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Background: Esthetic upper lateral cutaneous lip reconstruction preserves the apical triangle, nasolabial fold symmetry, and free margin position. The tunneled island pedicle flap (IPF) is a novel single-stage reconstruction to achieve these goals., Objectives: Describe the technique and patient and surgeon-reported outcomes for the tunneled IPF reconstruction of upper lateral cutaneous lip defects., Methods: Retrospective chart review of consecutive tunneled IPF reconstruction following Mohs micrographic surgery (MMS) at a tertiary care center between 2014 and 2020. Patients rated their scars using the validated Patient Scar Assessment Scale (PSAS), and independent surgeons rated scars using the validated Observer Scar Assessment Scale (OSAS). Descriptive statistics were generated for patient demographics and tumor defect characteristics., Results: Twenty upper lateral cutaneous lip defects were repaired with the tunneled IPF. Surgeons rated scars with a composite OSAS score of 11.83 ± 4.29 (mean, SD) [scale of 5 (normal skin) to 50 (worst scar imaginable)] and an overall scar score of 2.81 ± 1.11 [scale of 1 (normal skin) to 10 (worst scar imaginable)]. Patients rated their scars with a composite PSAS score of 10 ± 5.39 [scale of 6 (best possible score) to 60 (worst)] and with an overall score of 2.2 ± 1.78 [scale of 1 (normal skin) and 10 (very different from normal skin)]. One flap was surgically revised for pincushioning, but none experienced necrosis, hematoma, or infection., Conclusions: The tunneled IPF is a single-stage reconstruction for upper lateral cutaneous lip defects with favorable scar ratings by patients and observers., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

The Veterans' Pain Care Organizational Improvement Comparative Effectiveness (VOICE) study is a 12-month pragmatic randomized comparative effectiveness trial conducted at ten United States Veterans Affairs (VA) health care sites. The overall goal was to test interventions to improve pain while reducing opioid use among VA patients with moderate-severe chronic pain despite treatment with long-term opioid therapy (LTOT). Aims were 1) to compare lower-intensity telecare collaborative pain management (TCM) versus higher-intensity integrated pain team management (IPT), and 2) to test the option of switching to buprenorphine (versus no option) in a high-dose subgroup. Recruitment challenges included secular trends in opioid prescribing and the COVID-19 pandemic. Participants were recruited over 3.5 years. Of 6966 potentially eligible patients, 4731 (67.9%) were contacted for telephone eligibility interview; of those contacted, 3398 (71.8%) declined participation, 359 (7.6%) were ineligible, 821 (24.2%) enrolled, and 820 (24.1%) were randomized. The most common reason for declining was satisfaction with pain care (n = 731). The most common reason for ineligibility was not having moderate-severe chronic pain (n = 110). Compared with the potentially eligible population, randomized participants were slightly younger, more often female, had similar prescribed opioids, and had similar or higher rates of pain and mental health diagnoses. The enrolled patient number was lower than the original target, but sufficient to power planned analyses. In conclusion, the VOICE trial enrolled a diverse sample similar to the population of VA patients receiving LTOT. Results will add substantially to limited existing evidence for interventions to improve pain while reducing opioid use. ClinicalTrials.gov identifier: NCT03026790., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Background: The COVID-19 pandemic has strained health care systems and has resulted in widespread critical care staffing shortages, negatively impacting the quality of care delivered., Research Question: How have hospitals' emergency responses to the pandemic influenced the well-being of frontline intensivists, and do any potential strategies exist to improve their well-being and to help preserve the critical care workforce?, Study Design and Methods: We conducted semistructured interviews of intensivists at clusters of tertiary and community hospitals located in six regions across the United States between August and November 2020 using the "four S" framework of acute surge planning (ie, space, staff, stuff, and system) to organize the interview guide. We then used inductive thematic analysis to identify themes describing the influence of hospitals' emergency responses on intensivists' well-being., Results: Thirty-three intensivists from seven tertiary and six community hospitals participated. Intensivists reported experiencing substantial moral distress, particularly because of restricted visitor policies and their perceived negative impacts on