Antigen-specific and cross-reactive T cells in protection and disease.

Human T cells have a diverse T-cell receptor (TCR) repertoire that endows them with the ability to identify and defend against a broad spectrum of antigens. The universe of possible antigens that T cells may encounter, however, is even larger. To effectively surveil such a vast universe, the T-cell repertoire must adopt a high degree of cross-reactivity. Likewise, antigen-specific and cross-reactive T-cell responses play pivotal roles in both protective and pathological immune responses in numerous diseases. In this review, we explore the implications of these antigen-driven T-cell responses, with a particular focus on CD8+ T cells, using infection, neurodegeneration, and cancer as examples. We also summarize recent technological advances that facilitate high-throughput profiling of antigen-specific and cross-reactive T-cell responses experimentally, as well as computational biology approaches that predict these interactions.

Quantitation of Nuclear Magnetic Resonance Spectra at Earth's Magnetic Field.

The inherently quantitative nature of nuclear magnetic resonance (NMR) spectroscopy is one of the most attractive aspects of this analytical technique. Quantitative NMR analyses have typically been limited to high-field (>1 T) applications. The aspects for quantitation at low magnetic fields (<1 mT) have not been thoroughly investigated and are shown to be impacted by the complex signatures that arise at these fields from strong heteronuclear J-couplings. This study investigates quantitation at Earth's magnetic field (∼50 µT) for a variety of samples in strongly, weakly, and uncoupled spin systems. To achieve accurate results in this regime, the instrumentation, experimental acquisition, processing, and theoretical aspects must be considered and reconciled. Of particular note is the constant field nuclear receptivity equation, which has been re-derived in this study to account for strong coupling and quality factor effects. The results demonstrate that the quantitation of homonuclear molecular groups, determination of heteronuclear pseudoempirical formulas, and mixture analysis are all feasible at Earth's magnetic field in a greatly simplified experimental system.

Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial.

BACKGROUND: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. METHODS: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. RESULTS: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.

The 1H T1 dispersion curve of fentanyl citrate to identify NQR parameters.

We report the 1H T1 dispersion curve between 0 and 5 â€‹MHz for the synthetic opioid fentanyl citrate (C28H36N2O8). The structures in the curve can be used to estimate the 14N nuclear quadrupole resonance (NQR) frequencies of the material. Density functional theory predictions of the NQR parameters of several fentanyl citrate compounds are also reported. The predictions for the aniline nitrogen are consistent with structures in the observed T1 data. To help interpret the fentanyl citrate results the T1 dispersion curve for the explosive ammonium nitrate is also presented.

Recurring Vivid Dreams in an Older Hmong Man With Complex Trauma Experience and Cognitive Impairment.

INTRODUCTION: Health care workers need to consider the culture and ethnic preferences prevalent in the Hmong community in order to provide optimal care. We describe an older Hmong man to illustrate the challenges faced and competencies needed by primary care. CASE PRESENTATION: An 80-year-old non-English speaking Hmong man with diabetes, nerve sheath tumor, and hypertension presented to the outpatient clinic with his grandson complaining of sleep problems. He had had 2 vivid recurring dreams during the previous few months. Memory assessment was significant for dementia. DISCUSSION: This case addresses the complexity in taking care of a non-English speaking Hmong older man who has memory loss, trauma in adulthood, multiple caregivers, and sleep problems. CONCLUSIONS: A careful history from patient and family to get to know their cultural preferences and attitudes was helpful. Identification of the primary caregiver was critical in providing care.

Quantification of skeletal metastases in castrate-resistant prostate cancer predicts progression-free and overall survival.

