IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners.

BACKGROUND: The prevalence of tuberculosis among men who work in the gold mines of South Africa is among the highest in the world, but a fraction of miners demonstrate consistently negative results upon tuberculin skin test (TST) and IFN-γ release assay (IGRA). We hypothesized that these "resisters" (RSTRs) may display unconventional immune signatures of exposure to M. tuberculosis (M.tb). METHODS: In a cohort of RSTRs and matched controls with latent TB infection (LTBI), we profiled the functional breadth of M.tb antigen-specific T cell and antibody responses using multi-parameter flow cytometry and systems serology, respectively. FINDINGS: RSTRs and LTBI controls both exhibited IFN-γ independent T-cell and IgG antibody responses to M.tb-specific antigens ESAT-6 and CFP-10. Antigen-specific antibody Fc galactosylation and sialylation were higher among RSTRs. In a combined T-cell and antibody analysis, M.tb lysate-stimulated TNF secretion by T cells correlated positively with levels of purified protein derivative-specific IgG. A multivariate model of the combined data was able to differentiate RSTR and LTBI subjects. INTERPRETATION: IFN-γ independent immune signatures of exposure to M.tb, which are not detected by approved clinical diagnostics, are readily detectable in an occupational cohort uniquely characterized by intense and long-term infection pressure. Further, TNF may mediate a coordinated response between M.tb-specific T-cells and B-cells. FUNDING: This work was supported by the US National Institutes of Health (R01-AI124348 to Boom, Stein, and Hawn; R01-AI125189 and R01-AI146072 to Seshadri; and 75N93019C00071 to Fortune, Alter, Seshadri, and Boom), the Doris Duke Charitable Foundation (Davies), the Bill & Melinda Gates Foundation (OPP1151836 and OPP1109001 to Hawn; and OPP1151840 to Alter), Mass Life Science Foundation (Fortune), and Good Ventures Fund (Fortune).

Hybrid immunity expands the functional humoral footprint of both mRNA and vector-based SARS-CoV-2 vaccines.

Despite the successes of current coronavirus disease 2019 (COVID-19) vaccines, waning immunity, the emergence of variants of concern, and breakthrough infections among vaccinees have begun to highlight opportunities to improve vaccine platforms. Real-world vaccine efficacy studies have highlighted the reduced risk of breakthrough infections and diseases among individuals infected and vaccinated, referred to as hybrid immunity. Thus, we sought to define whether hybrid immunity shapes the humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) following Pfizer/BNT162b2, Moderna mRNA-1273, ChadOx1/AZD1222, and Ad26.COV2.S vaccination. Each vaccine exhibits a unique functional humoral profile in vaccination only or hybrid immunity. However, hybrid immunity shows a unique augmentation of S2-domain-specific functional immunity that was poorly induced for the vaccination only. These data highlight the importance of natural infection in breaking the immunodominance away from the evolutionarily unstable S1 domain and potentially affording enhanced cross-variant protection by targeting the more highly conserved S2 domain of SARS-CoV-2.

Soy isoflavones decrease fibroglandular breast tissue measured by magnetic resonance imaging in premenopausal women: A 2-year randomized double-blind placebo controlled clinical trial.

