Evolving Approaches for Pharmacological Therapy of Obesity.

Obesity is a global health concern. Progress in understanding the physiology of obesity and weight reduction has provided new drug targets. Development and testing of new antiobesity medications (AOMs) has the potential to quickly expand options for treatment. In this review, we briefly summarize the physiology of obesity and weight reduction, as well as medications currently approved for weight management. We highlight the increasing use of incretin and nutrient-stimulated hormone-based therapies. We conclude with an overview of AOMs progressing through the pipeline and discuss their implications for the rapidly evolving field of obesity management.

Coupled social and ecological change drove the historical extinction of the California grizzly bear (Ursus arctos californicus).

Large carnivores (order Carnivora) are among the world's most threatened mammals due to a confluence of ecological and social forces that have unfolded over centuries. Combining specimens from natural history collections with documents from archival records, we reconstructed the factors surrounding the extinction of the California grizzly bear (Ursus arctos californicus), a once-abundant brown bear subspecies last seen in 1924. Historical documents portrayed California grizzlies as massive hypercarnivores that endangered public safety. Yet, morphological measurements on skulls and teeth generate smaller body size estimates in alignment with extant North American grizzly populations (approx. 200 kg). Stable isotope analysis (δ13C, δ15N) of pelts and bones (n = 57) revealed that grizzlies derived less than 10% of their nutrition from terrestrial animal sources and were therefore largely herbivorous for millennia prior to the first European arrival in this region in 1542. Later colonial land uses, beginning in 1769 with the Mission era, led grizzlies to moderately increase animal protein consumption (up to 26% of diet), but grizzlies still consumed far less livestock than otherwise claimed by contemporary accounts. We show how human activities can provoke short-term behavioural shifts, such as heightened levels of carnivory, that in turn can lead to exaggerated predation narratives and incentivize persecution, triggering rapid loss of an otherwise widespread and ecologically flexible animal.

The past, present, and future of behavioral obesity treatment.

Over the last century, hundreds of evaluations have been conducted to examine weight-management interventions related to diet, physical activity, and behavior therapy. These investigations have contributed to a growing body of knowledge that has consistently advanced the field of obesity treatment, while also revealing some persistent challenges. This narrative review summarizes key findings from randomized controlled trials conducted in adults that have combined diet, physical activity, and behavior therapy, an approach variously referred to as behavioral treatment, comprehensive lifestyle modification, or intensive lifestyle intervention. The review shows that current behavioral approaches induce average reductions in baseline body weight of 5 to 10% at 6 to 12 months. Such losses have proven effective in reducing the risk of type 2 diabetes in persons with impaired glucose tolerance and in improving other obesity-related complications. These benefits have also been associated with reductions in healthcare costs. Despite these advances, behavioral treatment is challenged by the need for larger losses to achieve optimal improvements in health, by difficulties associated with maintaining weight loss, and by barriers limiting access to treatment. New anti-obesity medications, when combined with behavioral obesity treatment, hold promise of addressing the first two issues.

Carnitine Palmitoyl Transferase Deficiency in a University Immunology Practice.

PURPOSE: This report describes the clinical manifestations of 35 patients sent to a University Immunology clinic with a diagnosis of fatigue and exercise intolerance who were identified to have low carnitine palmitoyl transferase activity on muscle biopsies. RECENT FINDINGS: All of the patients presented with fatigue and exercise intolerance and many had been diagnosed with fibromyalgia. Their symptoms responded to treatment of the metabolic disease. Associated symptoms included bloating, diarrhea, constipation, gastrointestinal reflux symptoms, recurrent infections, arthritis, dyspnea, dry eye, visual loss, and hearing loss. Associated medical conditions included Hashimoto thyroiditis, Sjogren's syndrome, seronegative arthritis, food hypersensitivities, asthma, sleep apnea, and vasculitis. This study identifies clinical features that should alert physicians to the possibility of an underlying metabolic disease. Treatment of the metabolic disease leads to symptomatic improvement.

Pursuing equity in cancer care: implementation, challenges and preliminary findings of a public cancer referral center in rural Rwanda.

