were included. Twenty-eight (18%) patients had a preoperative history of radiation to the scalp. The mean follow-up time after DRT placement was 2.6 months (SD: 4.5 mo). The estimated probability of DRT survival at 2 months was 91% (95% CI: 83%-100%) in nonirradiated patients and 65% (95% CI: 48%-88%) in irradiated patients. In the 55 patients with a bony wound base, preoperative head radiation was associated with a higher likelihood of DRT loss (hazard ratio: 11). Half the irradiated defects experienced uncomplicated total wound closure using Integra Wound Matrix Dressing with or without second-stage reconstruction. CONCLUSIONS: Dermal regeneration template can offer durable coverage in nonirradiated scalp defects. Although DRT loss is more likely in irradiated scalp defects, successful DRT-based reconstruction is possible in select cases.

A purified reconstituted bilayer matrix shows improved outcomes in treatment of non-healing diabetic foot ulcers when compared to the standard of care: Final results and analysis of a prospective, randomized, controlled, multi-centre clinical trial.

As the incidence of diabetic foot ulcers (DFU) increases, better treatments that improve healing should reduce complications of these ulcers including infections and amputations. We conducted a randomized controlled trial comparing outcomes between a novel purified reconstituted bilayer membrane (PRBM) to the standard of care (SOC) in the treatment of non-healing DFUs. This study included 105 patients who were randomized to either of two treatment groups (n = 54 PRBM; n = 51 SOC) in the intent to treat (ITT) group and 80 who completed the study per protocol (PP) (n = 47 PRBM; n = 33 SOC). The primary endpoint was the percentage of wounds closed after 12 weeks. Secondary outcomes included percent area reduction, time to healing, quality of life, and cost to closure. The DFUs that had been treated with PRBM healed at a higher rate than those treated with SOC (ITT: 83% vs. 45%, p = 0.00004, PP: 92% vs. 67%, p = 0.005). Wounds treated with PRBM also healed significantly faster than those treated with SOC with a mean of 42 versus 62 days for SOC (p = 0.00074) and achieved a mean wound area reduction within 12 weeks of 94% versus 51% for SOC (p = 0.0023). There were no adverse events or serious adverse events that were related to either the PRBM or the SOC. In comparison to the SOC, DFUs healed faster when treated with PRBM. Thus, the use of this PRBM is an effective option for the treatment of chronic DFUs.

Proposal regarding potential causes related to certain complications with dental implants and adjacent natural teeth: Physics applied to prosthodontics.

PURPOSE: Complications can and do occur with implants and their restorations with causes having been proposed for some single implant complications but not for others. METHODS: A review of pertinent literature was conducted. A PubMed search of vibration, movement, and dentistry had 175 citations, while stress waves, movement, and dentistry had zero citations as did stress waves, movement. This paper discusses the physics of vibration, elastic and inelastic collision, and stress waves as potentially causative factors related to clinical complications. RESULTS: Multiple potential causes for interproximal contact loss have been presented, but it has not been fully understood. Likewise, theories have been suggested regarding the intrusion of natural teeth when they are connected to an implant as part of a fixed partial denture as well as intrusion when a tooth is located between adjacent implants, but the process of intrusion, and resultant extrusion, is not fully understood. A third complication with single implants and their crowns is abutment screw loosening with several of the clinical characteristics having been discussed but without determining the underlying process(es). CONCLUSIONS: Interproximal contact loss, natural tooth intrusion, and abutment screw loosening are common complications that occur with implant retained restorations. Occlusion is a significant confounding variable. The hypothesis is that vibration, or possibly stress waves, generated from occlusal impact forces on implant crowns and transmitted to adjacent teeth, are the causative factors in these events. Since occlusion appears to play a role in these complications, it is recommended that occlusal contacts provide centralized stability on implant crowns and not be located on any inclined surfaces that transmit lateral forces that could be transmitted to an adjacent tooth and cause interproximal contact loss or intrusion. The intensity, form, and location of proximal contacts between a natural tooth located between adjacent single implant crowns seem to play a role in the intrusion of the natural tooth. Currently, there is a lack of information about the underlying mechanisms related to these occurrences and research is needed to define any confounding variables.

