Association of Participation in Medicare's Oncology Care Model With Spending, Utilization, and Quality Outcomes Among Commercially Insured and Medicare Advantage Members.

PURPOSE: The Oncology Care Model (OCM), a value-based payment model for traditional Medicare beneficiaries with cancer, yielded total spending reductions that were outweighed by incentive payments, resulting in net losses to the Centers for Medicare & Medicaid Services. We studied whether the OCM yielded spillover effects in total episode spending, utilization, and quality among commercially insured and Medicare Advantage (MA) members, who were not targeted by the program. PATIENTS AND METHODS: This observational study used administrative claims from a large national payer, yielding 157,189 total patients with commercial insurance or MA with solid malignancies who initiated 229,376 systemic anticancer therapy episodes before (2012-2015) and during (2016-2021) the OCM at 125 OCM-participating practices (a subset of total OCM practices) and a 1:10 propensity-matched set of 860 non-OCM practices. We used difference-in-differences analyses to assess the association between the OCM and total episode spending, defined as medical spending during a 6-month episode. Secondary outcomes included hospitalization and emergency department (ED) utilization and quality measures. RESULTS: From the pre-OCM to the OCM period, mean total episode payments increased from $45,504 in US dollars (USD) to $46,239 USD for OCM-participating practices, and increased from $50,519 USD to $58,591 USD for non-OCM practices (adjusted difference-in-differences -$6,287 USD [95% CI, -$10,076 USD to -$2,498 USD], P = .001). The OCM was associated with adjusted spending decreases for both high-risk (-$6,756 USD [95% CI, -$10,731 USD to -$2,781 USD], P = .001) and low-risk (-$4,171 USD [95% CI, -$7,799 USD to -$543 USD], P = .025) episodes. OCM-associated spending reductions were strongest for outpatient (-$5,243 USD [95% CI, -$8,589 USD to -$1,897 USD], P = .002) and infused/injected anticancer drug (-$3,031 USD [95% CI, -$5,193 USD to -$869 USD], P = .006) spending. There were no associations between OCM participation and changes in hospital or ED utilization nor quality of care. CONCLUSION: The OCM was associated with reductions in spending for nontargeted members, a spillover effect.

Diagnostic Approach to the Patient with Altered Mental Status.

Acute encephalopathy is a common presenting symptom in the emergency room and complicates many hospital and intensive care unit admissions. The evaluation of patients with encephalopathy poses several challenges: limited history and examination due to the patient's mental status, broad differential diagnosis of systemic and neurologic etiologies, low yield of neurodiagnostic testing due to the high base rate of systemic causes, and the importance of identifying less common neurologic causes of encephalopathy that can be life-threatening if not identified and treated. This article discusses the differential diagnosis of acute encephalopathy, presents an approach to the history and examination in a patient with encephalopathy, reviews the literature on the yield of neurodiagnostic testing in this population, and provides a diagnostic framework for the evaluation of patients with altered mental status.

Single turnover transient state kinetics reveals processive protein unfolding catalyzed by Escherichia coli ClpB.

Escherichia coli ClpB and Saccharomyces cerevisiae Hsp104 are AAA+ motor proteins essential for proteome maintenance and thermal tolerance. ClpB and Hsp104 have been proposed to extract a polypeptide from an aggregate and processively translocate the chain through the axial channel of its hexameric ring structure. However, the mechanism of translocation and if this reaction is processive remains disputed. We reported that Hsp104 and ClpB are non-processive on unfolded model substrates. Others have reported that ClpB is able to processively translocate a mechanically unfolded polypeptide chain at rates over 240 amino acids (aa) per second. Here, we report the development of a single turnover stopped-flow fluorescence strategy that reports on processive protein unfolding catalyzed by ClpB. We show that when translocation catalyzed by ClpB is challenged by stably folded protein structure, the motor enzymatically unfolds the substrate at a rate of ~0.9 aa s-1 with a kinetic step-size of ~60 amino acids at sub-saturating [ATP]. We reconcile the apparent controversy by defining enzyme catalyzed protein unfolding and translocation as two distinct reactions with different mechanisms of action. We propose a model where slow unfolding followed by fast translocation represents an important mechanistic feature that allows the motor to rapidly translocate up to the next folded region or rapidly dissociate if no additional fold is encountered.

