Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine.

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.

Leptin Does Not Mediate Hypertension Associated With Human Obesity.

Hypertension and obesity are known to be linked, with recent studies in mice proposing that leptin may be mediating this effect. This regulation, however, may not extend to humans, where a yet-to-be-identified factor is likely the underlying cause of hypertension.

The RNA export and RNA decay complexes THO and TRAMP prevent transcription-replication conflicts, DNA breaks, and CAG repeat contractions.

Expansion of structure-forming CAG/CTG repetitive sequences is the cause of several neurodegenerative disorders and deletion of repeats is a potential therapeutic strategy. Transcription-associated mechanisms are known to cause CAG repeat instability. In this study, we discovered that Thp2, an RNA export factor and member of the THO (suppressors of transcriptional defects of hpr1Δ by overexpression) complex, and Trf4, a key component of the TRAMP (Trf4/5-Air1/2-Mtr4 polyadenylation) complex involved in nuclear RNA polyadenylation and degradation, are necessary to prevent CAG fragility and repeat contractions in a Saccharomyces cerevisiae model system. Depletion of both Thp2 and Trf4 proteins causes a highly synergistic increase in CAG repeat fragility, indicating a complementary role of the THO and TRAMP complexes in preventing genome instability. Loss of either Thp2 or Trf4 causes an increase in RNA polymerase stalling at the CAG repeats and other genomic loci, as well as genome-wide transcription-replication conflicts (TRCs), implicating TRCs as a cause of CAG fragility and instability in their absence. Analysis of the effect of RNase H1 overexpression on CAG fragility, RNAPII stalling, and TRCs suggests that RNAPII stalling with associated R-loops are the main cause of CAG fragility in the thp2Δ mutants. In contrast, CAG fragility and TRCs in the trf4Δ mutant can be compensated for by RPA overexpression, suggesting that excess unprocessed RNA in TRAMP4 mutants leads to reduced RPA availability and high levels of TRCs. Our results show the importance of RNA surveillance pathways in preventing RNAPII stalling, TRCs, and DNA breaks, and show that RNA export and RNA decay factors work collaboratively to maintain genome stability.

Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo.

While studying transgene expression after systemic administration of lentiviral vectors, we found that splenic B cells are robustly transduced, regardless of the types of pseudotyped envelope proteins. However, the administration of two different pseudotypes resulted in transduction of two distinct B cell populations, suggesting that each pseudotype uses unique and specific receptors for its attachment and entry into splenic B cells. Single-cell RNA sequencing analysis of the transduced cells demonstrated that different pseudotypes transduce distinct B cell subpopulations characterized by specific B cell receptor (BCR) genotypes. Functional analysis of the BCRs of the transduced cells demonstrated that BCRs specific to the pseudotyping envelope proteins mediate viral entry, enabling the vectors to selectively transduce the B cell populations that are capable of producing antibodies specific to their envelope proteins. Lentiviral vector entry via the BCR activated the transduced B cells and induced proliferation and differentiation into mature effectors, such as memory B and plasma cells. BCR-mediated viral entry into clonally specific B cell subpopulations raises new concepts for understanding the biodistribution of transgene expression after systemic administration of lentiviral vectors and offers new opportunities for BCR-targeted gene delivery by pseudotyped lentiviral vectors.

Subgenomic RNA identification in SARS-CoV-2 genomic sequencing data.

We have developed periscope, a tool for the detection and quantification of subgenomic RNA (sgRNA) in SARS-CoV-2 genomic sequence data. The translation of the SARS-CoV-2 RNA genome for most open reading frames (ORFs) occurs via RNA intermediates termed "subgenomic RNAs." sgRNAs are produced through discontinuous transcription, which relies on homology between transcription regulatory sequences (TRS-B) upstream of the ORF start codons and that of the TRS-L, which is located in the 5' UTR. TRS-L is immediately preceded by a leader sequence. This leader sequence is therefore found at the 5' end of all sgRNA. We applied periscope to 1155 SARS-CoV-2 genomes from Sheffield, United Kingdom, and validated our findings using orthogonal data sets and in vitro cell systems. By using a simple local alignment to detect reads that contain the leader sequence, we were able to identify and quantify reads arising from canonical and noncanonical sgRNA. We were able to detect all canonical sgRNAs at the expected abundances, with the exception of ORF10. A number of recurrent noncanonical sgRNAs are detected. We show that the results are reproducible using technical replicates and determine the optimum number of reads for sgRNA analysis. In VeroE6 ACE2+/- cell lines, periscope can detect the changes in the kinetics of sgRNA in orthogonal sequencing data sets. Finally, variants found in genomic RNA are transmitted to sgRNAs with high fidelity in most cases. This tool can be applied to all sequenced COVID-19 samples worldwide to provide comprehensive analysis of SARS-CoV-2 sgRNA.