BACKGROUND & AIMS: Populations consuming soy have reduced risk for breast cancer, but the mechanisms are unclear. We tested the hypothesis that soy isoflavones, which have ovarian hormone-like effects, can reduce fibroglandular breast tissue (FGBT, 'breast density'), a strong risk marker for breast cancer. METHODS: Premenopausal women (age 30-42 years) were randomized to consume isoflavones (136.6 mg as aglycone equivalents, n = 99) or placebo (n = 98) for 5 days per week up to 2 years, and changes in breast composition measured by magnetic resonance imaging at baseline and yearly intervals were compared after square root transformation using linear mixed effects regression models. RESULTS: By intention-to-treat analyses (n = 194), regression coefficients (ß estimates) of the interaction of time and isoflavone treatment were -0.238 (P = 0.06) and -0.258 (P < 0.05) before and after BMI adjustment, respectively for FGBT, 0.620 (P < 0.05) and 0.248 (P = 0.160), respectively for fatty breast tissue (FBT), and -0.155 (P < 0.05) and -0.107 (P < 0.05), respectively for FGBT as percent of total breast (FGBT%). ß Estimates for interaction of treatment with serum calcium were -2.705 for FBT, and 0.588 for FGBT% (P < 0.05, before but not after BMI adjustment). BMI (not transformed) was related to the interaction of treatment with time (ß = 0.298) or with calcium (ß = -1.248) (P < 0.05). Urinary excretion of isoflavones in adherent subjects (n = 135) significantly predicted these changes in breast composition. Based on the modeling results, after an average of 1.2, 2.2 and 3.3 years of supplementation, a mean decrease of FGBT by 5.3, 12.1, and 19.3 cc, respectively, and a mean decrease of FGBT% by 1.37, 2.43, and 3.50%, respectively, were estimated for isoflavone exposure compared to placebo treatment. Subjects with maximum isoflavone excretion were estimated to have 38 cc less FGBT (or ∼3.13% less FGBT%) than subjects without isoflavone excretion. Decrease in FGBT and FGBT% was more precise with daidzein than genistein. CONCLUSIONS: Soy isoflavones can induce a time- and concentration-dependent decrease in FGBT, a biomarker for breast cancer risk, in premenopausal women, and moderate effects of calcium on BMI and breast fat, suggesting a beneficial effect of soy consumption. TRIAL REGISTRATION: www. CLINICALTRIALS: gov identifier: NCT00204490. TRIAL REGISTRATION: www. CLINICALTRIALS: gov identifier: NCT00204490.

Hybrid immunity expands the functional humoral footprint of both mRNA and vector-based SARS-CoV-2 vaccines

The COVID-19 pandemic catalyzed a revolution in vaccine development, leading to the testing and approval of several global vaccine platforms that have shown tremendous promise in curbing the pandemic. Yet, despite these successes, waning immunity, and the emergence of variants of concern linked to rising breakthrough infections among vaccinees, have begun to highlight opportunities to improve vaccine platforms and deployment. Real-world vaccine efficacy has highlighted the reduced risk of breakthrough infection and disease among individuals infected and vaccinated, otherwise referred to as hybrid immunity. Hybrid immunity points to the potential for more vigorous or distinct immunity primed by the infection and may confer enhanced protection from COVID-19. Beyond augmented hybrid induced neutralizing antibody and T cell immune responses, here we sought to define whether hybrid immunity may shape the functional humoral immune response to SARS-CoV-2 following Pfizer/BNT162b2 and Moderna mRNA1273 mRNA-based, and ChadOx1/AZ1222 and Ad26.COV2.S vector-based SARS-CoV-2 vaccination. Each vaccine exhibited a unique functional humoral immune profile in the setting of naive or hybrid immunity. However, hybrid immunity showed a unique augmentation in S2-domain specific functional humoral immunity that was poorly induced in the setting of naive immune response. These data highlight the immunodominant effect of the S1-domain in the setting of natural immunity, which is highly variable during viral evolution, and the importance of natural infection in breaking this immunodominance in driving immunity to the S2 region of the SARS-CoV-2 S2 domain that is more conserved across variants of concern.

Perspectives of internal medicine residency clinics: A national survey of US medical directors.

Background: Ambulatory training is an integral component of internal medicine residency programs, yet details regarding operational processes in resident continuity clinics remain limited. Methods: We surveyed a convenience sample of medical directors of residency practices between 2015 and 2019 (n = 222) to describe and share operational and scheduling processes in internal medicine resident continuity clinics in the US. Results: Among residency practices, support for the medical director role ranged substantially, but was most commonly reported at 11%-20% full-time-equivalent support. By the end of the survey period, the majority of programs (65.1%) reported obtaining patient-centered medical home (PCMH) certification (level 1-3). For new patient appointments, 34.9% of programs reported a 1-7 day wait and 25.8% reported an 8-14 day wait. Wait times for new appointments were generally shorter for PCMH certified practices (P = 0.029). No-show rates were most commonly 26%-50% for new patients and 11%-25% for established patients. Most programs reported that interns see 3-4 patients per ½-day and senior residents see 5-6 patients per ½-day. Most interns and residents maintain a panel size of 51-120 patients. Discussion: Creating high-performing residency clinics requires a focus on core building blocks and operational processes. Based on the survey results and consensus opinion, we provide five summary recommendations related to (1) support for the medical director leadership role, (2) patient-centered and coordinated models of care, (3) support for patient scheduling, (4) recommended visit lengths, and (5) ancillary support, such as social work.

Acute Lymphoblastic Leukemia Presenting Initially as Spinal Cord Compression: When Chemotherapy Alone Is Enough.