Porcine blast injury model achieves prolonged elevation of intra-compartmental pressures without exogenous pressure manipulation.

BACKGROUND: Most existing animal models of acute compartment syndrome (ACS) rely on exogenous manipulation of intra-compartmental pressures to model ACS. The purpose of the current study was to evaluate the endogenous effect of a blast injury on porcine lower leg intra-compartmental pressures (ICP). METHODS: The hindlimb of juvenile Landrace pigs was fractured at the diaphyseal tibia and subjected to blasts of compressed air to mimic a blast injury. Injured and control legs underwent pre-operative continuous ICP monitoring. At 4.5 h post injury, the fracture was stabilized followed by closure of the anterior compartment fascia (continued compartment pressure model, CCPM) or four compartment fasciotomy. Pressure measurements were made after operative fixation. Select pigs in CCPM were harvested between 48 and 72 h post-injury to evaluate the duration of ICP elevation. RESULTS: Post-injury, the model created significantly elevated ICP compared to control limbs (54.5 ± 18.2 vs. 18.2 ± 4.9 mmHg; p < 0.001). Operative fixation and anterior compartment fascial closure further increased the ICP (Mean: 87.4 ± 42.5 mmHg) relative to the pre-operative state (p = 0.037). Fasciotomy returned baseline compartment pressures (Mean: 13.7 ± 10.2 mmHg) which were equivalent to control limbs (p = 0.117). Pressure measurements at the time of delayed harvest (48-72 h) demonstrated that elevated ICP persisted following injury (69.7 ± 55.12 mmHg). CONCLUSION: The current study demonstrates that a pilot porcine blast model elevates ICP comparable to existing animal models of compartment syndrome without exogenous ICP manipulation. ICP remained elevated at 48-72 h in the absence of fasciotomy.

Spending by the Veterans Health Administration for Medicare Advantage Dual Enrollees, 2011-2020.

This study assesses veterans' dual enrollment in the Veterans Health Administration (VHA) and Medicare Advantage and VHA spending from 2011 through 2020.

Functional comparison of human and murine equilibrative nucleobase transporter 1.

6-Mercaptopurine (6-MP) maintenance therapy is the mainstay for various types of leukemia and inflammatory bowel disease. 6-MP is associated with numerous adverse effects including gastrointestinal intolerance, myelotoxicity, and hepatotoxicity. This can lead to therapy discontinuation which is associated with a higher risk of relapse. Drug transporter expression is a known factor contributing to patient variability in drug response and toxicity. We have established that the SLC43A3-encoded equilibrative nucleobase transporter 1 (ENBT1) mediates the transport of 6-MP into human lymphocytes and human embryonic kidney 293 (HEK293) cell lines transfected with SLC43A3. ENBT1 is known to be expressed in the gastrointestinal tract, bone marrow, and the liver. However, the relationship between ENBT1 and 6-MP-associated adverse events, and its pharmacokinetics, is unknown. To validate the use of mouse models (e.g. slc43a3-null mice) for exploring this relationship, we assessed the functional similarities between human and murine ENBT1 using HEK293 cells transfected with the respective SLC43A3/slc43a3 constructs, and the leukemia cell lines MOLT-4 (human) and L1210 (murine). Based on in silico analyses of structural similarities between transporters, we hypothesized that human and murine ENBT1 will have similar 6-MP transport/inhibition kinetics and a similar impact on 6-MP-induced cytotoxicity. We show herein that mslc43a3-encoded mouse ENBT1 transports both [3H]6-MP and [3H]adenine with kinetics similar to those of hSLC43A3-encoded human ENBT1. Both are also similarly distributed in mouse and human tissues. Therefore, data obtained from mouse models where ENBT1 is disrupted or modified may provide clinically relevant insights on its roles in modulating the actions of 6-MP.