Reimagining How We Synthesize Information to Impact Clinical Care, Policy, and Research Priorities in Real Time: Examples and Lessons Learned from COVID-19.

Real-time clinical care, policy, and research decisions need real-time evidence synthesis. However, as we found during the COVID-19 pandemic, it is challenging to rapidly address key clinical and policy questions through rigorous, relevant, and usable evidence. Our objective is to present three exemplar cases of rapid evidence synthesis products from the Veterans Healthcare Administration Evidence Synthesis Program (ESP) and, in the context of these examples, outline ESP products, challenges, and lessons learned. We faced challenges in (1) balancing scientific rigor with the speed in which evidence synthesis was needed, (2) sorting through rapidly evolving large bodies of evidence, and (3) assessing the impact of evidence synthesis products on clinical care, policy, and research. We found solutions in (1) engaging stakeholders early, (2) utilizing artificial intelligence capabilities, (3) building infrastructure to establish living reviews, and (4) planning for dissemination to maximize impact.

Caring for Patients with Functional Impairment in Middle Age: Perspectives from Primary Care Providers and Geriatricians.

BACKGROUND: The prevalence of functional impairment is increasing among middle-aged adults and is associated with adverse health outcomes. Primary care providers (PCPs) and geriatricians may have important insights about optimal approaches to caring for these patients, but little is known about their perspectives. OBJECTIVE: To examine PCPs' and geriatricians' perspectives on clinical needs and optimal approaches to care for middle-aged patients with functional impairment. DESIGN: Qualitative study using semi-structured interviews. PARTICIPANTS: PCPs and geriatricians from outpatient practices in the San Francisco Bay area. APPROACH: Interviews focused on characteristics and care needs of middle-aged patients with functional impairment and models of care to address these needs. We analyzed interviews using hybrid deductive-inductive qualitative thematic analysis. KEY RESULTS: Clinicians (14 PCPs, 15 geriatricians) described distinct characteristics of functional impairment in middle-aged versus older adults, such as different rates of onset, but similar clinical needs. Despite these similar needs, clinicians identified age-specific barriers to delivering optimal care to middle-aged patients. These included system-level challenges such as limited access to insurance and social services; practice- and clinician-level barriers including inadequate clinician training; and patient-level factors including less access to family caregivers and perceptions of stigma. To overcome these challenges, clinicians suggested clinical approaches including addressing health-related social needs within healthcare systems; implementing practice-based models that are multi-disciplinary, team-based, and coordinated; training clinicians to effectively manage functional impairment; and expanding community-based services and supports to help patients navigate the medical system. Identified needs, challenges, and solutions were generally similar across geriatricians and PCPs. CONCLUSIONS: Clinicians face challenges in delivering optimal care to middle-aged patients who have functional impairments similar to their older counterparts but lack access to services and supports available to older people. These findings suggest the importance of increasing access to care models that address functional impairment regardless of age.

Metabolic and other morbid complications in congenital generalized lipodystrophy type 4.

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

Differential Electronic Survey Response: Does Survey Fatigue Affect Everyone Equally?

INTRODUCTION: Survey fatigue, a phenomenon where respondents lose interest or lack motivation to complete surveys, can undermine rigorously designed studies. Research during the COVID-19 pandemic capitalized on electronic surveys for maximum distribution, but with lower response rates. Additionally, it is unclear how survey fatigue affects surgical education stakeholders. This study aims to determine how response rates to an electronic survey, as a proxy for survey fatigue, differ among medical students (MS), surgery residents, and surgery faculty. METHODS: Electronic surveys evaluating the surgical clerkship educational environment were distributed to third year MS, residents, and faculty at three academic institutions. Two reminder emails were sent. Groups with low response rates (<30%) received additional prompting. Response rates were compared using a chi-square test. Demographics of all survey respondents were collected and discussed. Baseline characteristics of the MS class, residency program, and Department of Surgery faculty from one institution were gathered and compared to respondents. RESULTS: Surveys were sent to 283 third year MS, 190 surgery residents, and 374 surgical faculty. Response rates were 43%, 27%, and 20%, respectively (P < 0.0001). Male respondents, respondents of color, midlevel residents, and assistant professors had lower response rates compared to the baseline cohort. CONCLUSIONS: Our results demonstrate a statistically significant difference in survey response rates among MS, residents, and faculty, and have identified various targets for further investigation. Loss of interest in these groups should be further evaluated with a goal of decreasing survey fatigue, increasing survey response rates, and improving the quality of survey data collected.

