Comparative electroencephalography analysis: Marathon runners during tapering versus sedentary controls reveals no significant differences.

INTRODUCTION: Previous studies described various adaptive neuroplastic brain changes associated with physical activity (PA). EEG studies focused mostly on effects during or shortly after short bouts of exercise. This is the first study to investigate the capability of EEG to display PA-induced long-lasting plasticity in runners compared to a sedentary control group. METHODS: Thirty trained runners and 30 age- and sex-matched sedentary controls (SC) were included as a subpopulation of the ReCaP (Running effects on Cognition and Plasticity) study. PA was measured with the International Physical Activity Questionnaire (IPAQ). Resting-state EEG of the runners was recorded in the tapering phase of the training for the Munich marathon 2017. Power spectrum analyses were conducted using standardized low-resolution electromagnetic tomography (sLORETA) and included the following frequency bands: delta: 1.5-6 Hz, theta: 6.5-8.0 Hz, alpha1: 8.5-10 Hz, alpha2: 10.5-12.0 Hz, beta1: 12.5-18.0 Hz, beta2: 18.5-21.0 Hz, beta3: 21.5-30.0 Hz, and total power (1.5-30 Hz). RESULTS: PA (IPAQ) and BMI differed significantly between the groups. The other included demographic parameters were comparable. Statistical nonparametric mapping showed no significant power differences in EEG between the groups. DISCUSSION: Heterogeneity in study protocols, especially in time intervals between exercise cessation and EEG recordings and juxtaposition of acute exercise-induced effects on EEG in previous studies, could be possible reasons for the differences in results. Future studies should record EEG at different time points after exercise cessation and in a broader spectrum of exercise intensities and forms to further explore the capability of EEG in displaying long-term exercise-induced plasticity.

Using Photovoice to Explore Determinants of Health among Homeless and Unstably Housed Women.

The lived experiences of homeless and unstably housed women, including their health-related priorities, are understudied in smaller metropolitan and rural communities. In this study, we partnered with a day center for women who experience homelessness in Spokane, Washington. We used Photovoice, a community-based participatory action research method, to explore the health-related concerns, needs, and behavior of women who are homeless or unstably housed. Participant-generated photographs and group interview data were analyzed using thematic analysis. Three themes were generated: "These are my supports", "I'm trying to make my health better", and "[My] choices are very limited". The themes illustrated individual, interpersonal, community, and societal strengths and vulnerabilities aligned with the social ecological model. Participants demonstrated resourcefulness, creativity, and hope as they strived toward health improvement. Trauma-informed, strengths-based approaches that respect the autonomy of homeless and unstably housed women and that amplify their voices are needed to minimize power imbalances in research, policy, and practice. This includes an imperative for healthcare and social work programs to ready graduates to deliver effective, empathic services by increasing their knowledge of social determinants of health and of the stigma faced by marginalized communities. Moreover, collaborating with these communities when designing, implementing, and evaluating services is critical.

Further delineation of the phenotypic and metabolomic profile of ALDH1L2-related neurodevelopmental disorder.

ALDH1L2, a mitochondrial enzyme in folate metabolism, converts 10-formyl-THF (10-formyltetrahydrofolate) to THF (tetrahydrofolate) and CO2. At the cellular level, deficiency of this NADP+-dependent reaction results in marked reduction in NADPH/NADP+ ratio and reduced mitochondrial ATP. Thus far, a single patient with biallelic ALDH1L2 variants and the phenotype of a neurodevelopmental disorder has been reported. Here, we describe another patient with a neurodevelopmental disorder associated with a novel homozygous missense variant in ALDH1L2, Pro133His. The variant caused marked reduction in the ALDH1L2 enzyme activity in skin fibroblasts derived from the patient as probed by 10-FDDF, a stable synthetic analog of 10-formyl-THF. Additional associated abnormalities in these fibroblasts include reduced NADPH/NADP+ ratio and pool of mitochondrial ATP, upregulated autophagy and dramatically altered metabolomic profile. Overall, our study further supports a link between ALDH1L2 deficiency and abnormal neurodevelopment in humans.

Relative preference for distinct reinforcers maintaining destructive behavior.