BACKGROUND: Cancer services are inaccessible in many low-income countries, and few published examples describe oncology programs within the public sector. In 2011, the Rwanda Ministry of Health (RMOH) established Butaro Cancer Center of Excellence (BCCOE) to expand cancer services nationally. In hopes of informing cancer care delivery in similar settings, we describe program-level experience implementing BCCOE, patient characteristics, and challenges encountered. METHODS: Butaro Cancer Center of Excellence was founded on diverse partnerships that emphasize capacity building. Services available include pathology-based diagnosis, basic imaging, chemotherapy, surgery, referral for radiotherapy, palliative care and socioeconomic access supports. Retrospective review of electronic medical records (EMR) of patients enrolled between July 1, 2012 and June 30, 2014 was conducted, supplemented by manual review of paper charts and programmatic records. RESULTS: In the program's first 2 years, 2326 patients presented for cancer-related care. Of these, 70.5% were female, 4.3% children, and 74.3% on public health insurance. In the first year, 66.3% (n = 1144) were diagnosed with cancer. Leading adult diagnoses were breast, cervical, and skin cancer. Among children, nephroblastoma, acute lymphoblastic leukemia, and Hodgkin lymphoma were predominant. As of June 30, 2013, 95 cancer patients had died. Challenges encountered include documentation gaps and staff shortages. CONCLUSION: Butaro Cancer Center of Excellence demonstrates that complex cancer care can be delivered in the most resource-constrained settings, accessible to vulnerable patients. Key attributes that have made BCCOE possible are: meaningful North-south partnerships, innovative task- and infrastructure-shifting, RMOH leadership, and an equity-driven agenda. Going forward, we will apply our experiences and lessons learned to further strengthen BCCOE, and employ the developed EMR system as a valuable platform to assess long-term clinical outcomes and improve care.

Photobiomodulation delays the onset of skeletal muscle fatigue in a dose-dependent manner.

Photobiomodulation (PBM) therapy has been implicated as an effective ergogenic aid to delay the onset of muscle fatigue. The purpose of this study was to examine the dose-response ergogenic properties of PBM therapy and its ability to prolong time to task failure by enhancing muscle activity and delaying the onset of muscle fatigue using a static positioning task. Nine participants (24.3 ± 4.9 years) received three doses of near-infrared (NIR) light therapy randomly on three separate sessions (sham, 240, and 480 J). For the positioning task, participants held a 30 % one-repetition maximum (1-RM) load using the index finger until volitional fatigue. Surface electromyography (sEMG) of the first dorsal interosseous muscle was recorded for the length of the positioning task. Outcomes included time to task failure (TTF), muscle fatigue, movement accuracy, motor output variability, and muscle activity (sEMG). The 240-J dose significantly extended TTF by 26 % (p = 0.032) compared with the sham dose. TTF for the 240-J dose was strongly associated with a decrease in muscle fatigue (R (2) = 0.54, p = 0.024). Our findings show that a 240-J dose of NIR light therapy is efficacious in delaying the onset and extent of muscle fatigue during submaximal isometric positioning tasks. Our findings suggest that NIR light therapy may be used as an ergogenic aid during functional tasks or post-injury rehabilitation.

Barriers to physical activity and healthy diet among children ages 6 through 13 in a Mississippi elementary school.

The purpose of this study was to identify barriers to adequate physical activity and a healthy diet, investigate differences in the perceived barriers among subgroups, and determine predictors of high versus low total barrier scores in one inner-city elementary school. A mixed method design was used and included students ages 6 through 13 (n=110) and parents, teachers, and community leaders (n=20). Data were collected using questionnaires and focus groups. Quantitative findings revealed no differences in total barriers based on age, gender, number of parents, or household income; however, subscale differences among groups were noted. Qualitative findings indicated that perceived barriers to physical activity were knowledge-related, and barriers to healthy diet concerned access to healthy foods.

Insomnia, Short Sleep, and Their Treatments: Review of Their Associations with Weight.

PURPOSE OF REVIEW: Insomnia and short sleep have been linked with weight gain and obesity. However, these findings have not been consistent across studies. We review recent evidence for the association between insomnia, short sleep, and weight gain, as well as the relationship between behavioral and pharmacological treatments for sleep and weight. RECENT FINDINGS: The relationship between insomnia and obesity is mixed, with stronger associations between insomnia with short sleep and obesity than other presentations of insomnia. Short sleep is associated with weight gain. Z-drugs and benzodiazapines do not appear to impact weight, but many antidepressants and antipsychotics that are used for insomnia treatment do cause weight gain. The relationships between insomnia and short sleep with weight gain and obesity are inconsistent. More prospective trials are needed to identify mediators and moderators of this relationship to better develop and deliver effective interventions for both sleep and weight problems.