The ethics of natural immunity exemptions to vaccine mandates: the Supreme Court petition.

The Supreme Court of the United States has recently been petitioned to revisit legal issues pertaining to the lawfulness of imposing a vaccine mandate on individuals with proof of natural immunity during the COVID-19 pandemic. While the petition accepts that the protection of public health during COVID-19 was an important governmental interest, the petitioners maintain that the imposition of a vaccine mandate on individuals with natural immunity was not 'substantially related' to accomplishing that purpose. In this short report, we outline how some of the petition's general arguments interact with points we raised in a 2022 article in this journal defending natural immunity exemptions, in light of new evidence. In particular, we reflect on new evidence pertaining to differences between vaccine-induced immunity, natural immunity, and so-called 'hybrid' immunity. We suggest that the nuanced nature of this evidence highlights the importance of making fine-grained judgements about proportionality and necessity when considering vaccine mandates. We conclude by claiming that if future pandemics necessitate the imposition of vaccine mandates, then those seeking to justify them should clearly articulate the relevance (and the evidence) for the comparative protection of vaccine-induced, natural, and hybrid immunity.

Resource and animal use implications of the proposed REACH information requirements for endocrine disruptor assessment.

Revised information requirements for endocrine disruptor (ED) assessment of chemicals under the European Union's Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Regulation have been proposed. Implementation will substantially increase demands for new data to inform ED assessment. This article evaluates the potential animal use and financial resource associated with two proposed ED policy options, and highlights areas where further clarification is warranted. This evaluation demonstrates that studies potentially conducted to meet the proposed requirements could use tens of millions of animals, and that the approach is unlikely to be feasible in practice. Given the challenges with implementing either policy option and the need to minimise the reliance on animal testing, further consideration and clarification is needed on several aspects prior to implementation of the requirements. This includes how testing will be prioritised in a proportionate approach; how to harness new approach methodologies to waive higher-tier animal testing; and need for provision of clear guidance particularly in applying weight-of-evidence approaches. There is now a clear opportunity for the European Commission to lead the way in developing a robust and transparent ED assessment process for industrial chemicals which fully implements replacement, refinement, and reduction of the use of animals (the 3Rs).

"I'll fill in the gaps": perspectives of HHAs on promoting aging in place for older adults with low incomes.

Older adults with low incomes experience disproportionate rates of cognitive and functional impairment and an elevated risk of nursing home admission. Home health aides (HHAs) may have insight into how to optimize aging in place for this population, yet little is known about HHAs' perspectives on this topic. We conducted 6 focus groups with 21 English-speaking and 10 Spanish-speaking HHAs in Pennsylvania and New Jersey. Transcripts were analyzed using qualitative thematic analysis, and three themes emerged. First, HHAs described the uniqueness of their role within multidisciplinary care teams. Second, HHAs shared concrete interventions they employ to help their clients improve their function at home. Third, HHAs discussed barriers they face when helping clients age in place. Our findings suggest that HHAs have important insights into improving aging in place for older adults with low incomes and that their perspectives should be incorporated into care planning and intervention delivery.

Immunological design of commensal communities to treat intestinal infection and inflammation.