The literature offers few recommendations for sequencing exposure to treatment conditions with individuals with multiply maintained destructive behavior. Identifying relative preference for the functional reinforcers maintaining destructive behavior may be one means of guiding that decision. The present study presents a preliminary attempt at developing a robust relative preference and reinforcer assessment for individuals with multiply maintained destructive behavior. Guided and free-choice trials were implemented in which participants chose between two multiple-schedule arrangements, each of which programmed signaled periods of isolated reinforcer availability and unavailability. Consistent participant choice and responding during free-choice trials was then used to thin the corresponding schedule of reinforcement. The results demonstrated a strong preference for one of the two functional reinforcers for all four participants, yet preferences differed across participants and were not well predicted by responding in prior analyses.

Study protocol of a cluster-randomised controlled trial assessing a multimodal machine-based exercise training programme in senior care facilities over 6 months - the bestform study (best function of range of motion).

BACKGROUND: Physical functioning is a crucial factor for independence and quality of life in old age. The aim of the "bestform-Best function of range of motion" trial is to investigate the effects of a 6 months multimodal machine-based strength, coordination and endurance training on physical function, risk of falls and health parameters in older adults. METHODS: Bestform is a cluster-randomised trial including older adults ≥ 65 years living in senior care facilities in Southern Germany. Senior care facilities are randomly allocated to the control group with usual care (n ≥ 10 care facilities) and to the intervention group (n ≥ 10 care facilities), overall including ≥ 400 seniors. Residents belonging to the intervention group are offered a supervised machine-based exercise training programme twice weekly over 45-60 min over six months in small groups, while those in the usual care facilities will not receive active intervention. The primary outcome is the change in Short Physical Performance Battery over six months between groups. Secondary outcomes are change in risk of falling, fear of falling, number of falls and fall-related injuries, physical exercise capacity, handgrip strength, body composition, cardiac function, blood parameters, quality of life, risk of sarcopenia, activities of daily living, and cognition over three and six months. DISCUSSION: The bestform study investigates the change in physical function between seniors performing exercise intervention versus usual care over six months. The results of the study will contribute to the development of effective physical activity concepts in senior care facilities. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04207307. Registered December 2019.

An assessment of token value and effectiveness: A replication.

The purpose of the current study was to conduct a systematic replication of Fiske et al. (2015) to extend the behavior-analytic literature on token reinforcement. Specifically, the researchers addressed several of the limitations of Fiske et al. by including specific conditioning procedures, creating a controlled history of reinforcement with the token system, including participants with and without disabilities to extend the generality of the findings, and equating the magnitude of reinforcement across the primary and paired-token conditions. The current study evaluated the reinforcing value of tokens by using progressive-ratio schedules to compare the efficacy of primary reinforcement, paired tokens, and unpaired tokens. The results suggest that paired tokens may function as reinforcers, but they were not as consistently effective as primary reinforcers.

Binding to the conserved and stably folded guide RNA pseudoknot induces Cas12a conformational changes during ribonucleoprotein assembly.

Ribonucleoproteins (RNPs) comprise one or more RNA and protein molecules that interact to form a stable complex, which commonly involves conformational changes in the more flexible RNA components. Here, we propose that Cas12a RNP assembly with its cognate CRISPR RNA (crRNA) guide instead proceeds primarily through Cas12a conformational changes during binding to more stable, prefolded crRNA 5' pseudoknot handles. Phylogenetic reconstructions and sequence and structure alignments revealed that the Cas12a proteins are divergent in sequence and structure while the crRNA 5' repeat region, which folds into a pseudoknot and anchors binding to Cas12a, is highly conserved. Molecular dynamics simulations of three Cas12a proteins and their cognate guides revealed substantial flexibility for unbound apo-Cas12a. In contrast, crRNA 5' pseudoknots were predicted to be stable and independently folded. Limited trypsin hydrolysis, differential scanning fluorimetry, thermal denaturation, and CD analyses supported conformational changes of Cas12a during RNP assembly and an independently folded crRNA 5' pseudoknot. This RNP assembly mechanism may be rationalized by evolutionary pressure to conserve CRISPR loci repeat sequence, and therefore guide RNA structure, to maintain function across all phases of the CRISPR defense mechanism.

Capsular inflammation after immediate breast reconstruction - Gene expression patterns and inflammatory cell infiltration in irradiated and non-irradiated breasts.