"A safe, non-judgmental space where I can really challenge myself:" learner experiences in a virtual, case-based diagnostic reasoning conference for students.

Case-based diagnostic reasoning conferences, like morning reports, allow undergraduate medical trainees to practice diagnostic reasoning alongside senior clinicians. However, trainees have reported discomfort doing so. Peer-assisted learning offers an alternative approach. We describe the design, implementation, and evaluation of a virtual, student-only diagnostic reasoning conference that leverages peer-assisted learning. Student virtual morning report's (VMR) design was informed by social and cognitive congruence and experience-based learning. We evaluated participant experiences using a survey focused on participant perceptions of Student VMR's value, their methods for participation, and their preferences for Student VMR compared with VMR with more senior clinicians. 110 participants (28.9%) completed the survey. 90 participants (81.2%) reported that Student VMR was educational. Compared to VMR, participants reported being more likely to participate in Student VMR by turning on their video (50.0%), presenting a case (43.6%), verbally participating (44.5%), or participating in the chat (70.0%). Strengths included a safe learning environment to practice DR and the opportunity to engage with an international learning community. When asked whether they preferred Student VMR or non-Student VMR, most respondents (64.5%, 71/110) identified that they did not have a preference between the two. A student-focused DR conference may offer a valuable complement to, but not a replacement of, apprenticeship-based DR case conferences.

Subtotal Versus Total Parathyroidectomy for the Management of Tertiary Hyperparathyroidism: A Systematic Literature Review and Meta-Analysis of Optimal Surgical Modality.

Background: Surgery is the definitive treatment option for tertiary hyperparathyroidism (THPT), however, the optimal surgical approach remains unclear. We aimed to compare total parathyroidectomy (PTX) with auto-transplantation vs subtotal PTX for THPT through a systematic review and meta-analysis.Methods: PubMed, Embase, and Web of Science were searched for studies comparing outcomes of total vs subtotal PTX for THPT. A total of 28 studies (n = 1000 patients) met the inclusion criteria.Results: The mean age was 46.5 years and 53% were female. The proportion of females (59% vs 49%) was higher in the total PTX with auto-transplantation cohort (P = .008). Both procedures had similar preoperative calcium and PTH levels. Postoperative and 6-month calcium and PTH were also comparable between groups, except transiently higher post-operative PTH in the total PTX with auto-transplantation cohort (P = .03). Hypercalcemia cure rates were 98%-100% with no difference between surgical techniques (P = .67). Safety profiles were comparable and low.Conclusions: Total PTX with auto-transplantation and subtotal PTX yield similar efficacy and safety for THPT, with no significant differences in cure rates, recurrence, complications, or biochemical control.

Non-degenerate two-photon imaging of deep rodent cortex using indocyanine green in the water absorption window.

We present a novel approach for deep vascular imaging in rodent cortex at excitation wavelengths susceptible to water absorption using two-photon microscopy with photons of dissimilar wavelengths. We demonstrate that non-degenerate two-photon excitation (ND-2PE) enables imaging in the water absorption window from 1400-1550 nm using two excitation sources with temporally overlapped pulses at 1300 nm and 1600 nm that straddle the absorption window. We explore the brightness spectra of indocyanine green (ICG) and assess its suitability for imaging in the water absorption window. Further, we demonstrate in vivo imaging of the rodent cortex vascular structure up to 1.2 mm using ND-2PE. Lastly, a comparative analysis of ND-2PE at 1435 nm and single-wavelength, two-photon imaging at 1300 nm and 1435 nm is presented. Our work extends the excitation range for fluorescent dyes to include water absorption regimes and underscores the feasibility of deep two-photon imaging at these wavelengths.

Biochemical characterization of Mycobacterial RNA polymerases.