The immunological impact of individual commensal species within the microbiota is poorly understood limiting the use of commensals to treat disease. Here, we systematically profile the immunological fingerprint of commensals from the major phyla in the human intestine (Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria) to reveal taxonomic patterns in immune activation and use this information to rationally design commensal communities to enhance antibacterial defenses and combat intestinal inflammation. We reveal that Bacteroidetes and Firmicutes have distinct effects on intestinal immunity by differentially inducing primary and secondary response genes. Within these phyla, the immunostimulatory capacity of commensals from the Bacteroidia class (Bacteroidetes phyla) reflects their robustness of TLR4 activation and Bacteroidia communities rely solely on this receptor for their effects on intestinal immunity. By contrast, within the Clostridia class (Firmicutes phyla) it reflects the degree of TLR2 and TLR4 activation, and communities of Clostridia signal via both of these receptors to exert their effects on intestinal immunity. By analyzing the receptors, intracellular signaling components and transcription factors that are engaged by different commensal species, we identify canonical NF-κB signaling as a critical rheostat which grades the degree of immune stimulation commensals elicit. Guided by this immunological analysis, we constructed a cross-phylum consortium of commensals (Bacteroides uniformis, Bacteroides ovatus, Peptostreptococcus anaerobius and Clostridium histolyticum) which enhances innate TLR, IL6 and macrophages-dependent defenses against intestinal colonization by vancomycin resistant Enterococci, and fortifies mucosal barrier function during pathological intestinal inflammation through the same pathway. Critically, the setpoint of intestinal immunity established by this consortium is calibrated by canonical NF-κB signaling. Thus, by profiling the immunological impact of major human commensal species our work paves the way for rational microbiota reengineering to protect against antibiotic resistant infections and to treat intestinal inflammation.

Identification of subfunctionalized aggregate-remodeling J-domain proteins in Arabidopsis thaliana.

J-domain proteins (JDPs) are critical components of the cellular protein quality control machinery, playing crucial roles in preventing the formation and, solubilization of cytotoxic protein aggregates. Bacteria, yeast, and plants additionally have large, multimeric heat shock protein 100 (Hsp100)-class disaggregases that resolubilize protein aggregates. JDPs interact with aggregated proteins and specify the aggregate-remodeling activities of Hsp70s and Hsp100s. However, the aggregate-remodeling properties of plant JDPs are not well understood. Here we identify eight orthologs of Sis1 (an evolutionarily conserved Class II JDP of budding yeast) in Arabidopsis thaliana with distinct aggregate-remodeling functionalities. Six of these JDPs associate with heat-induced protein aggregates in vivo and co-localize with Hsp101 at heat-induced protein aggregate centers. Consistent with a role in solubilizing cytotoxic protein aggregates, an atDjB3 mutant had defects in both solubilizing heat-induced aggregates and acquired thermotolerance as compared with wild-type seedlings. Next, we used yeast prions as protein aggregate models to show that the six JDPs have distinct aggregate-remodeling properties. Results presented in this study, as well as findings from phylogenetic analysis, demonstrate that plants harbor multiple, evolutionarily conserved JDPs with capacity to process a variety of protein aggregate conformers induced by heat and other stressors.

When Functional Impairment Develops Early: Perspectives from Middle-Aged Adults.

BACKGROUND: Difficulty performing basic daily activities such as bathing and dressing ("functional impairment") affects more than 15% of middle-aged people, and this proportion is increasing. Little is known about the experiences and needs of individuals who develop functional impairment in middle age. OBJECTIVE: To examine the experiences and needs of adults who developed functional impairment in middle age. DESIGN: Qualitative study using semi-structured interviews. PARTICIPANTS: Forty patients aged 50-64 years who developed functional impairment in middle age, recruited from four primary care clinics in San Francisco. APPROACH: Interviews included open-ended questions about participants' daily life, ability to perform activities of daily living (ADLs), and needs related to functional impairment. We analyzed interviews using qualitative thematic analysis. KEY RESULTS: Interviews revealed several themes related to the psychosocial and physical impacts of developing functional impairment in middle age. Participants noted that losses associated with functional impairment, such as loss of independence, control, and social roles, caused conflict in their sense of identity. To cope with these losses, participants used strategies including acceptance, social comparison, adjusting standards, and engaging in valued life activities. Participants reflected on the intersection of their functional impairment with the aging process, noting that their impairments seemed premature compared to the more "natural" aging process in older adults. In terms of physical impacts, participants described how a lack of accommodations in the built environment exacerbated their impairments. While participants used behavioral strategies to overcome these challenges, unmet needs remained, resulting in downstream physical and psychological impacts including safety risks, falls, frustration, and fear. CONCLUSIONS: Unmet psychosocial and physical needs were common among middle-aged adults with functional impairment and led to negative downstream effects. Eliciting and addressing unmet needs may help mitigate downstream health consequences for this growing population, optimizing function and quality of life.

Defining Multimorbidity in Older Patients Hospitalized with Medical Conditions.