BACKGROUND: Capsular contracture following post-mastectomy radiotherapy (PMRT) is commonly seen in patients undergoing implant-based immediate breast reconstruction (IBR). Further understanding of the underlying biology is needed for the development of preventive or therapeutic strategies. Therefore, we conducted a comparative study of gene expression patterns in capsular tissue from breast cancer patients who had received versus those who had not received PMRT after implant-based IBR. METHODS: Biopsies from irradiated and healthy non-irradiated capsular tissue were harvested during implant exchange following IBR. Biopsies from irradiated (n = 13) and non-irradiated (n = 12) capsules were compared using Affymetrix microarrays to identify the most differentially regulated genes. Further analysis using immunohistochemistry was performed in a subset of materials to compare the presence of T cells, B cells, and macrophages. RESULTS: Enrichment testing using Gene Ontology (GO) analysis revealed that the 227 most differentially expressed genes were mainly involved in an inflammatory response. Twenty-one GO biological processes were identified [p < 0.05, false discovery rate (FDR) < 5%], several with B-cell-associated inflammation. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) analysis identified macrophages as the most common inflammatory cell type in both groups, further supported by immunostaining of CD68. Radiation remarkably increased B-cell infiltration in the capsular region of biopsies, as quantified by immunostaining of CD20 (p = 0.016). CONCLUSIONS: Transcript analysis and immunohistochemistry revealed inflammatory responses in capsular biopsies regardless of radiotherapy. However, the radiation response specifically involved B-cell-associated inflammatory responses.

Basic and applied research on extinction bursts.

Discontinuation of the contingency between a response and its reinforcer sometimes produces a temporary increase in the response before its rate decreases, a phenomenon called the extinction burst. Prior clinical and basic studies on the prevalence of the extinction burst provide highly disparate estimates. Existing theories on the extinction burst fail to account for the dynamic nature of this phenomenon, and the basic behavioral processes that control response bursting remain poorly understood. In this paper, we first review the basic and applied literature on the extinction burst. We then describe a recent refinement of the concatenated matching law called the temporally weighted matching law that appears to resolve the above-mentioned issues regarding the extinction burst. We present illustrative translational data based conceptually on the model. Finally, we discuss specific recommendations derived from the temporally weighted matching law regarding procedures clinicians could implement to potentially mitigate or prevent extinction bursts.

Exploratory Metabolomics Underscores the Folate Enzyme ALDH1L1 as a Regulator of Glycine and Methylation Reactions.

Folate (vitamin B9) is involved in one-carbon transfer reactions and plays a significant role in nucleic acid synthesis and control of cellular proliferation, among other key cellular processes. It is now recognized that the role of folates in different stages of carcinogenesis is complex, and more research is needed to understand how folate reactions become dysregulated in cancers and the metabolic consequences that occur as a result. ALDH1L1 (cytosolic 10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism expressed in many tissues, is ubiquitously downregulated in cancers and is not expressed in cancer cell lines. The RT4 cell line (derived from papillary bladder cancer) which expresses high levels of ALDH1L1 represents an exception, providing an opportunity to explore the metabolic consequences of the loss of this enzyme. We have downregulated this protein in RT4 cells (shRNA driven knockdown or CRISPR driven knockout) and compared metabolomes of ALDH1L1-expressing and -deficient cells to determine if metabolic changes linked to the loss of this enzyme might provide proliferative and/or survival advantages for cancer cells. In this study, cell extracts were analyzed using Ultra High Performance Liquid Chromatography High Resolution Mass Spectrometry (UHPLC-HR-MS). A total of 13,339 signals were identified or annotated using an in-house library and public databases. Supervised and unsupervised multivariate analysis revealed metabolic differences between RT4 cells and ALDH1L1-deficient clones. Glycine (8-fold decrease) and metabolites derived from S-adenosylmethionine utilizing pathways were significantly decreased in the ALDH1L1-deficient clones, compared with RT4 cells. Other changes linked to ALDH1L1 downregulation include decreased levels of amino acids, Krebs cycle intermediates, and ribose-5-phosphate, and increased nicotinic acid. While the ALDH1L1-catalyzed reaction is directly linked to glycine biosynthesis and methyl group flux, its overall effect on cellular metabolism extends beyond immediate metabolic pathways controlled by this enzyme.