Multiple evolutionary transitions of reproductive strategies in a phylum of aquatic colonial invertebrates.

Parental care is considered crucial for the enhanced survival of offspring and evolutionary success of many metazoan groups. Most bryozoans incubate their young in brood chambers or intracoelomically. Based on the drastic morphological differences in incubation chambers across members of the order Cheilostomatida (class Gymnolaemata), multiple origins of incubation were predicted in this group. This hypothesis was tested by constructing a molecular phylogeny based on mitogenome data and nuclear rRNA genes 18S and 28S with the most complete sampling of taxa with various incubation devices to date. Ancestral character estimation suggested that distinct types of brood chambers evolved at least 10 times in Cheilostomatida. In Eucratea loricata and Aetea spp. brooding evolved unambiguously from a zygote-spawning ancestral state, as it probably did in Tendra zostericola, Neocheilostomata, and 'Carbasea' indivisa. In two further instances, brooders with different incubation chamber types, skeletal and non-skeletal, formed clades (Scruparia spp., Leiosalpinx australis) and (Catenicula corbulifera (Steginoporella spp. (Labioporella spp., Thalamoporella californica))), each also probably evolved from a zygote-spawning ancestral state. The modular nature of bryozoans probably contributed to the evolution of such a diverse array of embryonic incubation chambers, which included complex constructions made of polymorphic heterozooids, and maternal zooidal invaginations and outgrowths.

Free Tissue Transfer in Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis.

OBJECTIVE: Free tissue transfer is a powerful reconstructive method for patients with substantial diabetic foot ulcers. This study aimed to perform an updated systematic review and meta-analysis investigating the flap characteristics, concurrent revascularisation rates, complications, and outcomes associated with free tissue transfer in diabetic foot ulcers. METHODS: Two reviewers performed a systematic review of various databases since their inception, with no language restriction. Only data for free tissue transfer in non-traumatic diabetic foot ulcer patients were extracted from included studies where a heterogeneous population was studied. Outcome data were pooled using random effects meta-analysis for binomial data. RESULTS: Of 632 studies identified, 67 studies encompassing 1 846 patients and 1 871 free flaps were included. A median of 18 patients [IQR 9, 37] per study, with a median age of 58.5 years [56, 63], were followed up for a median of 15 months [7, 25]. Most studies had serious risk of bias (n = 47 studies, 70%); sixteen (24%) had moderate risk of bias; and four (6%) had low risk of bias. The proportion of patients who underwent revascularisation was 75% (95% CI 60 - 87%; n = 36 studies) with a median time of 8 days between procedures. The pooled complete flap survival, major amputation, and ambulation rates were 88% (85 - 92%, n = 49 studies), 10% (7 - 14%, n = 50 studies), and 87% (80 - 92%, n = 36 studies), respectively. Death at individual study follow up was 6% (3 - 10%, n = 26 studies). The overall certainty of evidence was very low. CONCLUSION: Free tissue transfer may be a useful treatment modality for recalcitrant diabetic foot ulcers in selected patients. Future studies should investigate long term functional outcomes and aim to develop patient selection algorithms to select the most suitable candidates for this procedure.

Uncoupling DNA damage from chromatin damage to detoxify doxorubicin.

The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.

Effects of Plant-Based Protein Consumption on Kidney Function and Mineral Bone Disorder Outcomes in Adults With Stage 3-5 Chronic Kidney Disease: A Systematic Review.