Cognitive distortions as a mediator of the relationship between dispositional mindfulness and psychological distress among college students.

OBJECTIVE: This study examined the mediating role of cognitive distortions (CDs) in the relationship between dispositional mindfulness (DM) and psychological distress, and considered gender as a potential moderator of these mediation models. PARTICIPANTS: Four hundred and forty-six college students (63.9% female; M = 20.52 years; 87.4% undergraduate, 12.6% graduate level) participated. METHODS: Self-report measures of DM, CDs, anxiety, depression, and perceived stress were completed with data collected from April to October of 2020. RESULTS: Females scored significantly higher than males on anxiety, depression, perceived stress, and CDs. CDs partially mediated the relationship between DM and all psychological distress variables. Gender moderated the mediation model predicting anxiety, with the indirect effect of DM on anxiety via CDs being stronger for females than males. CONCLUSION: Results support CDs as a possible mechanism underlying the association between DM and psychological distress with implications for targeting cognitive patterns in mindfulness-based interventions with college students.

Animal migration in the Anthropocene: threats and mitigation options.

Animal migration has fascinated scientists and the public alike for centuries, yet migratory animals are facing diverse threats that could lead to their demise. The Anthropocene is characterised by the reality that humans are the dominant force on Earth, having manifold negative effects on biodiversity and ecosystem function. Considerable research focus has been given to assessing anthropogenic impacts on the numerical abundance of species/populations, whereas relatively less attention has been devoted to animal migration. However, there are clear linkages, for example, where human-driven impacts on migration behaviour can lead to population/species declines or even extinction. Here, we explore anthropogenic threats to migratory animals (in all domains - aquatic, terrestrial, and aerial) using International Union for the Conservation of Nature (IUCN) Threat Taxonomy classifications. We reveal the diverse threats (e.g. human development, disease, invasive species, climate change, exploitation, pollution) that impact migratory wildlife in varied ways spanning taxa, life stages and type of impact (e.g. from direct mortality to changes in behaviour, health, and physiology). Notably, these threats often interact in complex and unpredictable ways to the detriment of wildlife, further complicating management. Fortunately, we are beginning to identify strategies for conserving and managing migratory animals in the Anthropocene. We provide a set of strategies that, if embraced, have the potential to ensure that migratory animals, and the important ecological functions sustained by migration, persist.

Oxygen saturation can predict pediatric pneumonia in a resource-limited setting.

BACKGROUND: The World Health Organization (WHO) recommends using age-specific respiratory rates for diagnosing pneumonia in children. Past studies have evaluated the WHO criteria with mixed results. OBJECTIVE: We examined the accuracy of clinical and laboratory factors for diagnosing pediatric pneumonia in resource-limited settings. METHODS: We conducted a retrospective chart review of children under 5 years of age presenting with respiratory complaints to three rural hospitals in Rwanda who had received a chest radiograph. Data were collected on the presence or absence of 31 historical, clinical, and laboratory signs. Chest radiographs were interpreted by pediatric radiologists as the gold standard for diagnosing pneumonia. Overall correlation and test characteristics were calculated for each categorical variable as compared to the gold standard. For continuous variables, we created receiver operating characteristic (ROC) curves to determine their accuracy for predicting pneumonia. RESULTS: Between May 2011 and April 2012, data were collected from 147 charts of children with respiratory complaints. Approximately 58% of our sample had radiologist-diagnosed pneumonia. Of the categorical variables, a negative blood smear for malaria (χ(2) = 6.21, p = 0.013) and the absence of history of asthma (χ(2) = 4.48, p = 0.034) were statistically associated with pneumonia. Of the continuous variables, only oxygen saturation had a statistically significant area under the ROC curve (AUC) of 0.675 (95% confidence interval [CI] 0.581-0.769 and p = 0.001). Respiratory rate had an AUC of 0.528 (95% CI 0.428-0.627 and p = 0.588). CONCLUSION: Oxygen saturation was the best clinical predictor for pediatric pneumonia and should be further studied in a prospective sample of children with respiratory symptoms in a resource-limited setting.

The contingent reputational benefits of selective exposure to partisan information.

