Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor.

During mammalian ontogeny, haematopoietic stem cells (HSCs) translocate from the fetal liver to the bone marrow, where haematopoiesis occurs throughout adulthood. Unique features of bone that contribute to a microenvironmental niche for stem cells might include the known high concentration of calcium ions at the HSC-enriched endosteal surface. Cells respond to extracellular ionic calcium concentrations through the seven-transmembrane-spanning calcium-sensing receptor (CaR), which we identified as being expressed on HSCs. Here we show that, through the CaR, the simple ionic mineral content of the niche may dictate the preferential localization of adult mammalian haematopoiesis in bone. Antenatal mice deficient in CaR had primitive haematopoietic cells in the circulation and spleen, whereas few were found in bone marrow. CaR-/- HSCs from fetal liver were normal in number, in proliferative and differentiative function, and in migration and homing to the bone marrow. Yet they were highly defective in localizing anatomically to the endosteal niche, behaviour that correlated with defective adhesion to the extracellular matrix protein, collagen I. CaR has a function in retaining HSCs in close physical proximity to the endosteal surface and the regulatory niche components associated with it.

Social Determinants and COVID-19 in a Community Health Center Cohort.

Associations between social determinants of health (SDOH), demographic factors including preferred language, and SARS-CoV-2 detection are not clear. We conducted a retrospective cohort study among those seeking testing for SARS-CoV-2 at a multi-site, urban community health center. Logistic regression and exact matching methods were used to identify independent predictors of SARS-CoV-2 detection among demographic, SDOH, and neighborhood-level variables. Of 1,361 included individuals, SARS-CoV-2 was detected among 266 (19.5%). Logistic regression demonstrated that SARS-CoV-2 detection was less likely in White participants relative to Hispanic participants (adjusted odds ratio [aOR] 0.18, 95% confidence interval [CI] 0.05-0.46). and more likely in patients who prefer Spanish relative to those that prefer English (aOR 2.04, 95% CI 1.43-2.96). No observed SDOH predicted SARS-CoV-2 detection in adjusted models. A robustness analysis using a matched subset of the study sample produced findings similar to those in the main analysis. Preferring to receive care in Spanish is an independent predictor of SARS-CoV-2 detection in a community health center cohort.

The residency application abyss: insights and advice.

Most medical students apply for residency training upon completion of medical school. The choice of specialty is one of a student's first major career decisions, and the application process often results in considerable anxiety, as it is competitive, unpredictable, and requires a significant investment of time and money. This article, which addresses several important facets of the residency application using both experiential and evidence-based data, is organized chronologically into sections that describe a logical approach to applying for residency: choice of a specialty, the personal statement, the interview day, and developing a rank list. A list of relevant websites is also included. This paper is a resource that provides timely and tangible guidance to medical students applying for residency training.

Screening for Social Determinants of Health Among Children: Patients' Preferences for Receiving Information to Meet Social Needs and a Comparison of Screening Instruments.

To characterize optimal strategies for screening for social determinants of health (SDOH) among children, the authors performed a cross-sectional study of parents and adolescents ages ≥13 years in a community health center. Participants were queried about how they prefer to receive information about social needs resources and 2 screening instruments were compared: Well Child Care, Evaluation, Community Resources, Advocacy, Referral, Education (WE CARE) and Accountable Health Communities (AHC). In July 2019, 154 parents and 21 adolescents were surveyed. Surveys were administered via tablet and required 5.6 minutes (standard deviation [SD] 3.9 minutes) for parents and 3.9 minutes (SD 1.4 minutes) for adolescents to complete. Parents identified technology (text message, email) and informational printouts as preferred mechanisms for information receipt (58% and 32% of participants, respectively); adolescents preferred text message (57%) and printouts (19%). Few (<10% overall) preferred in-person consultation with a care coordinator. Adolescent/parent pairs (n = 19 pairs) agreed, on average across SDOH, 82% of the time for WE CARE and 85% for AHC. AHC elicited more positive screens than WE CARE for housing insecurity (12% of parents versus 7%) and food insecurity (47% versus 16%) but fewer positive screens than WE CARE for difficulties paying for utilities (27% versus 39%). Routine screening for SDOH in children requires 2-3 minutes per screening instrument. Screening can target parents of young children and either adolescents themselves or their parents. Families prefer to receive information about meeting social needs via technologically-based methods as opposed to in-person consultation with enabling services providers.