Spinal cord compression (SCC) is a rare initial presentation and complication of acute lymphoblastic leukemia (ALL) with nearly all reported cases occurring in the pediatric population. We report a 38-year-old previously healthy man who presented with acute on chronic lower back pain, gait instability, urinary retention, and severe thrombocytopenia. Radiologic examination revealed two soft tissue masses of the thoracic spine associated with compression fractures causing spinal canal narrowing and cord compression. Bone marrow biopsy confirmed the diagnosis of ALL. Immediate initiation of high-dose corticosteroids and systemic chemotherapy resolved the patient's symptoms without radiation therapy or surgical intervention. After two courses of chemotherapy, the patient achieved complete remission in the bone marrow. Rapid administration of chemotherapy alone in this case resulted in a complete resolution of SCC. Given the rarity of this complication in adults, no standardized treatment has been established. The success of this case recommends chemotherapy as the initial management of SCC in chemotherapy-naïve ALL.

Soy isoflavones interact with calcium and contribute to blood pressure homeostasis in women: a randomized, double-blind, placebo controlled trial.

BACKGROUND: Estrogens and calcium regulate vascular health but caused adverse cardiovascular events in randomized trials. OBJECTIVES: Whether phytoestrogenic soy isoflavones modulate the physiological effects of calcium on blood pressure was explored. DESIGN: A double-blind, randomized study assigned 99 premenopausal women to 136.6 mg isoflavones (as aglycone equivalents) and 98 to placebo for 5 days per week for up to 2 years. Blood pressure, serum calcium and urinary excretion of daidzein (DE) and genistein (GE) were measured repeatedly before and during treatment. RESULTS: Isoflavones did not affect blood pressure per intake dose assignment (i.e. intention-to-treat, n = 197), but significantly affected blood pressure per measured urinary excretion of isoflavones (i.e. per protocol analysis, n = 166). Isoflavones inversely moderated calcium effects on systolic blood pressure (SBP) (interaction term ß-estimates: - 3.1 for DE, - 12.86 for GE, all P < 0.05), and decreased diastolic blood pressure (DBP) (ß-estimates: - 0.84 for DE, - 2.82 for GE, all P < 0.05) after controlling for calcium. The net intervention effects between the maximum and no isoflavone excretion were - 17.7 and + 13.8 mmHg changes of SBP, respectively, at serum calcium of 10.61 and 8.0 mg/dL, and about 2.6 mmHg decrease of DBP. CONCLUSIONS: Moderation by isoflavones of the physiological effect of calcium tends to normalize SBP, and this effect is most significant when calcium concentrations are at the upper and lower limits of the physiological norm. Isoflavones decrease DBP independent of calcium levels. Further studies are needed to assess the impact of this novel micronutrient effect on blood pressure homeostasis and cardiovascular health. TRIAL REGISTRATION: www.clinicaltrials.gov identifier: NCT00204490.

Daidzein and genistein have differential effects in decreasing whole body bone mineral density but had no effect on hip and spine density in premenopausal women: A 2-year randomized, double-blind, placebo-controlled study.

Soy isoflavones are potentially beneficial phytoestrogens, but their tissue-selective effects in women are poorly understood. We tested the hypothesis that soy isoflavones affect bone mineral density (BMD), which may be influenced by individual differences in isoflavone metabolism and serum calcium levels. Ninety-nine healthy premenopausal women were randomized to isoflavones (136.6 mg aglycone equivalence) and 98 to placebo for 5 days per week for up to 2 years. BMD, serum calcium, and urinary excretion of daidzein and genistein were measured before and during treatment. In 129 adherent subjects, we found that isoflavone exposure, determined by urinary excretion levels, but not by dose assignment, interacted with serum calcium in affecting whole body BMD, but not hip and spine BMD. The regression coefficient was -0.042 for genistein excretion (GE) and 0.091 for the interaction between GE and serum calcium (all P < .05). Daidzein excretion had similar but marginal effect. Genistein significantly decreased whole body BMD only at low normal serum calcium levels but increased whole body BMD at higher serum calcium levels. Comparing maximum to minimum GE, mean changes in whole body BMD were +0.033 and -0.113 g/cm2 at serum calcium levels of 10 and 8.15 mg/dL, respectively. These associations were not evident by intention-to-treat analysis, which could not model for inter-individual differences in isoflavone metabolism. In summary, soy isoflavones decrease whole body BMD only when serum calcium is low. Isoflavones are dietary substances that may influence calcium homeostasis by releasing calcium from bone while sparing the common fracture risk sites hip and spine.