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis (Mtb). While eukaryotic species employ several specialized RNA polymerases (Pols) to fulfill the RNA synthesis requirements of the cell, bacterial species use a single RNA polymerase (RNAP). To contribute to the foundational understanding of how Mtb and the related non-pathogenic mycobacterial species, Mycobacterium smegmatis (Msm), perform the essential function of RNA synthesis, we performed a series of in vitro transcription experiments to define the unique enzymatic properties of Mtb and Msm RNAPs. In this study, we characterize the mechanism of nucleotide addition used by these bacterial RNAPs with comparisons to previously characterized eukaryotic Pols I, II, and III. We show that Mtb RNAP and Msm RNAP demonstrate similar enzymatic properties and nucleotide addition kinetics to each other but diverge significantly from eukaryotic Pols. We also show that Mtb RNAP and Msm RNAP uniquely bind a nucleotide analog with significantly higher affinity than canonical nucleotides, in contrast to eukaryotic RNA polymerase II. This affinity for analogs may reveal a vulnerability for selective inhibition of the pathogenic bacterial enzyme.IMPORTANCETuberculosis, caused by the bacterium Mycobacterium tuberculosis (Mtb), remains a severe global health threat. The World Health Organization (WHO) has reported that tuberculosis is second only to COVID-19 as the most lethal infection worldwide, with more annual deaths than HIV and AIDS (WHO.int). The first-line treatment for tuberculosis, Rifampin (or Rifampicin), specifically targets the Mtb RNA polymerase. This drug has been used for decades, leading to increased numbers of multi-drug-resistant infections (Stephanie, et al). To effectively treat tuberculosis, there is an urgent need for new therapeutics that selectively target vulnerabilities of the bacteria and not the host. Characterization of the differences between Mtb enzymes and host enzymes is critical to inform these ongoing drug design efforts.

Long term safety and outcomes after atrial shunting for heart failure with preserved or mildly reduced ejection fraction: 5-year and 3-year follow-up in the REDUCE LAP-HF I and II trials.

BACKGROUND: There is a little evidence regarding long-term safety and efficacy for atrial shunt devices in heart failure (HF). METHODS: The REDUCE LAP-HF I (n = 44) and II (n = 621) trials (RCT-I and -II) were multicenter, randomized, sham-controlled trials of patients with HF and ejection fraction >40%. Outcome data were analyzed from RCT-I, a mechanistic trial with 5-year follow-up, and RCT-II, a pivotal trial identifying a responder group (n = 313) defined by exercise PVR <1.74 WU and no cardiac rhythm management device with 3-year follow-up. RESULTS: At 5 years in RCT I, there were no differences in cardiovascular (CV) mortality, HF events, embolic stroke, or new-onset atrial fibrillation between groups. After 3 years in RCT II, there was no difference in the primary outcome (hierarchical composite of CV mortality, stroke, HF events, and KCCQ) between shunt and sham in the overall trial. Compared to sham, those with responder characteristics in RCT-II had a better outcome with shunt (win ratio 1.6 [95% CI 1.2-2.2], P = .006; 44% reduction in HF events [shunt 9 vs. control 16 per 100 patient-years], P = .005; and greater improvement in KCCQ overall summary score [+17.9 ± 20.0 vs. +7.6 ± 20.4], P < .001), while nonresponders had significantly more HF events. Shunt treatment at 3 years was associated with a higher rate of ischemic stroke (3.2% vs. 0%, 95% CI 2%-6.1%, P = .032) and lower incidence of worsening kidney dysfunction (10.7% vs. 19.3%, P = .041). CONCLUSIONS: With up to 5 years of follow up, adverse events were low in patients receiving atrial shunts. In the responder group, atrial shunt treatment was associated with a significantly lower HF event rate and improved KCCQ compared to sham through 3 years of follow-up. GOV REGISTRATION: NCT02600234, NCT03088033.

Perceived Chronic Traumatic Encephalopathy and Suicidality in Former Professional Football Players.