Cardiopulmonary exercise testing excludes significant disease in patients recovering from COVID-19.

OBJECTIVE: Post-COVID-19 syndrome presents a health and economic challenge affecting ~10% of patients recovering from COVID-19. Accurate assessment of patients with post-COVID-19 syndrome is complicated by health anxiety and coincident symptomatic autonomic dysfunction. We sought to determine whether either symptoms or objective cardiopulmonary exercise testing could predict clinically significant findings. METHODS: 113 consecutive military patients were assessed in a comprehensive clinical pathway. This included symptom reporting, history, examination, spirometry, echocardiography and cardiopulmonary exercise testing (CPET) in all, with chest CT, dual-energy CT pulmonary angiography and cardiac MRI where indicated. Symptoms, CPET findings and presence/absence of significant pathology were reviewed. Data were analysed to identify diagnostic strategies that may be used to exclude significant disease. RESULTS: 7/113 (6%) patients had clinically significant disease adjudicated by cardiothoracic multidisciplinary team (MDT). These patients had reduced fitness (V̇O2 26.7 (±5.1) vs 34.6 (±7.0) mL/kg/min; p=0.002) and functional capacity (peak power 200 (±36) vs 247 (±55) W; p=0.026) compared with those without significant disease. Simple CPET criteria (oxygen uptake (V̇O2) >100% predicted and minute ventilation (VE)/carbon dioxide elimination (V̇CO2) slope <30.0 or VE/V̇CO2 slope <35.0 in isolation) excluded significant disease with sensitivity and specificity of 86% and 83%, respectively (area under the receiver operating characteristic curve (AUC) 0.89). The addition of capillary blood gases to estimate alveolar-arterial gradient improved diagnostic performance to 100% sensitivity and 78% specificity (AUC 0.92). Symptoms and spirometry did not discriminate significant disease. CONCLUSIONS: In a population recovering from SARS-CoV-2, there is reassuringly little organ pathology. CPET and functional capacity testing, but not reported symptoms, permit the exclusion of clinically significant disease.

Association of Chronic Kidney Disease and Complications Following Acute Torsional Ankle Fracture.

BACKGROUND: Although chronic kidney disease (CKD) has been associated with poor outcomes following traumatic fractures, there is a scarcity of literature describing the effect on outcomes of ankle fractures. We will examine the impact of CKD on clinical outcomes following torsional ankle fracture, including complications and unplanned surgical procedures. METHODS: A retrospective review of 1981 adult patients with torsional ankle fractures treated at a level 1 trauma center was performed to identify patients with CKD based on glomerular filtration rate. Demographic, injury, and treatment-related characteristics were collected. Outcomes included any unplanned procedure: implant removal, debridement, revision, arthrodesis, and amputation; in addition to complications of superficial infection, deep infection, and implant irritation. Patients with CKD were matched with patients without CKD by propensity score matching. Univariate comparisons between groups were conducted using chi-square and Mann-Whitney U tests. RESULTS: 136 patients (68 with CKD and 68 without CKD) were analyzed. Of the 68 patients with CKD, the mean stage of disease was 3.7 with 24% on dialysis for a mean length of 4.1 years. Patients without CKD were more likely to undergo primary ORIF (100% vs 54%, P < .001). Thirty-five percent of patients with CKD had surgical complications vs 19% in the cohort without (P = .07). Patients with open fractures, dislocation, and chronic kidney disease were, respectively, 5.19, 3.77, and 3.91 times more likely to have any complication (P = .02, P = .05, P = .05). Patients with CKD were more likely to undergo unplanned arthrodesis (P = .01). Only dislocation was an independent predictor for unplanned procedure (odds ratio = 5.08, P = .026). CONCLUSION: Following torsional ankle fracture, CKD is associated with increased likelihood of having a complication or an unplanned arthrodesis. Open fractures and dislocation at time of injury are also associated with complications. Our findings encourage caution about surgical treatment of ankle fractures in patients with CKD. LEVEL OF EVIDENCE: Level III, retrospective, comparative, prognostic.

Progressive machine-based resistance training for prevention and treatment of sarcopenia in the oldest old: A systematic review and meta-analysis.

