Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression. Here we studied the role of the serotonin 2C receptor (5-HT
R) in weight regulation and ...behavior. Using exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT
R (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity. Using the 5-HT
R agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we demonstrate that 5-HT
R is involved in the regulation of human appetite, weight and behavior. Our findings suggest that melanocortin receptor agonists might be effective in treating severe obesity in individuals carrying HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.
Medicare Advantage (MA) has grown rapidly since the Affordable Care Act; nearly one-third of Medicare beneficiaries now choose MA. An assessment of the comparative value of the 2 options is ...confounded by an apparent selection bias favoring MA, as reflected in mortality differences. Previous assessments have been hampered by lack of access to claims diagnosis data for the MA population. An indirect comparison of mortality as an outcome variable was conducted by modeling mortality on a traditional fee-for-service (FFS) Medicare data set, applying the model to an MA data set, and then evaluating the ratio of actual-to-predicted mortality in the MA data set. The mortality model adjusted for clinical conditions and demographic factors. Model development considered the effect of potentially greater coding intensity in the MA population. Further analysis calculated ratios for subpopulations. Predicted, risk-adjusted mortality was lower in the MA population than in FFS Medicare. However, the ratio of actual-to-predicted mortality (0.80) suggested that the individuals in the MA data set were less likely to die than would be predicted had those individuals been enrolled in FFS Medicare. Differences between actual and predicted mortality were particularly pronounced in low income (dual eligibility), nonwhite race, high morbidity, and Health Maintenance Organization (HMO) subgroups. After controlling for baseline clinical risk as represented by claims diagnosis data, mortality differences favoring MA over FFS Medicare persisted, particularly in vulnerable subgroups and HMO plans. These findings suggest that differences in morbidity do not fully explain differences in mortality between the 2 programs.
Medicare Advantage (MA) has grown rapidly since the Affordable Care Act; nearly one-third of Medicare beneficiaries now choose MA. An assessment of the comparative value of the 2 options is ...confounded by an apparent selection bias favoring MA, as reflected in mortality differences. Previous assessments have been hampered by lack of access to claims diagnosis data for the MA population. An indirect comparison of mortality as an outcome variable was conducted by modeling mortality on a traditional fee-for-service (FFS) Medicare data set, applying the model to an MA data set, and then evaluating the ratio of actual-to-predicted mortality in the MA data set. The mortality model adjusted for clinical conditions and demographic factors. Model development considered the effect of potentially greater coding intensity in the MA population. Further analysis calculated ratios for subpopulations. Predicted, risk-adjusted mortality was lower in the MA population than in FFS Medicare. However, the ratio of actual-to-predicted mortality (0.80) suggested that the individuals in the MA data set were less likely to die than would be predicted had those individuals been enrolled in FFS Medicare. Differences between actual and predicted mortality were particularly pronounced in low income (dual eligibility), nonwhite race, high morbidity, and Health Maintenance Organization (HMO) subgroups. After controlling for baseline clinical risk as represented by claims diagnosis data, mortality differences favoring MA over FFS Medicare persisted, particularly in vulnerable subgroups and HMO plans. These findings suggest that differences in morbidity do not fully explain differences in mortality between the 2 programs.
ABSTRACT
In this series of papers, we employ several machine learning (ML) methods to classify the point-like sources from the miniJPAS catalogue, and identify quasar candidates. Since no ...representative sample of spectroscopically confirmed sources exists at present to train these ML algorithms, we rely on mock catalogues. In this first paper, we develop a pipeline to compute synthetic photometry of quasars, galaxies, and stars using spectra of objects targeted as quasars in the Sloan Digital Sky Survey. To match the same depths and signal-to-noise ratio distributions in all bands expected for miniJPAS point sources in the range 17.5 ≤ r < 24, we augment our sample of available spectra by shifting the original r-band magnitude distributions towards the faint end, ensure that the relative incidence rates of the different objects are distributed according to their respective luminosity functions, and perform a thorough modelling of the noise distribution in each filter, by sampling the flux variance either from Gaussian realizations with given widths, or from combinations of Gaussian functions. Finally, we also add in the mocks the patterns of non-detections which are present in all real observations. Although the mock catalogues presented in this work are a first step towards simulated data sets that match the properties of the miniJPAS observations, these mocks can be adapted to serve the purposes of other photometric surveys.