BACKGROUND: The term "multimorbidity" identifies high-risk, complex patients and is conventionally defined as ≥2 comorbidities. However, this labels almost all older patients as multimorbid, making this definition less useful for physicians, hospitals, and policymakers. OBJECTIVE: Develop new medical condition-specific multimorbidity definitions for patients admitted with acute myocardial infarction (AMI), heart failure (HF), and pneumonia patients. We developed three medical condition-specific multimorbidity definitions as the presence of single, double, or triple combinations of comorbidities - called Qualifying Comorbidity Sets (QCSs) - associated with at least doubling the risk of 30-day mortality for AMI and pneumonia, or one-and-a-half times for HF patients, compared to typical patients with these conditions. DESIGN: Cohort-based matching study PARTICIPANTS: One hundred percent Medicare Fee-for-Service beneficiaries with inpatient admissions between 2016 and 2019 for AMI, HF, and pneumonia. MAIN MEASURES: Thirty-day all-location mortality KEY RESULTS: We defined multimorbidity as the presence of ≥1 QCS. The new definitions labeled fewer patients as multimorbid with a much higher risk of death compared to the conventional definition (≥2 comorbidities). The proportions of patients labeled as multimorbid using the new definition versus the conventional definition were: for AMI 47% versus 87% (p value<0.0001), HF 53% versus 98% (p value<0.0001), and pneumonia 57% versus 91% (p value<0.0001). Thirty-day mortality was higher among patients with ≥1 QCS compared to ≥2 comorbidities: for AMI 15.0% versus 9.5% (p<0.0001), HF 9.9% versus 7.0% (p <0.0001), and pneumonia 18.4% versus 13.2% (p <0.0001). CONCLUSION: The presence of ≥2 comorbidities identified almost all patients as multimorbid. In contrast, our new QCS-based definitions selected more specific combinations of comorbidities associated with substantial excess risk in older patients admitted for AMI, HF, and pneumonia. Thus, our new definitions offer a better approach to identifying multimorbid patients, allowing physicians, hospitals, and policymakers to more effectively use such information to consider focused interventions for these vulnerable patients.

Mortality Among Older Medical Patients at Flagship Hospitals and Their Affiliates.

BACKGROUND: We define a "flagship hospital" as the largest academic hospital within a hospital referral region and a "flagship system" as a system that contains a flagship hospital and its affiliates. It is not known if patients admitted to an affiliate hospital, and not to its main flagship hospital, have better outcomes than those admitted to a hospital outside the flagship system but within the same hospital referral region. OBJECTIVE: To compare mortality at flagship hospitals and their affiliates to matched control patients not in the flagship system but within the same hospital referral region. DESIGN: A matched cohort study PARTICIPANTS: The study used hospitalizations for common medical conditions between 2018-2019 among older patients age ≥ 66 years. We analyzed 118,321 matched pairs of Medicare patients admitted with pneumonia (N=57,775), heart failure (N=42,531), or acute myocardial infarction (N=18,015) in 35 flagship hospitals, 124 affiliates, and 793 control hospitals. MAIN MEASURES: 30-day (primary) and 90-day (secondary) all-cause mortality. KEY RESULTS: 30-day mortality was lower among patients in flagship systems versus control hospitals that are not part of the flagship system but within the same hospital referral region (difference= -0.62%, 95% CI [-0.88%, -0.37%], P<0.001). This difference was smaller in affiliates versus controls (-0.43%, [-0.75%, -0.11%], P=0.008) than in flagship hospitals versus controls (-1.02%, [-1.46%, -0.58%], P<0.001; difference-in-difference -0.59%, [-1.13%, -0.05%], P=0.033). Similar results were found for 90-day mortality. LIMITATIONS: The study used claims-based data. CONCLUSIONS: In aggregate, within a hospital referral region, patients treated at the flagship hospital, at affiliates of the flagship hospital, and in the flagship system as a whole, all had lower mortality rates than matched controls outside the flagship system. However, the mortality advantage was larger for flagship hospitals than for their affiliates.

Detection of anti-androgenic activity of chemicals in fish studies: a data review.