Construction of a Pediatrics Risk Score to Predict High Health Care Costs Among a Community Health Center Cohort.

Risk-stratification strategies are needed for ambulatory pediatric populations. The authors sought to develop age-specific risk scores that predict high health care costs among an urban population. A retrospective cohort study was performed of children ages 1-18 years who received care at Fair Haven Community Health Care (FHCHC), a community health center in New Haven, Connecticut. Cost was estimated from charges in the electronic health record (EHR), which is shared with the only hospital system in the city. Using multivariable logistic regression models, independent predictors of being in the top decile of total charges during the 2017 calendar year were identified, drawing from covariates collected from the EHR prior to 2017. Random forest modeling was used to verify the feature importance of significant covariates and model performance from 2017 cost data were compared to those using 2018 cost data. Regression models were used to construct age-specific nomograms to predict cost. Among 8960 children who received care at FHCHC in the 18 months prior to 2017, covariate frequencies clustered in age groups 1-5 years, 6-11 years, and 12-18 years, so 3 age-specific models were constructed. Prior utilization variables predicted future costs, as did younger children who received specialty care and older children with behavioral health diagnoses. Final models for each age group had C statistics ≥0.68 using both 2017 and 2018 cost data. Prediction models can draw from elements accessible in the EHR to predict cost of ambulatory pediatric patients. Strategies to impact utilization among high-risk children are needed.

Limited T cell receptor diversity of HCV-specific T cell responses is associated with CTL escape.

Escape mutations are believed to be important contributors to immune evasion by rapidly evolving viruses such as hepatitis C virus (HCV). We show that the majority of HCV-specific cytotoxic T lymphocyte (CTL) responses directed against viral epitopes that escaped immune recognition in HCV-infected chimpanzees displayed a reduced CDR3 amino acid diversity when compared with responses in which no CTL epitope variation was detected during chronic infection or with those associated with protective immunity. Decreased T cell receptor (TCR) CDR3 amino acid diversity in chronic infection could be detected long before the appearance of viral escape mutations in the plasma. In both chronic and resolved infection, identical T cell receptor clonotypes were present in liver and peripheral blood. These findings provide a deeper understanding of the evolution of CTL epitope variations in chronic viral infections and highlight the importance of the generation and maintenance of a diverse TCR repertoire directed against individual epitopes.

A fatal case of paraquat ingestion: clinical course and review of pathophysiology.

BACKGROUND: Exposure to the dipyridyl herbicide paraquat can cause many manifestations of toxicity, and is a common method of suicide in developing countries. CASE REPORT: We present a case of a 20 year old healthy gentleman who intentionally overdosed on paraquat in a suicide attempt. He presented to the hospital within 4 hours of ingestion. Despite standard supportive measures, the patient's clinical condition worsened. He developed ulceration of his oral mucosa. He also developed acute non-oliguric renal failure and acute liver injury. After his mental status began to deteriorate, the patient expired. CONCLUSIONS: There are several therapies that may have helped this patient's condition. An explanation about the pathophysiology of toxicity and updated information on treatment is provided for this common condition with poor prognosis.

The Association of Loneliness and Non-prescribed Opioid Use in Patients With Opioid Use Disorder.