Importance: Participation in American-style football (ASF) has been linked to chronic traumatic encephalopathy neuropathological change (CTE-NC), a specific neuropathologic finding that can only be established at autopsy. Despite being a postmortem diagnosis, living former ASF players may perceive themselves to have CTE-NC. At present, the proportion and clinical correlates of living former professional ASF athletes with perceived CTE who report suicidality are unknown. Objective: To determine the proportion, clinical correlates, and suicidality of living former professional ASF players with perceived CTE. Design, Setting, and Participants: A cross-sectional study within the Football Players Health Study at Harvard University was conducted from 2017 to 2020. Using electronic and paper surveys, this population-based study included former ASF players who contracted with a professional league from 1960 to 2020 and volunteered to fill out a baseline survey. Data for this study were analyzed from June 2023 through March 2024. Exposures: Data included demographics, football-related exposures (eg, position, career duration), and current health problems (anxiety, attention-deficit/hyperactivity disorder, depression, diabetes, emotional and behavioral dyscontrol symptoms, headache, hyperlipidemia, hypertension, low testosterone level, pain, sleep apnea, and subjective cognitive function). Main Outcomes and Measures: The proportion of participants reporting perceived CTE. Univariable and multivariable models were used to determine clinical and suicidality correlates of perceived CTE. Results: Among 4180 former professional ASF players who volunteered to fill out a baseline survey, 1980 (47.4%) provided follow-up data (mean [SD] age, 57.7 [13.9] years). A total of 681 participants (34.4%) reported perceived CTE. Subjective cognitive difficulties, low testosterone level, headache, concussion signs and symptoms accrued during playing years, depressive/emotional and behavioral dyscontrol symptoms, pain, and younger age were significantly associated with perceived CTE. Suicidality was reported by 171 of 681 participants with perceived CTE (25.4%) and 64 of 1299 without perceived CTE (5.0%). After adjusting for established suicidality predictors (eg, depression), men with perceived CTE remained twice as likely to report suicidality (odds ratio, 2.06; 95% CI, 1.36-3.12; P < .001). Conclusions and Relevance: This study found that approximately one-third of living former professional ASF players reported perceived CTE. Men with perceived CTE had an increased prevalence of suicidality and were more likely to have health problems associated with cognitive impairment compared with men without perceived CTE. Perceived CTE represents a novel risk factor for suicidality and, if present, should motivate the diagnostic assessment and treatment of medical and behavioral conditions that may be misattributed to CTE-NC.

Deterministic fabrication of graphene hexagonal boron nitride moiré superlattices.

The electronic properties of moiré heterostructures depend sensitively on the relative orientation between layers of the stack. For example, near-magic-angle twisted bilayer graphene (TBG) commonly shows superconductivity, yet a TBG sample with one of the graphene layers rotationally aligned to a hexagonal Boron Nitride (hBN) cladding layer provided experimental observation of orbital ferromagnetism. To create samples with aligned graphene/hBN, researchers often align edges of exfoliated flakes that appear straight in optical micrographs. However, graphene or hBN can cleave along either zig-zag or armchair lattice directions, introducing a [Formula: see text] ambiguity in the relative orientation of two flakes. By characterizing the crystal lattice orientation of exfoliated flakes prior to stacking using Raman and second-harmonic generation for graphene and hBN, respectively, we unambiguously align monolayer graphene to hBN at a near-[Formula: see text], not [Formula: see text], relative twist angle. We confirm this alignment by torsional force microscopy of the graphene/hBN moiré on an open-face stack, and then by cryogenic transport measurements, after full encapsulation with a second, nonaligned hBN layer. This work demonstrates a key step toward systematically exploring the effects of the relative twist angle between dissimilar materials within moiré heterostructures.

Grace periods in comparative effectiveness studies of sustained treatments.