OBJECTIVE: To report a simplified and effective method for substratification of M1 castrate-resistant prostate cancer (CRPC) by correlating progression-free (PFS) and overall survival (OS) with simple quantification of skeletal metastases. PATIENTS AND METHODS: In all, 561 men with M1 CRPC were studied longitudinally. Individual bone scan disease burden, quantified by counting bone metastasis number, was correlated with clinical outcome using specific threshold points of 1-4, 5-20 and >20 detectable lesions. RESULTS: Patients with a higher metastasis number had a shorter PFS and OS (hazard ratio [HR] 2.0, 95% confidence interval [CI] 1.7-2.4; P < 0.001). Patients with 1-4 metastases had much better PFS and OS than those with 5-20 metastases. The median PFS and OS in the latter was 10.9 (95% CI 8.4-12.8) and 22.1 (95% CI: 18.5-24.5) months, respectively. PFS and OS for patients with >20 metastases were shorter still [median 5.3 (95% CI 3.4-6.9) months and 13.3 (95% CI 11.3-17.6) months, respectively]. Dichotomising into cohorts with 1-4 and ≥5 metastases, the latter group had considerably poorer PFS [8.4 (95% CI 6.8-10.3) months; P < 0.001) and OS [18.7 (95% CI 17.5-22.1) months; P < 0.001]. CONCLUSIONS: Dichotomising patients with CRPC into cohorts with 1-4 or ≥5 skeletal metastases identifies a better and a worse cohort in a manner that is easy and clinically accessible. This simple method facilitates disease stratification and patient management, enabling clinicians to counsel patients more effectively about long-term outcomes and to help select intervention therapies more effectively.

Metabolic disposition of AZD8931, an oral equipotent inhibitor of EGFR, HER2 and HER3 signalling, in rat, dog and man.

1. This series of studies in rats, dogs and humans (Clinicaltrials.gov identifier: NCT01284595) investigated the pharmacokinetics, tissue distribution, metabolism and excretion of the EGFR, HER2 and HER3 signalling inhibitor AZD8931. 2. Single oral or intravenous doses of 2-(4-[4-(3-chloro-2-fluoro[U-(14)C]-phenylamino)-7-methoxy-quinazolin-6-yloxy]-piperidin-1-yl)-N-methyl-acetamide difumarate ([(14)C]-AZD8931) were administered. 3. AZD8931 absorption was rapid in all species. Following [(14)C]-AZD8931 administration to rats, radioactivity was widely and rapidly distributed, with the highest levels in organs of metabolism and excretion (gastrointestinal tract, liver). Following oral and intravenous [(14)C]-AZD8931 administration, excretion of radioactivity by all species occurred predominantly via the bile into faeces, with <5% of the dose being eliminated in urine. In all species, AZD8931 was principally cleared by metabolism. The major route of metabolism was hydroxylation and O-demethylation in rat, and aryl ring oxidation in dog. Metabolism of AZD8931 in humans was attributed to three pathways; oxidation and amine or ether cleavage around the piperidine ring with subsequent glucuronide or sulphate conjugation. 4. AZD8931 is largely cleared by metabolism in the rat, dog and human. Excretory profiles indicate that there are no unique human metabolites.

Bilateral persistent sciatic artery with aneurysm formation and review of the literature.

Persistent sciatic artery (PSA) is an uncommon medical condition that can result in limb loss if it is not recognized or corrected. It is associated with 14% limb loss and 86% formation of aneurysm of the sciatic artery. In this study we describe a patient with bilateral persistent sciatic arteries associated with multiple aneurysms who presented with a large aneurysm formation and limb ischemia. The patient was treated with PSA embolization and exclusion of the aneurysm in the right leg with vein bypass. All reported cases in the English literature between 1965 and 2012 were reviewed and management options were compared.

Pituitary Disorders.

In this article, we will review common pituitary disorders. There are 6 hormones secreted by the anterior pituitary gland: thyroid-stimulating hormone, adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, growth hormone, and prolactin. The posterior pituitary gland stores and releases the hormones made in the hypothalamus, oxytocin and antidiuretic hormone, based on the body's needs. This article will discuss the role of these hormones, conditions and symptoms that occur with elevated or reduced hormone levels, as well as the evaluation and treatment of these pituitary disorders.