The muscle disease sarcopenia, which is characterised by a loss of muscle strength, muscle quantity, and physical performance, restricts mobility and independence in an ageing society. The aim of this systematic review and meta-analysis is to analyse the effects that long-term progressive resistance training interventions performed on weight machines have on sarcopenia (European Working Group on Sarcopenia in Older People) and how the interventions are composed. In total, 779 articles published between 2000 and 2020 were scanned (PubMed, Web of Science, CINAHL) and 14 randomised controlled trials were included within the review. Populations, interventions, control groups and outcomes were analysed. Subsequent meta-analysis (10 studies, 902 participants) revealed that the time needed in a chair-stand-test, as an indicator for leg strength, was predominantly reduced, whereas grip strength remained unchanged after the interventions. Data concerning the effects of machine-based progressive resistance training on muscle quantity were insufficient for meta-analysis. Physical performance measured by undergoing the Timed-Up-and-Go-test, gait speed test, Short Physical Performance Battery and 6 min-walk-test improved significantly as well. The quality of evidence (GRADE) in the analysed studies was low or moderate. In summary, machine-based progressive resistance training has the potential to reverse sarcopenia in the oldest old, as reflected by enhanced muscle strength and physical performance. The systematic review revealed promising initial results for muscle quantity.

Differentiating aspartic acid isomers and epimers with charge transfer dissociation mass spectrometry (CTD-MS).

The ability to understand the function of a protein often relies on knowledge about its detailed structure. Sometimes, seemingly insignificant changes in the primary structure of a protein, like an amino acid substitution, can completely disrupt a protein's function. Long-lived proteins (LLPs), which can be found in critical areas of the human body, like the brain and eye, are especially susceptible to primary sequence alterations in the form of isomerization and epimerization. Because long-lived proteins do not have the corrective regeneration capabilities of most other proteins, points of isomerism and epimerization that accumulate within the proteins can severely hamper their functions and can lead to serious diseases like Alzheimer's disease, cancer and cataracts. Whereas tandem mass spectrometry (MS/MS) in the form of collision-induced dissociation (CID) generally excels at peptide characterization, MS/MS often struggles to pinpoint modifications within LLPs, especially when the differences are only isomeric or epimeric in nature. One of the most prevalent and difficult-to-identify modifications is that of aspartic acid between its four isomeric forms: L-Asp, L-isoAsp, D-Asp, and D-isoAsp. In this study, peptides containing isomers of Asp were analyzed by charge transfer dissociation (CTD) mass spectrometry to identify spectral features that could discriminate between the different isomers. For the four isomers of Asp in three model peptides, CTD produced diagnostic ions of the form cn+57 on the N-terminal side of iso-Asp residues, but not on the N-terminal side of Asp residues. Using CTD, the L- and D forms of Asp and isoAsp could also be differentiated based on the relative abundance of y- and z ions on the C-terminal side of Asp residues. Differentiation was accomplished through a chiral discrimination factor, R, which compares an ion ratio in a spectrum of one epimer or isomer to the same ion ratio in the spectrum of a different epimer or isomer. The R values obtained using CTD are as robust and statistically significant as other fragmentation techniques, like radical directed dissociation (RDD). In summary, the extent of backbone and side-chain fragments produced by CTD enabled the differentiation of isomers and epimers of Asp in a variety of peptides.

Predictors of cardiopulmonary fitness in cancer-affected and -unaffected women with a pathogenic germline variant in the genes BRCA1/2 (LIBRE-1).

Physical activity (PA) helps prevention and aftercare of sporadic breast cancer (BC), cardiopulmonary fitness (CPF) being an age-independent predictor of tumor-specific mortality. Therefore, we wanted to identify predictors of CPF (represented by peak oxygen uptake: VO2peak) in BRCA1/2 mutation carriers whose risk of developing BC is high. We used cross-sectional data from 68 BRCA1/2 germline mutation carrying women participating in the randomized, prospective, controlled clinical study LIBRE-1. Assessments included cardiopulmonary exercise testing, medical and lifestyle history plus socioeconomic status. Additionally, the participants completed a psychological questionnaire regarding their attitude, subjective norms, perceived behavior control and intention towards PA. A multivariate logistic regression model was used to identify predictors for participants reaching their age- and sex-adjusted VO2peak reference values. 22 participants (median age: 40 years, interquartile range (IQR) 33-46) were cancer-unaffected and 46 cancer-affected (median age: 44 years, IQR 35-50). The strongest predictor for reaching the reference VO2peak value was attitude towards PA (Odds Ratio 3.0; 95% Confidence Interval 1.3-8.4; p = 0.021). None of the other predictors showed a significant association. A positive attitude towards PA seems to be associated with VO2peak, which should be considered in developing therapeutic and preventive strategies.Trial registrations: NCT02087592; DRKS00005736.