OBJECTIVE: To investigate the relationship between loneliness and non-prescribed opioid use in patients diagnosed with opioid use disorder (OUD). METHODS: This was a cohort study conducted at a federally qualified health center (FQHC) in New Haven, CT. Patients who were treated for OUD by health center providers and prescribed buprenorphine were eligible. Participants were asked to complete the UCLA-Loneliness Scale Version 3. From the electronic medical record, we collected patient demographic and clinical characteristics as well as the results of biological fluid testing obtained throughout their treatment course since entry into care. Multivariable logistic regression was performed to identify independent predictors of the detection of non-prescribed opioids within biological fluid. RESULTS: Of the 82 patients enrolled in the study, 33 (40.3%) of the participants had at least 1 biological fluid test positive for non-prescribed opioids after maintenance onto buprenorphine treatment. A higher loneliness score was associated with increased odds of non-prescribed opioids (adjusted odds ratio 1.16; 95% confidence interval 1.06-1.27). Patient age, the number of problems on the problems list, and cocaine use were also positively associated with the presence of non-prescribed opioids whereas having diabetes was negatively associated. CONCLUSIONS: Among the individuals being treated with buprenorphine for OUD, loneliness may be a risk factor for the use of non-prescribed opioids or treatment failure.

Thymocyte emigration is mediated by active movement away from stroma-derived factors.

T cells leave the thymus at a specific time during differentiation and do not return despite elaboration of known T cell chemoattractants by thymic stroma. We observed differentiation stage-restricted egress of thymocytes from an artificial thymus in which vascular structures or hemodynamics could not have been playing a role. Hypothesizing that active movement of cells away from a thymic product may be responsible, we demonstrated selective reduction in emigration from primary thymus by inhibitors of active movement down a concentration gradient (chemofugetaxis). Immature intrathymic precursors were insensitive to an emigration signal, whereas mature thymocytes and peripheral blood T cells were sensitive. Thymic stroma was noted to elaborate at least two proteins capable of inducing emigration, one of which was stromal cell-derived factor-1. Thymic emigration is mediated, at least in part, by specific fugetaxis-inducing factors to which only mature cells respond.

Cutaneous extensively drug-resistant tuberculosis.

A 48-year-old immunocompetent man without known exposure to tuberculosis had a > 10-year history of recurrent skin lesions. Cutaneous tuberculosis without any current or past history of pulmonary tuberculosis was diagnosed. Culture of biopsy specimens showed the organism to be resistant to multiple first-line and second-line agents. The patient had a broad, vigorous CD4-specific immune response against multiple tuberculosis antigens. This case is the first report of cutaneous extensively drug-resistant tuberculosis.

The prognostic significance of P-glycoprotein, multidrug resistance-related protein 1 and lung resistance protein in pediatric acute lymphoblastic leukemia: a retrospective study of 295 newly diagnosed patients by the Children's Oncology Group.

Multidrug resistance (MDR) is a phenomenon by which cells become resistant to an array of structurally unrelated chemotherapeutic agents. The prognostic value that P-glycoprotein (Pgp), multidrug resistance-related protein 1 (MRP1), and lung resistance protein (LRP) have in the setting of pediatric acute lymphoblastic leukemia (ALL) is controversial. In a retrospective study, we analyzed samples obtained from 295 similarly treated pediatric ALL patients to assess whether the overexpression and/or function of these proteins at diagnosis affects outcome. Most patients (70%, 207/295) did not overexpress an MDR protein. A small number of patients expressed functional Pgp (1%, 3/295) and some overexpressed functional MRP1 (10%, 19/295), with a statistically significant number of the latter being of T-lineage as opposed to pre-B (P < 0.001). A small number of patients (2%, 6/295) also overexpressed both Pgp and MRP1. Additional patients expressed increased levels of LRP. Elevated levels of these proteins at diagnosis did not correlate with risk factors and did not predict an adverse prognosis. Life-table estimates and Kaplan-Meier plots did not show any significant differences between patients who overexpressed an MDR protein compared with those who did not, nor was any difference noted when the different MDR + groups were compared with one another. These data strongly support the conclusion that the overexpression of these functional drug efflux pumps at diagnosis does not contribute to treatment failure in pediatric ALL.

Geographic Localization of Housestaff Inpatients Improves Patient-Provider Communication, Satisfaction, and Culture of Safety.