patients, families, and staff. Intensivists also frequently reported burnout symptoms as a result of their experiences with patient death, exhaustion over the pandemic's duration, and perceived lack of support from colleagues and hospitals. We identified several potentially modifiable factors perceived to improve morale, including the proactive provision of mental health resources, establishment of formal backup schedules for physicians, and clear actions demonstrating that clinicians are valued by their institutions., Interpretation: Restrictive visitation policies contributed to moral distress as reported by intensivists, highlighting the need to reconsider the risks and benefits of these policies. We also identified several interventions as perceived by intensivists that may help to mitigate moral distress and to improve burnout as part of efforts to preserve the critical care workforce., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Aims: The Gulf War Illness programs (GWI) of the United States Department of Veteran Affairs and the Department of Defense Congressionally Directed Medical Research Program collaborated with experts to develop Common Data Elements (CDEs) to standardize and systematically collect, analyze, and share data across the (GWI) research community., Main Methods: A collective working group of GWI advocates, Veterans, clinicians, and researchers convened to provide consensus on instruments, case report forms, and guidelines for GWI research. A similar initiative, supported by the National Institute of Neurologic Disorders and Stroke (NINDS) was completed for a comparative illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and provided the foundation for this undertaking. The GWI working group divided into two sub-groups (symptoms and systems assessment). Both groups reviewed the applicability of instruments and forms recommended by the NINDS ME/CFS CDE to GWI research within specific domains and selected assessments of deployment exposures. The GWI CDE recommendations were finalized in March 2018 after soliciting public comments., Key Findings: GWI CDE recommendations are organized in 12 domains that include instruments, case report forms, and guidelines. Recommendations were categorized as core (essential), supplemental-highly recommended (essential for specified conditions, study types, or designs), supplemental (commonly collected, but not required), and exploratory (reasonable to use, but require further validation). Recommendations will continually be updated as GWI research progresses., Significance: The GWI CDEs reflect the consensus recommendations of GWI research community stakeholders and will allow studies to standardize data collection, enhance data quality, and facilitate data sharing., (Copyright © 2018. Published by Elsevier Inc.)

Background: The COVID-19 pandemic resulted in unprecedented adjustments to ICU organization and care processes globally., Research Questions: Did hospital emergency responses to the COVID-19 pandemic differ depending on hospital setting? Which strategies worked well to mitigate strain as perceived by intensivists?, Study Design and Methods: Between August and November 2020, we carried out semistructured interviews of intensivists from tertiary and community hospitals across six regions in the United States that experienced early or large surges of COVID-19 patients, or both. We identified themes of hospital emergency responses using the four S framework of acute surge planning: space, staff, stuff, system., Results: Thirty-three intensivists from seven tertiary and six community hospitals participated. Clinicians across both settings believed that canceling elective surgeries was helpful to increase ICU capabilities and that hospitals should establish clearly defined thresholds at which surgeries are limited during future surge events. ICU staff was the most limited resource; staff shortages were improved by the use of tiered staffing models, just-in-time training for non-ICU clinicians, designated treatment teams, and deployment of trainees. Personal protective equipment (PPE) shortages and reuse were widespread, causing substantial distress among clinicians; hands-on PPE training was helpful to reduce clinicians' anxiety. Transparency and involvement of frontline clinicians as stakeholders were important components of effective emergency responses and helped to maintain trust among staff., Interpretation: We identified several strategies potentially to mitigate strain as perceived by intensivists working in both tertiary and community hospital settings. Our study also demonstrated the importance of trust and transparency between frontline staff and hospital leadership as key components of effective emergency responses during public health crises., (Published by Elsevier Inc.)