Structural Characterization of Natural and Synthetic Macrocycles Using Charge-Transfer Dissociation Mass Spectrometry.

Research in natural products (NPs) has gained interest as drug developers turn to nature to combat problems with drug resistance, drug delivery, and emerging diseases. Whereas NPs offer a tantalizing source of new pharmacologically active compounds, their structural complexity presents a challenge for analytical characterization and organic synthesis. Of particular concern is the characterization of cyclic-, polycyclic-, or macrocyclic compounds. One example of endogenous compounds as inspiration for NP development are cobalamins, like vitamin B12. An example of exogenous NPs is the class of macrolides that includes erythromycin. Both classes of macrocycles feature analogues with a range of modifications on their macrocyclic cores, but because of their cyclic nature, they are generally resistant to fragmentation by collision-induced dissociation (CID). In the present work, charge-transfer dissociation (CTD) was employed, with or without supplemental collisional activation, to produce radical-driven, high-energy fragmentation products of different macrocyclic precursors. With the assistance of collisional activation of CTnoD products, CTD frequently cleaved two covalent bonds within the macrocycle cores to reveal rich, informative spectra that helped identify sites of modification and resolve structural analogues. In a third example of macrocycle fragmentation, CTD enabled an impurity in a biological sample to be characterized as a cyclic polymer of nylon-6,6. In each example, CTD spectra are starkly different from CID and are highly reminiscent of other high-energy fragmentation techniques like extreme ultraviolet dissociative photoionization (XUV-DPI) and electron ionization-induced dissociation (EID). The results indicate that CTD-MS is a useful tool for the characterization of natural and synthetic macrocycles.

Differentiation of leucine and isoleucine residues in peptides using charge transfer dissociation mass spectrometry (CTD-MS).

RATIONALE: The function of a protein or the binding affinity of an antibody can be substantially altered by the replacement of leucine (Leu) with isoleucine (Ile), and vice versa, so the ability to identify the correct isomer using mass spectrometry can help resolve important biological questions. Tandem mass spectrometry approaches for Leu/Ile (Xle) discrimination have been developed, but they all have certain limitations. METHODS: Four model peptides and two wild-type peptide sequences containing either Leu or Ile residues were subjected to charge transfer dissociation (CTD) mass spectrometry on a modified three-dimensional ion trap. The peptides were analyzed in both the 1+ and 2+ charge states, and the results were compared to conventional collision-induced dissociation spectra of the same peptides obtained using the same instrument. RESULTS: CTD resulted in 100% sequence coverage for each of the studied peptides and provided a variety of side-chain cleavages, including d, w and v ions. Using CTD, reliable d and w ions of Xle residues were observed more than 80% of the time. When present, d ions are typically greater than 10% of the abundance of the corresponding a ions from which they derive, and w ions are typically more abundant than the z ions from which they derive. CONCLUSIONS: CTD has the benefit of being applicable to both 1+ and 2+ precursor ions, and the overall performance is comparable to that of other high-energy activation techniques like hot electron capture dissociation and UV photodissociation. CTD does not require chemical modifications of the precursor peptides, nor does it require additional levels of isolation and fragmentation.

Survival in breast cancer patients with a delayed DIEP flap breast reconstruction after adjustment for socioeconomic status and comorbidity.