Individuals often preferentially avoid information that contradicts and seek information that aligns with their prior beliefs-a tendency referred to as "selective exposure." Traditionally, prior research has focused on intrapersonal drivers of selective exposure, including avoidance of cognitive dissonance. We take a complementary approach by investigating the conditions under which interpersonal concerns drive selective exposure. Drawing on a large literature on impression management, we test a social signaling model of selective exposure, which predicts that (a) individuals shift their information selection decisions to signal to observers and (b) observers reward such shifts. We test this model in the domain of partisan politics in the United States across five financially incentivized, preregistered experiments (N = 3,598). Our results extend prior theory by identifying three key contingencies: the type of task on which observers expect to collaborate with actors, alignment of group membership between observers and actors, and the magnitude of demonstrated selective exposure. Overall, we find that tailoring one's information selection decisions can indeed have strategic value-but only under certain theoretically predictable conditions. Our work also identifies an actor-observer misalignment: While observers are sensitive to the type of future interaction with an actor, the actors themselves do not intuit this sensitivity. In the era of social media, when information selection decisions are more public than ever and the spread of misinformation is pervasive, understanding the ways in which reputational considerations shape decision making not only illuminates why selective exposure persists, but also suggests novel mitigation strategies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The Role of Lifestyle Modification with Second-Generation Anti-obesity Medications: Comparisons, Questions, and Clinical Opportunities.

PURPOSE OF REVIEW: This review examines lifestyle modification for obesity management with the goal of identifying treatment components that could support the use of a new generation of anti-obesity medications (AOMs). RECENT FINDINGS: Semaglutide reliably reduces baseline body weight by approximately 15% at 68 weeks, in contrast to 5-10% for lifestyle modification. Tirzepatide induces mean losses as great as 20.9%. Both medications reduce energy intake by markedly enhancing satiation and decreasing hunger, and they appear to lessen the need for traditional cognitive and behavioral strategies (e.g., monitoring food intake) to achieve calorie restriction. Little, however, is known about whether patients who lose weight with these AOMs adopt healthy diet and activity patterns needed to optimize body composition, cardiometabolic health, and quality of life. When used with the new AOMs, the focus of lifestyle modification is likely to change from inducing weight loss (through calorie restriction) to facilitating patients' adoption of dietary and activity patterns that will promote optimal changes in body composition and overall health.

Integrative dissection of gene regulatory elements at base resolution.

Although vast numbers of putative gene regulatory elements have been cataloged, the sequence motifs and individual bases that underlie their functions remain largely unknown. Here, we combine epigenetic perturbations, base editing, and deep learning to dissect regulatory sequences within the exemplar immune locus encoding CD69. We converge on a ∼170 base interval within a differentially accessible and acetylated enhancer critical for CD69 induction in stimulated Jurkat T cells. Individual C-to-T base edits within the interval markedly reduce element accessibility and acetylation, with corresponding reduction of CD69 expression. The most potent base edits may be explained by their effect on regulatory interactions between the transcriptional activators GATA3 and TAL1 and the repressor BHLHE40. Systematic analysis suggests that the interplay between GATA3 and BHLHE40 plays a general role in rapid T cell transcriptional responses. Our study provides a framework for parsing regulatory elements in their endogenous chromatin contexts and identifying operative artificial variants.

Chromatin complex dependencies reveal targeting opportunities in leukemia.

Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks.

Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma.

Amplification of MDM2 on supernumerary chromosomes is a common mechanism of P53 inactivation across tumors. Here, we investigated the impact of MDM2 overexpression on chromatin, gene expression, and cellular phenotypes in liposarcoma. Three independent regulatory circuits predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind mesenchymal gene enhancers. P53 and MDM2 co-occupy enhancers and promoters associated with P53 signaling. When highly expressed, MDM2 also binds thousands of P53-independent growth and stress response genes, whose promoters engage in multi-way topological interactions. Overexpressed MDM2 concentrates within nuclear foci that co-localize with PML and YY1 and could also contribute to P53-independent phenotypes associated with supraphysiologic MDM2. Importantly, we observe striking cell-to-cell variability in MDM2 copy number and expression in tumors and models. Whereas liposarcoma cells are generally sensitive to MDM2 inhibitors and their combination with pro-apoptotic drugs, MDM2-high cells tolerate them and may underlie the poor clinical efficacy of these agents.

Implementation of DNA Methylation Array Profiling in Pediatric Central Nervous System Tumors: The AIM BRAIN Project: An Australian and New Zealand Children's Haematology/Oncology Group Study.