Sex differences play a vital role in human brain structure and physiology. Previous reports have proposed evidence hinting at a metabolic advantage in female brains across adulthood. It remained to be determined whether this advantage would be maintained across the spectrum of cognitive impairment, up to and including dementia due to Alzheimer's disease (AD). Here, using a machine-learning algorithm, we explore sex differences in metabolic brain-age derived from fluorodeoxyglucose positron emission tomography imaging among cognitively healthy individuals and those affected by mild cognitive impairment and clinically probable AD. First, we report that cognitively healthy male participants showed a persistently "older" looking brains when compared to healthy female participants in term of metabolic brain age, confirming earlier reports. However, this distinction disappeared among MCI individuals and probable AD patients, and this loss could not be explained by an accompanying neurodegeneration. This would seem to indicate that females have a higher rate of decline in brain glucose metabolism when cognitively impaired to negate their prior advantage., (Copyright © 2021. Published by Elsevier Inc.)

The level of prediction error in the brain age estimation frameworks is associated with the authenticity of statistical inference on the basis of regression models. In this paper, we present an efficacious and plain bias-adjustment scheme using chronological age as a covariate through the training set for downgrading the prediction bias in a Brain-age estimation framework. We applied proposed bias-adjustment scheme coupled by a machine learning-based brain age framework on a large set of metabolic brain features acquired from 675 cognitively unimpaired adults through fluorodeoxyglucose positron emission tomography data as the training set to build a robust Brain-age estimation framework. Then, we tested the reliability of proposed bias-adjustment scheme on 75 cognitively unimpaired adults, 561 mild cognitive impairment patients as well as 362 Alzheimer's disease patients as independent test sets. Using the proposed method, we gained a strong R 2 of 0.81 between the chronological age and brain estimated age, as well as an excellent mean absolute error of 2.66 years on 75 cognitively unimpaired adults as an independent set; whereas an R 2 of 0.24 and a mean absolute error of 4.71 years was achieved without bias-adjustment. The simulation results demonstrated that the proposed bias-adjustment scheme has a strong capability to diminish prediction error in brain age estimation frameworks for clinical settings., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Learning visual-phonological associations is a key skill underlying successful reading acquisition. However, we are yet to understand the cognitive mechanisms that enable efficient learning in good readers, and those which are aberrant in individuals with developmental dyslexia. Here, we use a repeated cued-recall task to examine how typical and reading-impaired adults acquire novel associations between visual and phonological stimuli, incorporating a looking-at-nothing paradigm to probe implicit memory for target locations. Cued recall accuracy revealed that typical readers' recall of novel phonological associates was better than dyslexic readers' recall, and it also improved more with repetition. Eye fixation-contingent error analyses suggest that typical readers' greater improvement from repetition reflects their more robust encoding and/or retrieval of each instance in which a given pair was presented: whereas dyslexic readers tended to recall a phonological target better when fixating its most recent location, typical readers showed this pattern more strongly when the target location was consistent across multiple trials. Thus, typical readers' greater success in reading acquisition may derive from their better use of statistical contingencies to identify consistent stimulus features across multiple exposures. We discuss these findings in relation to the role of implicit memory in forming new visual-phonological associations as a foundational skill in reading, and areas of weakness in developmental dyslexia., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Sporadic Alzheimer's disease (AD), as opposed to its autosomal dominant form, is likely caused by a complex interaction of genetic, environmental, and health lifestyle factors. Twin studies indicate that sporadic AD heritability could be between 58% and 79%, around half of which is explained by the ε4 allele of the apolipoprotein E (APOE4). We hypothesized that genes associated with known risk factors for AD, namely hypertension, hypercholesterolemia, obesity, diabetes, and cardiovascular disease, would contribute significantly to the remaining heritability. We analyzed 22 AD-associated single-nucleotide polymorphisms (SNPs), associated with these risk factors, that were included in the sequencing data of the Alzheimer's Disease Neuroimaging Initiative 1 data set, which included 355 participants with mild cognitive impairment (MCI). We built survival models with the selected SNPs to predict progression of MCI to probable AD over the 10-year follow-up of the study. The rs391300 SNP, located on the serine racemase (SRR) gene and linked to increased susceptibility to type 2 diabetes, was associated with progression from MCI to probable AD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This manuscript describes the study protocol, recruitment outcomes, and baseline participant characteristics for the Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) trial. SPACE is a pragmatic randomized comparative effectiveness trial conducted in multiple VA primary care clinics within one VA health care system. The objective was to compare benefits and harms of opioid therapy versus non-opioid medication therapy over 12months among patients with moderate-to-severe chronic back pain or hip/knee osteoarthritis pain despite analgesic therapy; patients already receiving regular opioid therapy were excluded. Key design features include comparing two clinically-relevant medication interventions, pragmatic eligibility criteria, and flexible treat-to-target interventions. Screening, recruitment and study enrollment were conducted over 31months. A total of 4491 patients were contacted for eligibility screening; 53.1% were ineligible, 41.0% refused, and 5.9% enrolled. The most common reasons for ineligibility were not meeting pain location and severity criteria. The most common study-specific reasons for refusal were preference for no opioid use and preference for no pain medications. Of 265 enrolled patients, 25 withdrew before randomization. Of 240 randomized patients, 87.9% were male, 84.1% were white, and age range was 21-80years. Past-year mental health diagnoses were 28.3% depression, 17% anxiety, 9.4% PTSD, 7.9% alcohol use disorder, and 2.6% drug use disorder. In conclusion, although recruitment for this trial was challenging, characteristics of enrolled participants suggest we were successful in recruiting patients similar to those prescribed opioid therapy in usual care., (Published by Elsevier Inc.)

Toll-like receptor (TLR) agonists TLR 7/8, MEDI9197, is a imidazoquinoline analogue that can be used for cancer immunotherapy based on its efficacy toward a variety of tumors. Systemic administration of TLR agonists results in stimulation of the immune system throughout the entire body causing undesirable side effects. To minimize these adverse events, local administration of TLR agonists including intratumoral (IT) delivery has been introduced. Here, a poloxamer 407 thermogel formulation for IT delivery of a TLR 7/8 dual agonist, MEDI9197, is described in which the combination of the aqueous thermogel and the ethanolic TLR 7/8 dual agonist, MEDI9197, solution leads to precipitated drug particles within the gel. The in vitro release profile showed an initial burst followed by sustained release. A B16-OVA mouse tumor model was used to assess the in vivo pharmacokinetics, efficacy, and systemic cytokine and chemokine (cytokine) production of the poloxamer 407-based thermogel formulation. The pharmacokinetic evaluation showed that the agonist level within the tumor was reduced by ∼70% over 14 days while serum agonist levels indicated an initial burst at the 6-h time point followed by a drop in serum drug levels over the 14 days of the experiment. The tumor growth inhibition, survival, and serum cytokines for post-IT injection of the poloxamer 407 formulation showed that it slowly released TLR 7/8 agonist, MEDI9197, resulting in more efficacious tumor growth inhibition compared with control groups. In addition, the cytokine levels in circulation indicated that a dose increase led to a decrease in the serum inflammatory and interferon-inducible cytokines levels. This observation could be due to a reduction of drug diffusion and escape from the tumor site due to the precipitation of the drug inside the tumor leading to sustained release. IT delivery of TLR 7/8 dual agonist, MEDI9197, via a thermosensitive gel-based formulation was efficacious and could offer an alternate method of local drug delivery., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Calibrated fMRI based on arterial spin-labeling (ASL) and blood oxygen-dependent contrast (BOLD), combined with periods of hypercapnia and hyperoxia, can provide information on cerebrovascular reactivity (CVR), resting blood flow (CBF), oxygen extraction fraction (OEF), and resting oxidative metabolism (CMRO 2 ). Vascular and metabolic integrity are believed to be affected in Alzheimer's disease (AD), thus, the use of calibrated fMRI in AD may help understand the disease and monitor therapeutic responses in future clinical trials. In the present work, we applied a calibrated fMRI approach referred to as Quantitative O2 (QUO2) in a cohort of probable AD dementia and age-matched control participants. The resulting CBF, OEF and CMRO 2 values fell within the range from previous studies using positron emission tomography (PET) with 15 O labeling. Moreover, the typical parietotemporal pattern of hypoperfusion and hypometabolism in AD was observed, especially in the precuneus, a particularly vulnerable region. We detected no deficit in frontal CBF, nor in whole grey matter CVR, which supports the hypothesis that the effects observed were associated specifically with AD rather than generalized vascular disease. Some key pitfalls affecting both ASL and BOLD methods were encountered, such as prolonged arterial transit times (particularly in the occipital lobe), the presence of susceptibility artifacts obscuring medial temporal regions, and the challenges associated with the hypercapnic manipulation in AD patients and elderly participants. The present results are encouraging and demonstrate the promise of calibrated fMRI measurements as potential biomarkers in AD. Although CMRO 2 can be imaged with 15 O PET, the QUO2 method uses more widely available imaging infrastructure, avoids exposure to ionizing radiation, and integrates with other MRI-based measures of brain structure and function.