This study assesses whether geographic localization of housestaff patients contributes to improved patient knowledge of diagnosis, patient satisfaction, provider satisfaction, and workplace culture of safety. Due to national changes to graduate medical education, housestaff patients were localized to a single general medicine ward. Ninety-three patients prelocalization, 64 patients postlocalization, 26 localized physicians, and 10 localized nurses were surveyed. Validated questionnaires assessed patients' experiences during hospitalization, and physician and nurse job satisfaction. Fifty-seven percent of patients knew their diagnosis prior to localization, compared to 80% postlocalization (p < .0001). Prior to localization, 39% of patients who reported experiencing anxieties or fears during hospitalization felt physicians frequently discussed these emotions with them compared to 85% after localization (p < .0001). Before localization, 51% of patients stated that doctors spent 4 min or more daily with them discussing care, compared to 91% after localization (p < .0001). Both physician and nurse opinion significantly improved regarding some but not all aspects of collaboration, teamwork, patient safety, appropriate handling of errors, and culture of safety. The average length of stay was unchanged and the change in 30-day readmission rate was not statistically significant. Localization of patients to a single inpatient ward improved patient knowledge and satisfaction, and some aspects of interprofessional communication and workplace culture of safety.

The protease inhibitor ritonavir inhibits the functional activity of the multidrug resistance related-protein 1 (MRP-1).

BACKGROUND: Efflux pumps situated on the plasma membrane, such as P-glycoprotein (Pgp) and the multidrug resistance related-protein 1 (MRP-1), have been shown to extrude HIV protease inhibitors from the cell. MRP-1 is present on many barrier sites throughout the body, such as the blood-brain and blood-testis interfaces and could reduce the concentration of protease inhibitors in these sanctuary sites for HIV-1 replication. Factors that modulate efflux pump function in vivo are poorly defined. OBJECTIVE: To analyze the inhibitory potential of the anti-retroviral drugs indinavir, amprenavir, ritonavir, lamivudine or zidovudine to modulate MRP-1 function. METHODS: Effect of anti-HIV drugs on the efflux pump activity of MRP-1 was evaluated in the presence of increasing concentrations of human plasma, using UMCC-1/VP cells which stably over-express MRP-1. MRP-1 activity was abrogated by probenecid. The potential of blocking MRP-1 function for an extended (3 day) time period, was also examined in MRP-1 over-expressing cells cultured with either probenecid or the anti-retroviral drugs and a cytotoxic compound (etoposide) that is transported by MRP-1. RESULTS: Ritonavir inhibited the functional activity of MRP-1 similarly to probenecid, as demonstrated by re-sensitization of MRP-1 over-expressing cells to cytotoxic effects of etoposide. Inhibition by ritonavir was inversely related to the concentration of human plasma added to the cells (r2 = 0.89). Other anti-HIV drugs didn't affect the MRP-1 mediated efflux of etoposide. CONCLUSIONS: These data may be exploitable to further improve sanctuary site concentrations of anti-HIV or anti-cancer drugs by using ritonavir as a lead compound to develop more potent MRP-1 inhibitors.

Association of patient recognition of inpatient physicians with knowledge and satisfaction.

Patient recognition of hospital providers is low and may affect patient knowledge and satisfaction with care. Our study aimed to determine the association between patient knowledge of their inpatient providers' face, name, or role with knowledge of their diagnosis, satisfaction with care, and 30-day readmission rate. We conducted a cross-sectional survey of inpatients discharged from medicine housestaff teams from 2008 to 2009. Patients identified providers by face, name, and role and stated their reason for hospitalization. The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey assessed patient satisfaction with care. Eighty-nine of 95 patients (94%) participated. Seventy-five percent of patients recognized one provider face, 28% knew at least one provider name, and 21% correctly stated provider roles. Fifty-seven percent of patients knew their diagnosis. Satisfaction with care via HCAHPS varied: 78% always felt treated with courtesy and respect; 75% felt doctors always listened; and 67% felt complete involvement in care decisions. In bivariate and multivariate analyses, knowledge of providers by face, name, or role was not associated with knowledge of diagnosis, satisfaction, or 30-day readmission rates (all p>.05). Thus, patient recognition of providers was not associated with their knowledge, satisfaction, or readmission.