On the effects of quadrupolar relaxation in Earth's field NMR spectra.

There is growing interest in using low-field magnetic resonance experiments for routine chemical characterization. Earth's field NMR is one such technique that can garner structural information and enable sample differentiation with low cost and highly portable designs. The resulting NMR spectra are primarily influenced by J-couplings, resulting in so-called J-coupled spectra (JCS). Many small molecules include atoms with NMR-active nuclei that are quadrupolar either at natural abundance or are often isotopically enriched (e.g.,2H, 6Li, 11B, 14N, 17O, etc.) where the effects of quadrupolar J-couplings and relaxation on JCS of strongly- and weakly-coupled spin systems have not been explored to date. Herein, using a set of seven fluoropyridine samples with unique substitution and J-couplings, we demonstrate that the 14N relaxation rates can induce drastic line-broadening in the JCS. This includes a previously unexplored unique line broadening mechanism enabled by strongly coupled spins at low-field. Numerical simulations are used to model and refine the magnitudes and signs of J-couplings, as well as indirectly determine the 14N relaxation rates in a single 1D experiment that has a higher fidelity than observed in high-field NMR experiments.

Acupuncture in Sports Medicine.

Acupuncture is gaining popularity and wider acceptance as a treatment modality within the field of sports medicine. Our objective was to provide a comprehensive review of the existing literature pertaining to acupuncture in sports medicine to shed light on approaches utilized in acupuncture while revealing its personalized nature and its impact on athletes' preparation, performance, and recovery. We evaluated acupuncture research in the context of medicine and sports-related injury treatment, assessing its impact on athletic performance across demographics of athletes. Athletes participating in most sports have shown positive outcomes from acupuncture interventions. Acupuncture improves peak oxygen levels, maximum heart rate, delayed-onset muscle soreness, pain, swelling, explosive force production, and joint mobility. Furthermore, the efficacy of acupuncture appears to be similar regardless of age and sex. Lastly, the acceptance of acupuncture is influenced by cultural factors, with Western and traditional East Asian cultures exhibiting distinct perspectives on its rationale and mechanisms of action. Traditional East Asian acupuncturists typically employ qi and meridian theories in their acupuncture practices, with the recent incorporation of Western concepts. Acupuncture shows promise as an effective treatment for musculoskeletal pain and neuropathies in athletes across different age groups and for addressing injuries in various sports. Our comprehensive review will enhance our understanding of acupuncture's potential as a complementary or distinct therapeutic approach compared to conventional therapies. Additionally, our review explores its specific applications within different sports and delves into the cultural dimensions involved in integrating this practice into modern sports medicine.

Nuclear quadrupole resonance spectroscopy with a femtotesla diamond magnetometer.

Radio frequency (RF) magnetometers based on nitrogen vacancy centers in diamond are predicted to offer femtotesla sensitivity, but previous experiments were limited to the picotesla level. We demonstrate a femtotesla RF magnetometer using a diamond membrane inserted between ferrite flux concentrators. The device provides ~300-fold amplitude enhancement for RF magnetic fields from 70 kHz to 3.6 MHz, and the sensitivity reaches ~70 fT√s at 0.35 MHz. The sensor detected the 3.6-MHz nuclear quadrupole resonance (NQR) of room-temperature sodium nitrite powder. The sensor's recovery time after an RF pulse is ~35 µs, limited by the excitation coil's ring-down time. The sodium-nitrite NQR frequency shifts with temperature as -1.00±0.02 kHz/K, the magnetization dephasing time is T2*=887±51 µs, and multipulse sequences extend the signal lifetime to 332±23 ms, all consistent with coil-based studies. Our results expand the sensitivity frontier of diamond magnetometers to the femtotesla range, with potential applications in security, medical imaging, and materials science.

An electronic medical record-derived real-time assessment scale for hospital readmission in the elderly.