Cefazolin-Related Acute Interstitial Nephritis with Associated Nephrotic-Range Proteinuria: A Case Report.

A 67-year-old male with history of well controlled type 2 diabetes mellitus and hypertension developed acute interstitial nephritis (AIN) with nephrotic-range proteinuria during treatment with cefazolin for methicillin-sensitive Staphylococcus aureus and Group B Streptococcus (GBS) bacteremia. The patient received intravenous cefazolin 2 g every 8 h for 4 weeks prior to presentation to the emergency department with abdominal distension, nausea, and vomiting. Investigations revealed a serum ascites albumin gradient of 1.0 with total protein of 1.8 g/dL suggestive of nephrotic syndrome, which was confirmed with a spot urine protein/creatinine ratio that estimated 7.95 g of protein per day. Serum creatinine was elevated compared with baseline. Urine studies showed sterile pyuria with 3+ protein and eosinophiluria. The patient was diagnosed with AIN with nephrotic-range proteinuria associated with cefazolin use. Cefazolin was discontinued and, within a couple of days, the patient's creatinine stabilized. He was discharged with prednisone 60 mg once a day for 10 days with a taper over 2 weeks for his AIN. The patient's creatinine and proteinuria slowly decreased over the next couple of weeks, however, did not recover to baseline. A Naranjo assessment score of 6 was obtained, indicating a probable relationship between the patient's AIN with nephrotic-range proteinuria and his use of cefazolin.

Novel effects of phytoestrogenic soy isoflavones on serum calcium and chloride in premenopausal women: A 2-year double-blind, randomized, placebo-controlled study.

BACKGROUND: Soy phytoestrogens are potential alternatives to postmenopausal hormone replacement therapy (HRT). Adverse effects of HRT such as myocardial infarction, stroke, and pulmonary embolism are mediated by calcium-induced signaling. OBJECTIVE: To determine whether soy isoflavones affect serum calcium in healthy female subjects. DESIGN: In a double-blind trial, 197 premenopausal women were randomly assigned to either isoflavone (N = 99) or placebo pills (N = 98) 5 days per week for up to 2 years, plus prenatal vitamins. Isoflavone pills contained 60 mg genistein, 60 mg daidzein and 16.6 mg glycitein (expressed as aglycone equivalents). All pills contained 15 mg riboflavin as an adherence marker. Blood chemistries and urinary daidzein, genistein and riboflavin were measured multiple times during the luteal phase before and during treatment. RESULTS: Analysis of the adherent population (N = 83 per group), revealed significantly strong associations between urinary levels of isoflavones and serum concentrations of calcium (regression coefficients 0.082 for daidzein and 0.229 for genistein, all P < 0.01) and chloride (regression coefficient, -1.537 for genistein, P < 0.0001), mediated in part by albumin. The effects amounted to mean changes of +0.24 mg/dL for calcium and -1.45 mEq/L for chloride, with each visit for subjects excreting the most vs. the least amounts of isoflavones. These associations were not evident in the intention-to-treat analysis (N = 197) that did not assess expected variations in isoflavone levels within and between subjects from metabolism and adherence. CONCLUSIONS: These novel and strong effects of soy isoflavones on calcium homeostasis have important implications for long term effects of these natural substances on cardiovascular diseases.

Riboflavin as an independent and accurate biomarker for adherence in a randomized double-blind and placebo-controlled clinical trial.

BACKGROUND: Medication adherence is critical for success of clinical trials. OBJECTIVE: To assess oral riboflavin is an adherence marker. METHODS: Riboflavin was incorporated into active treatment and placebo pills for a clinical trial lasting for 2 years. RESULTS: The accuracy (area under the receiver operating curve) of urinary riboflavin was 0.91 as a binary classifier of adherence, and was similar or better than for two active study ingredients daidzein (0.92) and genistein (0.87) (all p < 0.0001). Decreased adherence over time was similar in the two study groups. CONCLUSION: Riboflavin is an accurate and useful biomarker for study pill ingestion.

Similarity of fibroglandular breast tissue content measured from magnetic resonance and mammographic images and by a mathematical algorithm.