Oropouche virus (OROV) infection of humans is associated with a debilitating febrile illness that can progress to meningitis or encephalitis. First isolated from a forest worker in Trinidad and ...Tobago in 1955, the arbovirus OROV has since been detected throughout the Amazon basin with an estimated 500,000 human infections over 60 years. Like other members of the family
, the viral genome exists as 3 single-stranded negative-sense RNA segments. The medium-sized segment encodes a viral glycoprotein complex (GPC) that is proteolytically processed into two viral envelope proteins, Gn and Gc, responsible for attachment and membrane fusion. There are no therapeutics or vaccines to combat OROV infection, and we have little understanding of protective immunity to infection. Here, we generated a replication competent chimeric vesicular stomatitis virus (VSV), in which the endogenous glycoprotein was replaced by the GPC of OROV. Serum from mice immunized by intramuscular injection with VSV-OROV specifically neutralized wild-type OROV, and using peptide arrays we mapped multiple epitopes within an N-terminal variable region of Gc recognized by the immune sera. VSV-OROV lacking this variable region of Gc was also immunogenic in mice producing neutralizing sera that recognize additional regions of Gc. Challenge of both sets of immunized mice with wild-type OROV shows that the VSV-OROV chimeras reduce wild-type viral infection and suggest that antibodies that recognize the variable N terminus of Gc afford less protection than those that target more conserved regions of Gc.
Oropouche virus (OROV), an orthobunyavirus found in Central and South America, is an emerging public health challenge that causes debilitating febrile illness. OROV is transmitted by arthropods, and increasing mobilization has the potential to significantly increase the spread of OROV globally. Despite this, no therapeutics or vaccines have been developed to combat infection. Using vesicular stomatitis (VSV) as a backbone, we developed a chimeric virus bearing the OROV glycoproteins (VSV-OROV) and tested its ability to elicit a neutralizing antibody response. Our results demonstrate that VSV-OROV produces a strong neutralizing antibody response that is at least partially targeted to the N-terminal region of Gc. Importantly, vaccination with VSV-OROV reduces viral loads in mice challenged with wild-type virus. These data provide novel evidence that targeting the OROV glycoproteins may be an effective vaccination strategy to combat OROV infection.
En bloc celiac axis resection (CAR) for pancreatic cancer is considered increasingly after modern neoadjuvant chemotherapy (NAC). Appleby and distal pancreatectomy with CAR are anatomically ...inaccurate terms, as tumors can extend beyond celiac axis proper, requiring concurrent resection of the proper hepatic artery and/or superior mesenteric artery.
A 3-level classification for CAR (class 1, 2, or 3) was developed after retrospective review of an arterial resection database describing anatomical variants that dictate pancreatectomy-type, formal arterial revascularization, and gastric preservation. Perioperative and oncologic outcomes were assessed.
Of 90 CARs for pancreatic cancer, 89% patients received NAC, 35% requiring chemotherapeutic switch. There were 41 class 1, 33 class 2, and 16 class 3 CARs, with arterial and venous revascularization performed 62% and 66%, respectively. Ninety-day mortality decreased to 4% in the last 50 cases (p = 0.035); major morbidity was unchanged (55%). Any hepatic or gastric ischemia occurred in 20% and 10% patients, respectively, and arterial revascularization was protective. R0 resection rate (88%) was associated with chemoradiation (p = 0.004). Median overall survival was 36.2 months, superior with NAC (8.0 vs. 43.5 months). Predictors of survival after NAC included chemotherapy duration, carbohydrate antigen 19-9 response, pathologic response, and lymph node status. Major pathologic response (p = 0.036) and extended duration NAC (p = 0.007) were independent predictors on multivariate analysis.
Current terminology for CAR inadequately describes all operative variants. Our classification, based on the largest single-center series, allows complex operative planning and standardized reporting across institutions. Extent of arterial involvement determines pancreatectomy type, need for arterial revascularization, and likelihood of gastric preservation. Operative mortality has improved, morbidity remains significant, and survival favorable after extended NAC with associated pathologic responses; given these factors, CAR should only be considered in fit patients with objective NAC responses at specialized centers.