DNA methylation array profiling for classifying pediatric central nervous system (CNS) tumors is a valuable adjunct to histopathology. However, unbiased prospective and interlaboratory validation studies have been lacking. The AIM BRAIN diagnostic trial involving 11 pediatric cancer centers in Australia and New Zealand was designed to test the feasibility of routine clinical testing and ran in parallel with the Molecular Neuropathology 2.0 (MNP2.0) study at Deutsches Krebsforschungszentrum (German Cancer Research Center). CNS tumors from 269 pediatric patients were prospectively tested on Illumina EPIC arrays, including 104 cases co-enrolled on MNP2.0. Using MNP classifier versions 11b4 and 12.5, we report classifications with a probability score ≥0.90 in 176 of 265 (66.4%) and 213 of 269 (79.2%) cases, respectively. Significant diagnostic information was obtained in 130 of 176 (74%) for 11b4, and 12 of 174 (7%) classifications were discordant with histopathology. Cases prospectively co-enrolled on MNP2.0 gave concordant classifications (99%) and score thresholds (93%), demonstrating excellent test reproducibility and sensitivity. Overall, DNA methylation profiling is a robust single workflow technique with an acceptable diagnostic yield that is considerably enhanced by the extensive subgroup and copy number profile information generated by the platform. The platform has excellent test reproducibility and sensitivity and contributes significantly to CNS tumor diagnosis.

Long-range phasing of dynamic, tissue-specific and allele-specific regulatory elements.

Epigenomic maps identify gene regulatory elements by their chromatin state. However, prevailing short-read sequencing methods cannot effectively distinguish alleles, evaluate the interdependence of elements in a locus or capture single-molecule dynamics. Here, we apply targeted nanopore sequencing to profile chromatin accessibility and DNA methylation on contiguous ~100-kb DNA molecules that span loci relevant to development, immunity and imprinting. We detect promoters, enhancers, insulators and transcription factor footprints on single molecules based on exogenous GpC methylation. We infer relationships among dynamic elements within immune loci, and order successive remodeling events during T cell stimulation. Finally, we phase primary sequence and regulatory elements across the H19/IGF2 locus, uncovering primate-specific features. These include a segmental duplication that stabilizes the imprinting control region and a noncanonical enhancer that drives biallelic IGF2 expression in specific contexts. Our study advances emerging strategies for phasing gene regulatory landscapes and reveals a mechanism that overrides IGF2 imprinting in human cells.

Analogies for a No-Analog World: Tackling Uncertainties in Reintroduction Planning.

Species reintroductions involve considerable uncertainty, especially in highly altered landscapes. Historical, geographic, and taxonomic analogies can help reduce this uncertainty by enabling conservationists to better assess habitat suitability in proposed reintroduction sites. We illustrate this approach using the example of the California grizzly, an iconic species proposed for reintroduction.

Outcomes of Low-Intensity Treatment of Acute Lymphoblastic Leukemia at Butaro Cancer Center of Excellence in Rwanda.

PURPOSE: Children with acute lymphoblastic leukemia (ALL) in low-income countries have disproportionately lower cure rates than those in high-income countries. At Butaro Cancer Center of Excellence (BCCOE), physicians treated patients with ALL with the first arm of the Hunger Protocol, a graduated-intensity method tailored for resource-limited settings. This article provides the first published outcomes, to our knowledge, of patients with ALL treated with this protocol. METHODS: This is a retrospective descriptive study of patients with ALL enrolled at BCCOE from July 1, 2012 to June 30, 2014; data were collected through December 31, 2015. Descriptive statistics were used to calculate patient demographics, disease characteristics, and outcomes; event-free survival was assessed at 2 years using the Kaplan-Meier method. RESULTS: Forty-two consecutive patients with ALL were included. At the end of the study period, 19% (eight) were alive without evidence of relapse: three completed treatment and five were continuing treatment. Among the remaining patients, 71% (30) had died and 10% (four) were lost to follow-up. A total of 83% (25) of the deaths were disease related, 3% (one) treatment-related, and 13% (four) unclear. Event-free survival was 22% (95% CI, 11% to 36%), considering lost to follow-up as an event, and 26% (95% CI, 13% to 41%) if lost to follow-up is censored. CONCLUSION: As expected, relapse was the major cause of failure with this low-intensity regimen. However, toxicity was acceptably low, and BCCOE has decided to advance to intensity level 2. These results reflect the necessity of a data-driven approach and a continual improvement process to care for complex patients in resource-constrained settings.