PURPOSE: Overall survival in breast cancer patients receiving a delayed deep inferior epigastric perforator (DIEP) flap breast reconstruction is better than in those without delayed breast reconstruction. This study aimed at determining the impact of socioeconomic status (SES) and comorbidity on these observations. MATERIALS AND METHODS: This matched cohort study included all consecutive women undergoing a delayed DIEP flap reconstruction at Karolinska University Hospital, Sweden, between 1999 and 2013. Controls had not received any delayed breast reconstruction and were relapse-free after a corresponding follow-up interval. Matching was by year of and age at mastectomy, tumour stage and lymph node status. Charlson Comorbidity Index (CCI) and socioeconomic data were obtained from national registers. Associations with breast cancer-specific (BCSS) and overall survival (OS) were investigated by Kaplan-Meier survival estimates and Cox proportional hazard regression analysis. RESULTS: Women in the DIEP group (N = 254) more often continued education after primary school (88.6% versus 82.6%, P = 0.026), belonged to the high-income group (76.0% versus 63.1%, P < 0.001), were in a partnership (57.1% versus 55.7%, P = 0.024) and healthier (median CCI 1.00 (range 0-13) versus 2.00 (range 0-16), P = 0.021) than the control group (N = 729). After adjustment for tumour and treatment factors, SES and comorbidity, OS remained significantly better for the DIEP group than the control group (HR 2.27, 95% CI 1.44-3.55). CONCLUSION: Women with a delayed DIEP flap reconstruction are a subgroup of higher socioeconomic status and better health. Higher survival estimates for the DIEP group persisted after adjusting for those differences, suggesting the presence of further unmeasured covariates.

Knockout of Putative Tumor Suppressor Aldh1l1 in Mice Reprograms Metabolism to Accelerate Growth of Tumors in a Diethylnitrosamine (DEN) Model of Liver Carcinogenesis.

Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) is commonly downregulated in human cancers through promoter methylation. We proposed that ALDH1L1 loss promotes malignant tumor growth. Here, we investigated the effect of the Aldh1l1 mouse knockout (Aldh1l1-/-) on hepatocellular carcinoma using a chemical carcinogenesis model. Fifteen-day-old male Aldh1l1 knockout mice and their wild-type littermate controls (Aldh1l1+/+) were injected intraperitoneally with 20 µg/g body weight of DEN (diethylnitrosamine). Mice were sacrificed 10, 20, 28, and 36 weeks post-DEN injection, and livers were examined for tumor multiplicity and size. We observed that while tumor multiplicity did not differ between Aldh1l1-/- and Aldh1l1+/+ animals, larger tumors grew in Aldh1l1-/- compared to Aldh1l1+/+ mice at 28 and 36 weeks. Profound differences between Aldh1l1-/- and Aldh1l1+/+ mice in the expression of inflammation-related genes were seen at 10 and 20 weeks. Of note, large tumors from wild-type mice showed a strong decrease of ALDH1L1 protein at 36 weeks. Metabolomic analysis of liver tissues at 20 weeks showed stronger differences in Aldh1l1+/+ versus Aldh1l1-/- metabotypes than at 10 weeks, which underscores metabolic pathways that respond to DEN in an ALDH1L1-dependent manner. Our study indicates that Aldh1l1 knockout promoted liver tumor growth without affecting tumor initiation or multiplicity.

Increased salvage rates with early reexploration: A retrospective analysis of 547 free flap cases.

BACKGROUND: Free flap complications are generally rare, but not negligible since they may exert paramount impact on both patients and care providers. The aim of the study was to identify risk factors for reexploration and assess predictors associated with increased salvage rates. METHODS: A retrospective cohort study was conducted for free flaps performed between 2006 and 2015. Patient demographics, indications and flap types were analyzed together with complications and time to reexploration. RESULTS: Among 547 consecutive free flaps, 11.5% required acute reexploration. Hematoma together with vascular compromise was the main cause (41.9%) for reexploration, followed by hematoma only (19.4%), venous (16.1%) and arterial (6.5%) thrombosis. Hematoma was associated with an increased risk for concomitant vascular complication (p < 0.02). The incidence of total and partial flap necrosis was 3.5% and 3.7% respectively. There was an overall 71.4% salvage rate. The median time from detection of a compromised flap to reexploration was 3.0 h. Significantly higher salvage rates were observed for cases reexplored within (82.4%) compared to after (57.1%) 3.0 h (OR 3.50 (95% CI 1.10 to 11.13, p = 0.034)). CONCLUSIONS: The current study highlights the importance of early intervention, including evacuation of hematomas that may lead to vascular compromise. Adequate monitoring of venous outflow was found necessary to improve flap salvage rates, whereas arterial complications were mainly related to persistent arterial injury in traumatized extremities with reduced salvage rates. Free flap surgery requires trained staff and immediate access to operating facilities to ensure high flap survival rates.