Researchers are often interested in estimating the effect of sustained use of a treatment on a health outcome. However, adherence to strict treatment protocols can be challenging for individuals in practice and, when non-adherence is expected, estimates of the effect of sustained use may not be useful for decision making. As an alternative, more relaxed treatment protocols which allow for periods of time off treatment (i.e. grace periods) have been considered in pragmatic randomized trials and observational studies. In this article, we consider the interpretation, identification, and estimation of treatment strategies which include grace periods. We contrast natural grace period strategies which allow individuals the flexibility to take treatment as they would naturally do, with stochastic grace period strategies in which the investigator specifies the distribution of treatment utilization. We estimate the effect of initiation of a thiazide diuretic or an angiotensin-converting enzyme inhibitor in hypertensive individuals under various strategies which include grace periods.

Harnessing Compositional Gradients to Elucidate Phase Behaviors toward High Performance Polymer Semiconductor Blends.

Polymer semiconductor/insulator blends offer a promising avenue to achieve desired mechanical properties, environmental stability, and high device performance in organic field-effect transistors. A comprehensive understanding of process-structure-property relationships necessitates a thorough exploration of the composition space to identify transitions in performance, morphology, and phase behavior. Hence, this study employs a high-throughput gradient thin film library, enabling rapid and continuous screening of composition-morphology-device performance relationships in conjugated polymer blends. Applied to a donor-acceptor copolymer blend, this technique efficiently surveys a broad composition range, capturing trends in device performance across the gradient. Furthermore, characterizing the gradient library using microscopy and depth profiling techniques pinpointed composition-dependent transitions in morphology. To validate the results and gain deeper insights, uniform-composition experiments were conducted on select compositions within and outside the gradient range. Depth profiling experiments on the constant composition films unveil the presence of the semiconducting polymer at the air interface, with apparent enrichment of the semiconductor at the substrate interface at low ratios of the semiconducting component, transitioning to a more even distribution within the bulk of the film at higher ratios. The generalizability of the gradient approach was further confirmed by its application to a homopolymer under different solution processing conditions.

Strain surveillance during chemotherapy to improve cardiovascular outcomes: the SUCCOUR-MRI trial.

BACKGROUND AND AIMS: The detection of cancer therapy-related cardiac dysfunction (CTRCD) by reduction of left ventricular ejection fraction (LVEF) during chemotherapy usually triggers the initiation of cardioprotective therapy. This study addressed whether the same approach should be applied to patients with worsening of global longitudinal strain (GLS) without attaining thresholds of LVEF. METHODS: Strain sUrveillance during Chemotherapy for improving Cardiovascular Outcomes (SUCCOUR-MRI) was a prospective multicentre randomized controlled trial involving 14 sites. Of 355 patients receiving anthracyclines with normal baseline LVEF, 333 patients (age 59±13 years, 79% women) with at least one other CTRCD risk factor, able to undergo magnetic resonance imaging (MRI), GLS and 3D echocardiography were tracked over 12 months. A total of 105 patients (age 59±13 years, 75% women, 69% breast cancer) developing GLS-CTRCD (>12% relative reduction of GLS without a change in LVEF) between cardioprotection with neurohormonal antagonists versus usual care were randomized. The primary endpoint was 12-month change in MRI-LVEF; the secondary endpoint was MRI LVEF-defined CTRCD. RESULTS: During follow-up, 2 patients died and 2 developed heart failure. Most patients were randomized at 3 months (62%). Median doses of angiotensin inhibition/blockade and beta-blockade were 75% and 50% of respective targets; 21 (43%) had side-effects attributed to cardioprotection. Due to a smaller LVEF change from baseline with cardioprotection than usual care (-2.5±5.4% vs -5.6±5.9%, p=0.009), follow-up LVEF was higher after cardioprotection (59±5% vs 55±6%, p<0.0001). After adjustment for baseline LVEF, the mean (95% confidence interval) difference in the change in LVEF between the two groups was -3.6% (-1.8% to -5.5%, p<0.001). After cardioprotection, 1/49 patients developed 12-month LVEF-CTRCD, compared to 6/56 in usual care (p=0.075). GLS improved at 3 months post-randomization in the cardioprotection group, with little change with usual care. CONCLUSIONS: In patients with isolated GLS reduction after anthracyclines, cardioprotection is associated with better preservation of 12-month MRI-LVEF compared with usual care.