OBJECTIVE: "Readmission risk score", a 20-point, 4-dimensional tool, is generated from the electronic medical record. This study was performed to evaluate the ability of the readmission risk score to predict 30-day readmissions among older hospitalized patients. METHODS: A retrospective study was conducted utilizing data from the electronic medical record. Using a cutoff value of 7, the readmission score sensitivity was 61%, specificity was 22%, positive predictive value 12%, negative predictive value 77%. The positive and negative likelihood ratios were 0.8 and 1.8, respectively. CONCLUSION: The readmission risk score was associated with 30-day readmissions (median score of readmitted vs not readmitted patients was 8 vs. 5; P = 0.001), and it may be better at identifying those who are not at risk for readmission.

Can Variables From the Electronic Health Record Identify Delirium at Bedside?

Delirium, a common and serious disorder in older hospitalized patients, remains underrecognized. While several delirium predictive models have been developed, only a handful have focused on electronic health record (EHR) data. This prospective cohort study of older inpatients (≥65 years old) aimed to determine if variables within our health system's EHR could be used to identify delirium among hospitalized patients at the bedside. Trained researchers screened daily for delirium using the 3-minute diagnostic Confusion Assessment Method (3D-CAM). Patient demographic and clinical variables were extracted from the EHR. Among 408 participants, mean age was 75 years, 60.8% were female, and 82.6% were Black. Overall rate of delirium was 16.7%. Patients with delirium were older and more likely to have an infection diagnosis, prior dementia, higher Charlson comorbidity severity of illness score, lower Braden Scale score, and higher Morse Fall Scale score in the EHR (P<0.01 for all). On multivariable analysis, a prior diagnosis of dementia (odds ratio: 5.0, 95% CI: 2.5-10.3) and a Braden score of <18 (odds ratio: 2.8, 95% CI: 1.5-5.1) remained significantly associated with delirium among hospitalized patients. Further research in the development of an automated delirium prediction model is needed.

Tetramer-Associated T Cell Receptor Sequencing.

Linking antigen specificity to T cell receptor (TCR) sequences is critical, albeit challenging, to both understanding T cell biology and developing T cell-based therapeutics. Here, we describe in detail tetramer-associated TCR sequencing (TetTCR-Seq), a novel approach to tackling this challenge. TetTCR-Seq is accomplished by multiplexing DNA-barcoded peptide-MHC (pMHC) tetramers, allowing for simultaneous recall of antigen specificity and TCR sequences after single cell sequencing. Additionally, TetTCR-Seq simplifies labor and cuts cost by taking advantage of in vitro transcription and translation (IVTT) to generate peptide libraries and DNA barcodes, in parallel, from the same template. Thus, TetTCR-Seq is a powerful technology capable of quickly and affordably surveying the T cell repertoire for hundreds of antigen specificities in a single experiment.

The current landscape of Acute Care for Elders units in the United States.

BACKGROUND: The clinical benefits of Acute Care for Elders (ACE) units have been established for over 25 years. However, how widely disseminated ACE units are in the United States and the degree of fidelity to the key elements of this model of care are unknown. Our objective was to identify all existing ACE units in the United States and to obtain detailed information about variations in implementation. METHODS: The strategy to identify current ACE units began with online searches and snowball sampling using contacts from professional societies and workgroups. Next, a request for information regarding the existence of ACE units was sent to the remaining US hospitals listed in a national hospital database. An online survey was sent to identified ACE unit contacts to capture information on implementation characteristics and the five key elements of ACE units. RESULTS: There were 3692 hospitals in the database with responses from 2055 (56%) hospitals reporting the presence or absence of an ACE unit. We identified 68 hospitals (3.3%) with an existing or previous ACE unit. Of these 68 hospitals, 50 (74%) completed the survey and reported that 43 ACE units were currently open and 7 had been closed. Of the 43 currently open ACE units, most are affiliated with an academic hospital and there is variable implementation of each of the five key ACE elements (from 69% to 98%). CONCLUSIONS: Among the 50 hospitals to complete the survey, 43 current ACE units were identified, with variable fidelity to the key elements. Estimates of prevalence of ACE units and fidelity to key elements are limited by nonresponses to the national survey request by nearly half of hospitals.

