Morphine produces immunosuppressive effects in nonhuman primates at the proteomic and cellular levels.

Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. To explore how these changes interact with lentiviral infections in vivo, animals from two nonhuman primate species (African green monkeys and pigtailed macaques) were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g. lymph node, colon, cerebrospinal fluid, and peripheral blood) before and after the administration of morphine (titrated up to a maximum dose of 5 mg/kg over a period of 20 days). Cellular immune, plasma cytokine, and proteome changes were measured and morphine-induced changes in these parameters were assessed on an interorgan, interindividual, and interspecies basis. In both species, morphine was associated with decreased levels of Ki-67(+) T-cell activation but with only minimal changes in overall T-cell counts, neutrophil counts, and NK cell counts. Although changes in T-cell maturation were observed, these varied across the various tissue/fluid compartments studied. Proteomic analysis revealed a morphine-induced suppressive effect in lymph nodes, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have direct relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the potential interplay between opioid abuse and the immunological response to an infective agent.

Levels of circulating myeloid subpopulations and of heme oxygenase-1 do not predict CD4(+) T cell recovery after the initiation of antiretroviral therapy for HIV disease.

The level (or frequency) of circulating monocyte subpopulations such as classical (CD14(hi)CD16(-)) and non-classical (CD14(dim)CD16(+)) monocytes varies during the course of HIV disease progression and antiretroviral therapy (ART). We hypothesized that such variation and/or differences in the degree to which these cells expressed the immunoregulatory enzyme, heme oxygenase-1 (HO-1), would be associated with CD4(+) T cell recovery after the initiation of ART. This hypothesis was tested in a cross-sectional study of four groups of HIV-infected subjects, including those who were seronegative, untreated virologic controllers [detectable viral load (VL) of <1000 copies/mL], untreated virologic non-controllers [VL > 10,000 copies/mL], and ART-mediated virologic controllers [VL < 75 copies/mL]. A longitudinal analysis of ART-treated subjects was also performed along with regression analysis to determine which biomarkers were associated with and/or predictive of CD4(+) T cell recovery. Suppressive ART was associated with increased levels of classical monocyte subpopulations (CD14(hi)CD16(-)) and decreased levels of non-classical monocyte populations (CD14(dim)CD16(+)). Among peripheral blood mononuclear cells (PBMCs), HO-1 was found to be most highly up-regulated in CD14(+) monocytes after ex vivo stimulation. Neither the levels of monocyte subpopulations nor of HO-1 expression in CD14(+) monocytes were significantly associated with the degree of CD4(+) T cell recovery. Monocyte subpopulations and HO-1 gene expression were, however, restored to normal levels by suppressive ART. These results suggest that the level of circulating monocyte subpopulations and their expression of HO-1 have no evident relationship to CD4(+) T cell recovery after the initiation of ART.

Characterizing patients hospitalized without an acute care indication: A retrospective cohort study.

BACKGROUND: Hospitalizations by patients who do not meet acute inpatient criteria are common and overburden healthcare systems. Studies have characterized these alternate levels of care (ALC) but have not delineated prolonged (pALC) versus short ALC (sALC) stays. OBJECTIVE: To descriptively compare pALC and sALC hospitalizations-groups we hypothesize have unique needs. DESIGNS, SETTINGS, AND PARTICIPANTS: A retrospective study of hospitalizations from March-April 2018 at an academic safety-net hospital. MAIN OUTCOME AND MEASURES: Levels of care for pALC (>3 days) and sALC (1-3 days) were determined using InterQual©, an industry standard utilization review tool for determining the clinical appropriateness of hospitalization. We examined sociodemographic and clinical characteristics. RESULTS: Of 2365 hospitalizations, 215 (9.1%) were pALC, 277 (11.7%) were sALC, and 1873 (79.2%) had no ALC days. There were 17,683 hospital days included, and 28.3% (n = 5006) were considered ALC. Compared to patients with sALC, those with pALC were older and more likely to be publicly insured, experience homelessness, and have substance use or psychiatric comorbidities. Patients with pALC were more likely to be admitted for care meeting inpatient criteria (89.3% vs. 66.8%, p < .001), had significantly more ALC days (median 8 vs. 1 day, p < .001), and were less likely to be discharged to the community (p < .001). CONCLUSIONS: Patients with prolonged ALC stays were more likely to be admitted for acute care, had greater psychosocial complexity, significantly longer lengths of stay, and unique discharge needs. Given the complexity and needs for hospitalizations with pALC days, intensive interdisciplinary coordination and resource mobilization are necessary.

By the Light of Day: Quality, Safety, and Education During the Overnight Admission Handoff.

Background Current duty hour restrictions have led to increased patient handoffs as well as increased use of faculty in the nocturnist role. Nocturnists typically supervise residents and perform direct patient care leading to a diversity of provider experience level during morning handoffs. In this study, we explored how the presence of nocturnists impacts perceptions patient safety, quality, and educational value of morning care transitions. Methods We performed a cross-sectional survey examining the housestaff and attending perceptions of the morning sign-out of overnight admissions from both night float residents and nocturnists in July of 2016. Survey responses were Likert-style format, querying respondents' level of agreement (1-5, strongly disagree to strongly agree) with statements. 108 providers responded (41% response rate) Results Relative to attendings, residents reported feeling like they had less time to ask questions (4.0 vs. 5.0, p < 0.001) and felt less comfortable asking questions of the nocturnist during handoff (4.0 vs. 5.0, p < 0.001). Residents were also less comfortable than attendings in changing a nocturnist's plan of care (4.0 vs. 5.0, p < 0.001). Housestaff reported that receiving signout from the overnight resident was more likely to improve their confidence managing similar conditions (4.0 vs. 3.0, p < 0.001). Conclusion The benefits of nocturnist supervision may come at an educational cost as trainees feel less comfortable asking questions or changing the plan of care. With increasingly prevalent night float systems and nocturnist providers, academic programs have to negotiate the balancing safe and high-quality patient care with creating positive learning environments and clear expectations.