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ABSTRACT
Astrophysical surveys rely heavily on the classification of sources as stars, galaxies, or quasars from multiband photometry. Surveys in narrow-band filters allow for greater discriminatory ...power, but the variety of different types and redshifts of the objects present a challenge to standard template-based methods. In this work, which is part of a larger effort that aims at building a catalogue of quasars from the miniJPAS survey, we present a machine learning-based method that employs convolutional neural networks (CNNs) to classify point-like sources including the information in the measurement errors. We validate our methods using data from the miniJPAS survey, a proof-of-concept project of the Javalambre Physics of the Accelerating Universe Astrophysical Survey (J-PAS) collaboration covering ∼1 deg2 of the northern sky using the 56 narrow-band filters of the J-PAS survey. Due to the scarcity of real data, we trained our algorithms using mocks that were purpose-built to reproduce the distributions of different types of objects that we expect to find in the miniJPAS survey, as well as the properties of the real observations in terms of signal and noise. We compare the performance of the CNNs with other well-established machine learning classification methods based on decision trees, finding that the CNNs improve the classification when the measurement errors are provided as inputs. The predicted distribution of objects in miniJPAS is consistent with the putative luminosity functions of stars, quasars, and unresolved galaxies. Our results are a proof of concept for the idea that the J-PAS survey will be able to detect unprecedented numbers of quasars with high confidence.
Background Although mortality and complication rates for abdominal aortic aneurysm (AAA) have declined over the last 20 years, operative complication rates and perioperative mortality are still high, ...specifically for repair of ruptures. The goal of this study was to determine the influence of insurance type and ethnicity while controlling for the influences of potential confounders on procedure selection and outcome following endovascular AAA repair (EVAR). Methods Using the Nationwide Inpatient Sample (NIS) database, we identified patients who underwent EVAR repair of ruptured and elective infrarenal AAA, between 1990 and 2003. Insurance type and ethnicity were analyzed against the primary outcome variables of mortality and major complications. The potential confounders of age, gender, operative location, diabetes, and Deyo index of comorbidities, were controlled. Results Bivariate analyses demonstrated significant differences between insurance types and ethnicity and mortality and complications. Patients who were self pay had adverse outcomes in comparison to Private insurance. Whites encountered less perioperative mortality and postoperative complications than Blacks and Hispanics. Conclusions After controlling for previously identified associative factors for AAA outcome, ethnicity and insurance type does influence EVAR surgical outcome. Subsequent studies that break down emergent repair vs elective surgery and that longitudinally stratify delay in surgery, or time to admission may be useful.
Abstract
Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically ...attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative
P. falciparum
LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant,
Pf
Δ
mei2
, lacking the
mei2-like RNA
gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of
Pf
Δ
mei2
make it a promising vaccine candidate, supporting further clinical evaluation.
Pf
Δ
mei2
(GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study.
Skeletal age (SA) is an estimate of biological maturity status that is commonly used in sport-related medical examinations. This study considered intra-observer reproducibility and inter-observer ...agreement of SA assessments among male tennis players.
SA was assessed with the Fels method in 97 male tennis players with chronological ages (CA) spanning 8.7-16.8 years. Radiographs were evaluated by two independent trained observers. Based on the difference between SA and CA, players were classified as late, average or early maturing; if a player was skeletally mature, he was noted as such as an SA is not assigned.
The magnitude of intra-individual differences between repeated SA assessments were d = 0.008 year (observer A) and d = 0.001 year (observer B); the respective coefficients of variation were 1.11% and 1.75%. Inter-observer mean differences were negligible (t = 1.252, p = 0.210) and the intra-class correlation coefficient was nearly perfect (ICC = 0.995). Concordance of classifications of players by maturity status between observers was 90%.
Fels SA assessments were highly reproducible and showed an acceptable level of inter-observer agreement between trained examiners. Classifications of players by skeletal maturity status based on assessments of the two observers were highly concordant, though not 100%. The results highlight the importance of experienced observers in skeletal maturity assessments.
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