Transcriptome and TCR Repertoire Measurements of CXCR3+ T Follicular Helper Cells Within HIV-Infected Human Lymph Nodes.

Follicular-helper T cells (TFH) are an essential arm of the adaptive immune system. Although TFH were first discovered through their ability to contribute to antibody affinity maturation through co-stimulatory interactions with B cells, new light has been shed on their ability to remain a complex and functionally plastic cell type. Due to a lack sample availability, however, many studies have been limited to characterizing TFH in mice or non-canonical tissue types, such as peripheral blood. Such constraints have resulted in a limited, and sometimes contradictory, understanding of this fundamental cell type. One subset of TFH receiving attention in chronic infection are CXCR3-expressing TFH cells (CXCR3+TFH) due to their abnormal accumulation in secondary lymphoid tissues. Their function and clonal relationship with other TFH subsets in lymphoid tissues during infection, however, remains largely unclear. We thus systematically investigated this and other subsets of TFH within untreated HIV-infected human lymph nodes using Mass CyTOF and a combination of RNA and TCR repertoire sequencing. We show an inflation of the CXCR3+TFH compartment during HIV infection that correlates with a lower HIV burden. Deeper analysis into this population revealed a functional shift of CXCR3+TFH away from germinal center TFH (GC-TFH), including the altered expression of several important transcription factors and cytokines. CXCR3+TFH also upregulated cell migration transcriptional programs and were clonally related to peripheral TFH populations. In combination, these data suggest that CXCR3+TFH have a greater tendency to enter circulation than their CXCR3- counterparts, potentially functioning through distinct modalities that may lead to enhanced defense.

Pediatric Office Procedures.

Pediatric patients are frequently evaluated in primary care clinics. Thus, there exists a need to understand common pediatric problems and to acquire a degree of familiarity with pediatric procedures. This article will review techniques and the current evidence for frequently performed pediatric procedures, including umbilical granuloma chemocautery, frenotomy, suture ligation of type B postaxial polydactyly, reduction of nursemaid's elbow, hair tourniquet removal, and tympanometry.

Prevalence of high-risk medications in patients enrolled in the Hospital Elder Life Program.

OBJECTIVE: The study aimed to assess the prevalence of newly prescribed antipsychotic/benzodiazepine medication, as well as 30-day readmissions, among Hospital Elder Life Program (HELP)-enrolled patients. DESIGN: Retrospective case-control study. SETTING: HELP intervention took place in eight hospital units. The standard care group was selected from eight additional hospital units. PARTICIPANTS: Hospitalized patients, aged 65 years and older, enrolled in HELP during between January 1, 2017 to December 31, 2018 were included in the HELP cohort. Patients hospitalized in eight additional units during the same time frame were part of the standard care group. MEASUREMENTS: Antipsychotic/benzodiazepine medications were pulled from the electronic health record. History of chronic mental illnesses were classified by ICD10 codes. Basic descriptive statistics were used to analyze patient characteristics and comorbidities. Chi-squared and t-tests were performed to detect statistical differences as appropriate. RESULTS: There were 1411 patients in the HELP group and 10,807 patients in the standard care group. The HELP group was likely to be older, female and to have a shorten length of stay (all p ≤ 0.02). Our study demonstrated that approximately 8.9% (n = 125) of patients enrolled in HELP received an order for antipsychotics during their hospital admission, while 31.5% (n = 3400) from the standard care group (p < 0.001). The difference in benzodiazepine prescription in patients enrolled in HELP was also less when comparing the two groups (22.8% HELP vs 25.6% standard care; p = 0.02). CONCLUSIONS: Patients enrolled in the HELP group were less likely to receive a prescription for antipsychotics or benzodiazepines. The majority of patients enrolled in HELP were discharged to a more independent environment (home or assisted living) and there was a relatively low 30-day readmission rate among HELP patients.