The extent to which the age-related decline in regional brain glucose uptake also applies to other important brain fuels is presently unknown. Ketones are the brain's major alternative fuel to glucose, so we developed a dual tracer positron emission tomography protocol to quantify and compare regional cerebral metabolic rates for glucose and the ketone, acetoacetate. Twenty healthy young adults (mean age, 26 years) and 24 healthy older adults (mean age, 74 years) were studied. In comparison with younger adults, older adults had 8 ± 6% (mean ± SD) lower cerebral metabolic rates for glucose in gray matter as a whole (p = 0.035), specifically in several frontal, temporal, and subcortical regions, as well as in the cingulate and insula (p ≤ 0.01, false discovery rate correction). The effect of age on cerebral metabolic rates for acetoacetate in gray matter did not reach significance (p = 0.11). Rate constants (min(-1)) of glucose (Kg) and acetoacetate (Ka) were significantly lower (-11 ± 6%; [p = 0.005], and -19 ± 5%; [p = 0.006], respectively) in older adults compared with younger adults. There were differential effects of age on Kg and Ka as seen by significant interaction effects in the caudate (p = 0.030) and post-central gyrus (p = 0.023). The acetoacetate index, which expresses the scaled residuals of the voxel-wise linear regression of glucose on ketone uptake, identifies regions taking up higher or lower amounts of acetoacetate relative to glucose. The acetoacetate index was higher in the caudate of young adults when compared with older adults (p ≤ 0.05 false discovery rate correction). This study provides new information about glucose and ketone metabolism in the human brain and a comparison of the extent to which their regional use changes during normal aging., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The Timing of Alcohol and Smoking Cessation (TASC) Study tested the optimal timing of smoking cessation treatment in an alcohol-dependent population. Previously reported results suggest that providing concurrent smoking cessation treatment adversely affects alcohol outcomes. The purpose of this analysis was to investigate whether there are ethnic differences in alcohol and tobacco outcomes among a diverse sample of alcohol-dependent smokers using data from the TASC trial in which 499 participants were randomized to either concurrent (during alcohol treatment) or delayed (6 months later) smoking intervention. This analysis focused on smokers of Caucasian (n=381) and African American (n=78) ethnicity. Alcohol outcomes included 6 months sustained alcohol abstinence rates and time to first use of alcohol post-treatment. Tobacco outcomes included 7-day point prevalence smoking abstinence. Random effects logistic regression analysis was used to investigate intervention group and ethnic differences in the longitudinally assessed alcohol outcomes. Alcohol abstinence outcomes were consistently worse in the concurrent group than the delayed group among Caucasians, but this was not the case for African Americans. No significant ethnic differences were observed in smoking cessation outcomes. Findings from this analysis suggest that concurrent smoking cessation treatment adversely affects alcohol outcomes for Caucasians but not necessarily for African Americans.