INTRODUCTION: Plant-based protein is of growing interest for dietary management of chronic kidney disease (CKD) and is hypothesized to preserve kidney function and reduce CKD-mineral bone disorder (MBD) complications, among other benefits. This systematic review aimed to summarize the available clinical trial evidence for the effect of plant-based protein on kidney function and CKD-MBD outcomes in adults with stage 3-5 CKD not on dialysis. METHODS: Searches of Medline, Embase, Agricola, CAB abstracts, Web of Science, Scopus, and hand searching were performed. Clinical trials with ≥8 participants ≥18 years of age with an estimated glomerular filtration rate <60 mL/min/1.73 m2 but not on dialysis were included. Additionally, only clinical trials with ≥1-week interventions with ≥50% dietary protein from plant-based sources and reported at least one outcome for both kidney function and CKD-MBD outcomes were included. Of the 10,962 identified abstracts, 32 met inclusion criteria and were assessed for risk of bias. RESULTS: Results for kidney function and CKD-MBD outcomes were heterogenous, with most studies having suboptimal methodological quality. In most of the studies (27/32), protein source was altered only secondarily to low-protein diet interventions. Thus, data synthesis and interpretation were focused on a subset of five studies that investigated a change in protein source only (i.e., animal vs. plant). Of this subset, four studies reported no change in kidney function, while one study reported a decrease. Three studies reported no change in serum phosphorus, and one study reported lower serum phosphorus following a vegetarian diet. Further, limited data and inconclusive results were observed for phosphaturic hormones, parathyroid hormone, and fibroblast growth factor-23. CONCLUSION: Current clinical trial evidence on plant-based protein interventions for preserving kidney function and preventing CKD-MBD is limited to inform clinical guidelines at this time. This systematic review emphasizes the ongoing need to research the effects of plant-based protein on kidney function and CKD-MBD outcomes.

An Integrated Health Belief Model: Predicting Uptake of the First COVID-19 Booster Vaccine.

Public health campaigns have turned to the Health Belief Model (HBM) as a guiding framework for the past six decades. Carpenter's 2010 HBM meta-analysis revealed important shortcomings as well as a path forward that has largely been ignored by recent COVID-19 research using this framework. Consistent with Carpenter's recommendations, this study on the uptake of the first COVID-19 booster vaccine focused on the overlooked interactional processes of the original HBM founders. Our study used SEM and Hayes's PROCESS 4.1 to explore the possibilities of the interdependent nature of the core three beliefs to form a model that is integrated. The study indicated that the core variables of the original HBM were significant predictors of the intent to take the first COVID-19 booster vaccine when considered in an interactional process framework. Our study results have implications for those designing public health advocacy campaigns regarding COVID-19 as it enters an endemic stage with future vaccines and medications.

Incidence and Risk Factors of Postoperative Complications After Rhinoplasty: A Multi-Institutional ACS-NSQIP Analysis.

OBJECTIVE: Despite the popularity of rhinoplasty, outcome research has been mainly limited to single-surgeon or single-institution reports. Therefore, we performed a multi-institutional analysis to present a broader portrait of the postoperative outcomes and risk factors for adverse events after rhinoplasty surgery. METHODS: We reviewed the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database (2009-2019) to identify patients who underwent rhinoplasty. The postoperative outcomes of interest included 30-day mortality, reoperation, readmission, and surgical and medical complications. We also analyzed risk factors for complication occurrence, including patient comorbidities and preoperative laboratory values. RESULTS: We identified 835 patients, 72% (n=602) of whom underwent a primary, 21% (n=175) a secondary, and 6.7% (n=58) a cleft nasal deformity procedure. The average patient age was 41±17 years, with most patients being female (n=472; 57%) and white (n=643; 77%). Complications rates were generally low, with reoperation (n=19; 2.3%) and superficial incisional infection (n=9; 1.1%) account for the most common general and surgical adverse event, respectively. Multivariable analysis revealed male sex ( P =0.04) and higher ASA scores ( P <0.0001) as risk factors for complications. Low serum albumin ( P =0.04) and hematocrit ( P =0.003) levels were associated with the occurrence of any complication, whereas low serum albumin ( P =0.02) also correlated with the incidence of surgical adverse events. CONCLUSION: Complication rates after rhinoplasty were overall low and seemed to correlate with male sex and ASA scores. We identified preoperative albumin and hematocrit as predictive biomarkers of adverse events. Preoperative nutritional optimization and management of low hematocrit may improve postoperative outcomes.