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BACKGROUND: Each year, approximately one million older adults die in American ICUs or survive with significant functional impairment. Inadequate symptom management, surrogates’ psychological distress and inappropriate healthcare use are major concerns. Pioneering work by Dr. J. Randall Curtis paved the way for integrating palliative care (PC) specialists to address these needs, but convincing proof of efficacy has not yet been demonstrated. DESIGN: We will conduct a multicenter patient-randomized efficacy trial of integrated specialty PC (SPC) versus usual care for 500 high-risk ICU patients over age 60 and their surrogate decision-makers from five hospitals in Pennsylvania. INTERVENTION: The intervention will follow recommended best practices for inpatient PC consultation. Patients will receive care from a multidisciplinary SPC team within 24 hours of enrollment that continues until hospital discharge or death. SPC clinicians will meet with patients, families, and the ICU team every weekday. SPC and ICU clinicians will jointly participate in proactive family meetings according to a predefined schedule. Patients in the control arm will receive routine ICU care. OUTCOMES: Our primary outcome is patient-centeredness of care, measured using the modified Patient Perceived Patient-Centeredness of Care (PPPC) scale. Secondary outcomes include surrogates’ psychological symptom burden and health resource utilization. Other outcomes include patient survival, as well as interprofessional collaboration. We will also conduct prespecified subgroup analyses using variables such as PC needs, measured by the Needs of Social Nature, Existential Concerns, Symptoms, and Therapeutic Interaction (NEST) scale. CONCLUSIONS: This trial will provide robust evidence about the impact of integrating SPC with critical care on patient, family, and health system outcomes.

ImportanceDiagnostic errors made during triage at nontrauma centers contribute to preventable morbidity and mortality after injury.ObjectiveTo test the feasibility, acceptability, and preliminary effect of a novel deliberate practice intervention to improve diagnostic reasoning in trauma triage.Design, Setting, and ParticipantsThis pilot randomized clinical trial was conducted online in a national convenience sample of 72 emergency physicians between January 1 and March 31, 2022, without follow-up.InterventionsParticipants were randomly assigned to receive either usual care (ie, passive control) or a deliberate practice intervention, consisting of 3 weekly, 30-minute, video-conferenced sessions during which physicians played a customized, theory-based video game while being observed by content experts (coaches) who provided immediate, personalized feedback on diagnostic reasoning.Main Outcomes and MeasuresUsing the Proctor framework of outcomes for implementation research, the feasibility, fidelity, acceptability, adoption, and appropriateness of the intervention was assessed by reviewing videos of the coaching sessions and conducting debriefing interviews with participants. A validated online simulation was used to assess the intervention’s effect on behavior, and triage among control and intervention physicians was compared using mixed-effects logistic regression. Implementation outcomes were analyzed using an intention-to-treat approach, but participants who did not use the simulation were excluded from the efficacy analysis.ResultsThe study enrolled 72 physicians (mean [SD] age, 43.3 [9.4] years; 44 men [61%]) but limited registration of physicians in the intervention group to 30 because of the availability of the coaches. Physicians worked in 20 states; 62 (86%) were board certified in emergency medicine. The intervention was delivered with high fidelity, with 28 of 30 physicians (93%) completing 3 coaching sessions and with coaches delivering 95% of session components (642 of 674). A total of 21 of 36 physicians (58%) in the control group participated in outcome assessment; 28 of 30 physicians (93%) in the intervention group participated in semistructured interviews, and 26 of 30 physicians (87%) in the intervention group participated in outcome assessment. Most physicians in the intervention group (93% [26 of 28]) described the sessions as entertaining and valuable; most (88% [22 of 25]) affirmed the intention to adopt the principles discussed. Suggestions for refinement included providing more time with the coach and addressing contextual barriers to triage. During the simulation, the triage decisions of physicians in the intervention group were more likely to adhere to clinical practice guidelines than those in the control group (odds ratio; 13.8, 95% CI, 2.8-69.6; P = .001).Conclusions and RelevanceIn this pilot randomized clinical trial, coaching was feasible and acceptable and had a large effect on simulated trauma triage decisions, setting the stage for a phase 3 trial.Trial RegistrationClinicalTrials.gov Identifier: NCT05168579

Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of central metabolic signaling, and mice with whole brain-, leptin receptor (LepRb) expressing cell-, or proopiomelanocortin neuron-specific PTP1B-deficiency are lean, leptin hypersensitive, and display improved glucose homeostasis. However, whether the metabolic effects of central PTP1B-deficiency are due to action within the hypothalamus remains unclear. Moreover, whether or not these effects are exclusively due to enhanced leptin signaling is unknown. Here we report that mice with hypothalamic PTP1B-deficiency (Nkx2.1-PTP1B(-/-)) display decreased body weight and adiposity on high-fat diet with no associated improvements in glucose tolerance. Consistent with previous reports, we find that hypothalamic deletion of the LepRb in mice (Nkx2.1-LepRb(-/-)) results in extreme hyperphagia and obesity. Interestingly, deletion of hypothalamic PTP1B and LepRb (Nkx2.1-PTP1B(-/-):LepRb(-/-)) does not rescue the hyperphagia or obesity of Nkx2.1-LepRb(-/-) mice, suggesting that hypothalamic PTP1B contributes to the central control of energy balance through a leptin receptor-dependent pathway.

Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuron-specific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron-specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b-/- mice) had reduced adiposity, improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron-specific deletion of the gene encoding SHP2 (referred to herein as POMC-Shp2-/- mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b-/- mice showed substantially improved glucose homeostasis on a high-fat diet, and hyperinsulinemic-euglycemic clamp studies revealed that insulin sensitivity in these mice was improved on a standard chow diet in the absence of any weight difference. In contrast, POMC-Shp2-/- mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and alpha-melanocyte-stimulating hormone (alphaMSH) peptide levels were markedly reduced in POMC-Shp2-/- mice. These studies implicate PTP1B and SHP2 as important components of POMC neuron regulation of energy balance and point to what we believe to be a novel role for SHP2 in the normal function of the melanocortin system.

OBJECTIVE—The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B are hypersensitive to insulin. Because PTP1B−/− mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously, we showed that brain-specific PTP1B−/− mice are protected against high-fat diet–induced obesity and glucose intolerance, whereas muscle-specific PTP1B−/− mice have increased insulin sensitivity independent of changes in adiposity. Here we studied the role of liver PTP1B in glucose homeostasis and lipid metabolism. RESEARCH DESIGN AND METHODS—We analyzed body mass/adiposity, insulin sensitivity, glucose tolerance, and lipid metabolism in liver-specific PTP1B−/− and PTP1Bfl/fl control mice, fed a chow or high-fat diet. RESULTS—Compared with normal littermates, liver-specific PTP1B−/− mice exhibit improved glucose homeostasis and lipid profiles, independent of changes in adiposity. Liver-specific PTP1B−/− mice have increased hepatic insulin signaling, decreased expression of gluconeogenic genes PEPCK and G-6-Pase, enhanced insulin-induced suppression of hepatic glucose production, and improved glucose tolerance. Liver-specific PTP1B−/− mice exhibit decreased triglyceride and cholesterol levels and diminished expression of lipogenic genes SREBPs, FAS, and ACC. Liver-specific PTP1B deletion also protects against high-fat diet–induced endoplasmic reticulum stress response in vivo, as evidenced by decreased phosphorylation of p38MAPK, JNK, PERK, and eIF2α and lower expression of the transcription factors C/EBP homologous protein and spliced X box-binding protein 1. CONCLUSIONS—Liver PTP1B plays an important role in glucose and lipid metabolism, independent of alterations in adiposity. Inhibition of PTP1B in peripheral tissues may be useful for the treatment of metabolic syndrome and reduction of cardiovascular risk in addition to diabetes.

Global reproductive health policy is based on assumptions, couched in scientific language, that technological methods of birth control are superior to traditional methods, use of these methods is more modern and "rational" than alternatives, and abortion should not be considered a form of birth control. The authority these assumptions have achieved in global health circles prevents alternative options from being considered. Our research on women's birth control experiences in Mongolia suggests that reproductive health programs based on such global assumptions fail to consider the local cultural contexts of reproductive decision-making address women's needs, and are therefore seriously flawed.

The existence of adult β-cell progenitors remains the most controversial developmental biology topic in diabetes research. It has been reported that β-cell progenitors can be activated by ductal ligation–induced injury of adult mouse pancreas and apparently act in a cell-autonomous manner to double the functional β-cell mass within a week by differentiation and proliferation. Here, we demonstrate that pancreatic duct ligation (PDL) does not activate progenitors to contribute to β-cell mass expansion. Rather, PDL stimulates massive pancreatic injury, which alters pancreatic composition and thus complicates accurate measurement of β-cell content via traditional morphometry methodologies that superficially sample the pancreas. To overcome this potential bias, we quantified β-cells from the entire pancreas and observed that β-cell mass and insulin content are totally unchanged by PDL-induced injury. Lineage-tracing studies using sequential administration of thymidine analogs, rat insulin 2 promoter–driven cre-lox, and low-frequency ubiquitous cre-lox reveal that PDL does not convert progenitors to the β-cell lineage. Thus, we conclude that β-cells are not generated in injured adult mouse pancreas.

A common dietary component that some people even take as a supplement is converted by the gut microbiota to harmful metabolites linked to heart disease. This finding has cautionary implications. See Article p.57 Stanley Hazen and colleagues show that gut flora can influence cardiovascular disease by metabolizing a dietary phospholipid. A targeted metabolomics approach was used to identify plasma metabolites whose levels predict future risk for experiencing a non-fatal heart attack, stroke or death in subjects undergoing cardiac evaluation. Plasma levels of three metabolites of dietary phosphatidylcholine — choline, betaine and trimethylamine N-oxide (TMAO) — are associated with increased risk of cardiovascular disease. The gut flora is known to have a role in TMAO formation from choline. In addition, experiments in atherosclerosis-prone mice show that dietary choline enhances macrophage foam-cell formation and lesion formation — but not if the gut flora is depleted with antibiotics. This work suggests new diagnostic and therapeutic approaches for atherosclerotic heart disease.