Radiation damage incurred by nuclear DNA is well documented and interest is increasing in the properties of 'bystander' factor(s) and their ability to induce radiation-like damage in cells never exposed to radiation. 'Bystander' and direct low-LET radiation effects on the mitochondria, and more particularly the mitochondrial genome are less well understood. In this study HPV-G cells (a human keratinocyte cell line derived from human neonatal foreskin transfected with the HPV-16 virus) were exposed to either gamma-radiation doses as low as 5 mGy and up to 5 Gy from a 60Co teletherapy unit, or to growth medium taken from similarly irradiated cells, i.e. irradiated cell conditioned medium (ICCM). Mutation and deletion analysis was performed on mitochondrial DNA (mtDNA) 4-96 h after exposure. Primers flanking the so-called mitochondrial 'common deletion' were employed to assess its possible induction. Single-strand conformation polymorphism (SSCP) analysis was conducted to identify induced point mutations. The relative mitochondrial number per cell was analysed by semi-quantitative PCR (sqPCR). Results indicate the induction of a relatively novel deletion in the mitochondrial genome as early as 12 h after direct exposure to doses as low as 0.5 Gy and 24 h after exposure to 0.5-Gy ICCM. SSCP analysis identified the induction of point mutations, in a non-consistent manner, in only the D-loop region of the mitochondrial genome and only in cells exposed to 5 Gy, and neither in cells exposed to lower doses of direct radiation nor in those exposed to ICCM. SqPCR also identified an increase in the number of mitochondria per cell after both exposure to low level gamma-radiation and ICCM, indicative of a possible mechanism to respond to mitochondrial stress by increasing the number of mitochondria per cell.

This manuscript describes the development and validation of measures assessing patient knowledge about the risks and benefits of prostate cancer (CaP) screening. The measures described include a 10-item knowledge index and four single-item measures, used in previous studies, that assess knowledge of: CaP natural history and treatment efficacy, expert disagreement over the value of CaP screening, and the accuracy of the prostate specific antigen (PSA) test for CaP. We assessed the validity and reliability of these measures on a sample of 1152 male veteran patients age 50 and older. All knowledge index items had acceptable levels of discrimination, difficulty, and reliability. The index demonstrated strong evidence for construct and criterion validity. Much weaker validity evidence was found for the four single-item knowledge questions. The 10-item index developed in this study provides a valid and reliable tool for assessing patient knowledge of the risks and benefits of CaP screening.

Recent work suggests that normal aging may be associated with decline in different brain systems. In the present study, young and aged Long-Evans rats were tested in a spatial version of the Morris water maze dependent on medial temporal lobe function and also on an odor discrimination reversal task previously used to investigate orbitofrontal function. Aged rats acquired the odor discrimination problems normally but were impaired in acquiring subsequent reversals of the problems. A subset of the aged rats also exhibited impaired spatial learning in the water maze. There was no correlation between reversal performance and spatial learning in the aged rats, indicating that the reversal learning impairment was not related to decline in medial temporal lobe function. Instead the performance of the aged rats on the odor discrimination task resembled that of young rats with neurotoxic lesions of orbitofrontal cortex. These data indicate that rats show independent decline of different brain systems during normal aging and suggest orbitofrontal cortex as one prefrontal area where changes may be localized for further study.

The establishment of anterior-posterior polarity in the Caenorhabditis elegans embryo requires the activity of the maternally expressed par genes. We report the identification and analysis of a new par gene, par-5. We show that par-5 is required for asynchrony and asymmetry in the first embryonic cell divisions, normal pseudocleavage, normal cleavage spindle orientation at the two-cell stage, and localization of P granules and MEX-5 during the first and subsequent cell cycles. Furthermore, par-5 activity is required in the first cell cycle for the asymmetric cortical localization of PAR-1 and PAR-2 to the posterior, and PAR-3, PAR-6, and PKC-3 to the anterior. When PAR-5 is reduced by mutation or by RNA interference, these proteins spread around the cortex of the one-cell embryo and partially overlap. We have shown by sequence analysis of par-5 mutants and by RNA interference that the par-5 gene is the same as the ftt-1 gene, and encodes a 14-3-3 protein. The PAR-5 14-3-3 protein is present in gonads, oocytes, and early embryos, but is not asymmetrically distributed. Our analysis indicates that the par-5 14-3-3 gene plays a crucial role in the early events leading to polarization of the C. elegans zygote.