Women with high breast density (BD) have a 4- to 6-fold greater risk for breast cancer than women with low BD. We found that BD can be easily computed from a mathematical algorithm using routine mammographic imaging data or by a curve-fitting algorithm using fat and nonfat suppression magnetic resonance imaging (MRI) data. These BD measures in a strictly defined group of premenopausal women providing both mammographic and breast MRI images were predicted as well by the same set of strong predictor variables as were measures from a published laborious histogram segmentation method and a full field digital mammographic unit in multivariate regression models. We also found that the number of completed pregnancies, C-reactive protein, aspartate aminotransferase, and progesterone were more strongly associated with amounts of glandular tissue than adipose tissue, while fat body mass, alanine aminotransferase, and insulin like growth factor-II appear to be more associated with the amount of breast adipose tissue. Our results show that methods of breast imaging and modalities for estimating the amount of glandular tissue have no effects on the strength of these predictors of BD. Thus, the more convenient mathematical algorithm and the safer MRI protocols may facilitate prospective measurements of BD.

Performance enhancement among adolescent players after 10 weeks of pitching training with appropriate baseball weights.

Compared with regulation-weight baseballs, lightweight baseballs generate lower torque on the shoulder and elbow joints without altering the pitching movement and timing. This study investigates the throwing accuracy, throwing velocity, arm swing velocity, and maximum shoulder external rotation (MSER) of adolescent players after 10 weeks of pitching training with appropriate lightweight baseballs. We assigned 24 adolescent players to a lightweight baseball group (group L) and a regulation-weight baseball group (group R) based on their pretraining throwing velocity. Both groups received pitching training 3 times per week for 10 weeks with 4.4- and 5-oz baseballs. The players' throwing accuracy, throwing velocity, arm swing velocity, and MSER were measured from 10 maximum efforts throws using a regulation-weight baseball before and after undergoing the pitching training. The results showed that the players in group L significantly increased their throwing velocity and arm swing velocity (p < 0.05) after 10 weeks of pitching training with the 4.4-oz baseball, whereas group R did not (p > 0.05). Furthermore, the percentage change in the throwing velocity and arm swing velocity of group L was significantly superior to that of group R (p < 0.05). Thus, we concluded that the 10 weeks of pitching training with an appropriate lightweight baseball substantially enhanced the arm swing velocity and throwing velocity of the adolescent baseball players. These findings suggest that using a lightweight baseball, which can reduce the risk of injury without altering pitching patterns, has positive training effects on players in the rapid physical growth and technique development stage.

Comparison of breast tissue measurements using magnetic resonance imaging, digital mammography and a mathematical algorithm.

Women with mostly mammographically dense fibroglandular tissue (breast density, BD) have a four- to six-fold increased risk for breast cancer compared to women with little BD. BD is most frequently estimated from two-dimensional (2D) views of mammograms by a histogram segmentation approach (HSM) and more recently by a mathematical algorithm consisting of mammographic imaging parameters (MATH). Two non-invasive clinical magnetic resonance imaging (MRI) protocols: 3D gradient-echo (3DGRE) and short tau inversion recovery (STIR) were modified for 3D volumetric reconstruction of the breast for measuring fatty and fibroglandular tissue volumes by a Gaussian-distribution curve-fitting algorithm. Replicate breast exams (N = 2 to 7 replicates in six women) by 3DGRE and STIR were highly reproducible for all tissue-volume estimates (coefficients of variation <5%). Reliability studies compared measurements from four methods, 3DGRE, STIR, HSM, and MATH (N = 95 women) by linear regression and intra-class correlation (ICC) analyses. Rsqr, regression slopes, and ICC, respectively, were (1) 0.76-0.86, 0.8-1.1, and 0.87-0.92 for %-gland tissue, (2) 0.72-0.82, 0.64-0.96, and 0.77-0.91, for glandular volume, (3) 0.87-0.98, 0.94-1.07, and 0.89-0.99, for fat volume, and (4) 0.89-0.98, 0.94-1.00, and 0.89-0.98, for total breast volume. For all values estimated, the correlation was stronger for comparisons between the two MRI than between each MRI versus mammography, and between each MRI versus MATH data than between each MRI versus HSM data. All ICC values were >0.75 indicating that all four methods were reliable for measuring BD and that the mathematical algorithm and the two complimentary non-invasive MRI protocols could objectively and reliably estimate different types of breast tissues.

Neurotoxicity associated with cancer therapy.

Neurologic complications can result from direct or indirect effects of cancer therapy. Treatment toxicity may affect both the central nervous system and the peripheral nervous system. Early recognition of these toxicities plays an important role in the management of patients with cancer.