A systematic review was conducted on the sensitivity of fish testing guidelines to detect the anti-androgenic activity of substances. Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) was used to investigate the conservation of the androgen receptor (AR) between humans and fish, and among fish species recommended in test guidelines. The AR is conserved between fish species and humans (i.e. ligand binding domain [LBD] homology ≥70%) and among the recommended fish species (LBD homology >85%). For model anti-androgens, we evaluated literature data on in vitro anti-androgenic activity in fish-specific receptor-based assays and changes in endpoints indicative of endocrine modulation from in vivo studies. Anti-androgenic activity was most consistently and reliably detected in in vitro and in vivo mechanistic studies with co-exposure to an androgen (spiggin in vitro assay, Rapid Androgen Disruption Activity Reporter [RADAR] Assay, and Androgenised Female Stickleback Screen). Regardless of study design (Fish Short-Term Reproduction Assay [FSTRA], Fish Sexual Development Test [FSDT], partial or full life-cycle tests), or endpoint (vitellogenin, secondary sexual characteristics, gonadal histopathology, sex ratio), there was no consistent evidence for detecting anti-androgenic activity in studies without androgen co-exposure, even for the most potent substances (while less potent substances may induce no (clear) response). Therefore, based on studies without androgen co-exposure (35 FSTRAs and 22 other studies), the other studies (including the FSDT) do not outperform the FSTRA for detecting potent anti-androgenic activity, which if suspected, would be best addressed with a RADAR assay. Overall, fish do not appear particularly sensitive to mammalian anti-androgens.

Divergent pathways of liver fat accumulation, oxidation, and secretion in lipodystrophy versus obesity-associated NAFLD.

BACKGROUND AND AIMS: Fatty liver is common in obesity as well as in partial lipodystrophy (PL) syndromes, characterized by deficient adipose tissue. Insulin resistance is key to fatty liver pathogenesis in both entities. We aimed to compare the contributions of insulin resistance and adipose tissue to hepatic steatosis in PL and non-syndromic, obesity-associated non-alcoholic fatty liver disease (NS-NAFLD). METHODS: In a cross-sectional comparison of people with NS-NAFLD (N = 73) and PL (N = 27), liver fat was measured by FibroScan® controlled attenuation parameter (CAP) and insulin resistance by HOMA-IR, Adipo-IR, and NMR-based LP-IR. RESULTS: Insulin resistance was greater in PL versus NS-NAFLD by HOMA-IR (p = 0.005), Adipo-IR (p = 0.01) and LP-IR (p = 0.05) while liver fat was comparable (304 vs. 324 dB/m, p = 0.12). Liver fat correlated with HOMA-IR in both groups, but CAP values were lower by 32 dB/m in PL compared with NS-NAFLD for any given HOMA-IR. In contrast, Adipo-IR and LP-IR correlated with CAP only in the NS-NAFLD group, suggesting different pathways for fat accumulation. Plasma free fatty acids, reflecting substrate input from the adipose tissue, were comparable between groups. However, the levels of ß-hydroxybutyrate, a marker of ß-oxidation, and large triglyceride-rich lipoprotein particles, a marker of VLDL secretion, were both higher in PL (p < 0.001 for both). CONCLUSION: Liver fat content was comparable in subjects with PL-associated NAFLD and NS-NAFLD, despite worse insulin resistance in partial lipodystrophy. Our data demonstrate higher triglyceride oxidation and export in PL, suggesting a compensatory shift of fat from liver storage into the circulation that does not occur in NS-NAFLD.

Management of Central and Peripheral Nervous System Tumors in Patients with Neurofibromatosis.

Neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis represent a diverse group of genetic tumor predisposition syndromes with a shared feature of tumors affecting the peripheral nerve sheaths. PURPOSE OF REVIEW: Many advancements have been made in understanding the biologic underpinnings of these conditions, and in 2016 the first drug was approved by the FDA to treat pediatric symptomatic unresectable plexiform neurofibromas. RECENT FINDINGS: Mek inhibitors have provided a much-needed therapeutic avenue for NF1 patients with unresectable plexiform neurofibromas (PN), both for reduction of tumor bulk and for improvement in symptoms. Selumetinib is the first FDA approved drug for PN, but is only approved for children. Some research suggests that alternative Mek inhibitors and other mixed tyrosine kinase inhibitors may have better efficacy in adults. Vascular endothelial growth factor (VEGF) inhibitor bevacizumab can prolong hearing and delay the need for surgery in NF2 patients with bilateral vestibular schwannomas. This article provides an update regarding considerations and approaches when treating the tumors associated with the neurofibromatoses (NF), including risk and prognosis metrics, clinical trial results, surgical techniques, and radiation therapy recommendations.