Acute Care for Patients Who Are Incarcerated: A Review.

IMPORTANCE: The United States has the world's highest rate of incarceration. Clinicians practicing outside of correctional facilities receive little dedicated training in the care of patients who are incarcerated, are unaware of guidelines for the treatment of patients in custody, and practice in health care systems with varying policies toward these patients. This review considers legal precedents for care of individuals who are incarcerated, frequently encountered terminology, characteristics of hospitalized incarcerated patients, considerations for clinical management, and challenges during transitions of care. OBSERVATIONS: The Eighth Amendment of the US Constitution mandates basic health care for incarcerated individuals within or outside of dedicated correctional facilities. Incarcerated patients in the acute hospital setting are predominantly young men who have received trauma-related admitting diagnoses. Hospital practices pertaining to privacy, physical restraint, discharge counseling, and surrogate decision-making are affected by a patient's incarcerated status under state or federal law, institutional policy, and individual health care professional practice. Transitions of care necessitate consideration of the disparate medical resources of correctional facilities as well as awareness of transitions unique to incarcerated individuals, such as compassionate release. CONCLUSIONS AND RELEVANCE: Patients who are incarcerated have a protected right to health care but may experience exceptions to physical comfort, health privacy, and informed decision-making in the acute care setting. Research on the management of issues associated with hospitalized incarcerated patients is limited and primarily focuses on the care of pregnant women, a small portion of all hospitalized incarcerated individuals. Clinicians and health care facilities should work toward creating evidence-based and legally supported guidelines for the care of incarcerated individuals in the acute care setting that balance the rights of the patient, responsibilities of the clinician, and safety mandates of the institution and law enforcement.

Acute Clinical Care for Transgender Patients: A Review.

Importance: Transgender is an umbrella term used to describe individuals whose gender identity and/or gender expression differs from assigned sex at birth. There are an estimated 1.4 million transgender adults in the United States, and this number is increasing. Clinicians will increasingly be caring for transgender patients. Topics considered in this narrative review include terminology, how to address transgender patients, obtaining an inclusive history that takes into account gender-affirming surgery, managing hormone therapy and other clinical issues, consideration for hospitalized patients, interpreting laboratory values in the setting of hormone use, legal issues, and considerations for health systems. Observations: Best practices in caring for a transgender patient include using a patient-identified name and pronoun, using gender-neutral terminology until the appropriate term is identified by the patient, and obtaining a surgical history inclusive of an anatomic inventory. Gender-affirming hormones can modify disease-specific risk factors or confer risk for in-hospital complications. They can also cause changes in laboratory values; however, studies are limited to observational studies and case series. Some data are derived and extrapolated from cisgender populations. There are also unique systems-based concerns, including lack of procedures for standardized collection of gender identity and lack of sufficiently comprehensive electronic health record platforms. Vulnerabilities exist for hospitalized transgender patients in the transition from the inpatient to outpatient care that require dedicated institutional efforts to address. Conclusions and Relevance: Clinicians should learn how to engage with transgender patients, appreciate that unique anatomy or the use of gender-affirming hormones may affect the prevalence of certain disease (eg, cardiovascular disease, venous thromboembolism, and osteoporosis), and be prepared to manage specific issues, including those related to hormone therapy. Health care facilities should work toward providing inclusive systems of care that correctly identify and integrate information about transgender patients into the electronic health record, account for the unique needs of these patients within the facility, and through education and policy create a welcoming environment for their care.

Unusual Radiographic Presentation of Pneumocystis Pneumonia in a Patient with AIDS.

Pneumocystis jirovecii pneumonia (PCP) typically presents as an interstitial and alveolar process with ground glass opacities on chest computed tomography (CT). The absence of ground glass opacities on chest CT is thought to have a high negative predictive value for PCP in individuals with AIDS. Here, we report a case of PCP in a man with AIDS who presented to our hospital with subacute shortness of breath and a nonproductive cough. While his chest CT revealed diffuse nodular rather than ground glass opacities, bronchoscopy with bronchoalveolar lavage and transbronchial biopsies confirmed the diagnosis of PCP and did not identify additional pathogens. PCP was not the expected diagnosis based on chest CT, but it otherwise fit well with the patient's clinical and laboratory presentation. In the era of combination antiretroviral therapy, routine prophylaxis for PCP, and increased use of computed tomography, it may be that PCP will increasingly present with nonclassical chest radiographic patterns. Clinicians should be aware of this presentation when selecting diagnostic and management strategies.

Detection of T lymphocytes specific for human endogenous retrovirus K (HERV-K) in patients with seminoma.

Human endogenous retrovirus K (HERV-K) is distinctive among the retroviruses that comprise about 8% of the human genome in that multiple HERV-K proviruses encode full-length viral proteins, and many HERV-K proviruses formed during recent human evolution. HERV-K gag proteins are found in the cytoplasm of primary tumor cells of patients with seminoma. We identified HERV-K-specific T cells in patients with a past history of seminoma using the interferon-gamma ELISPOT assay and an MHC-HERV-K peptide-specific tetramer. A minority of apparently healthy subjects without evident germ cell tumors also made HERV-K-specific T cell responses. In summary, we detected T cell reactivity to HERV-K peptides in both past seminoma patients and a minority of apparently healthy controls.

Emergence of drug-resistant HIV-1 variants in patients undergoing structured treatment interruptions.

We report the emergence of drug-resistant viral mutations in chronically HIV-infected individual undergoing structured treatment interruptions (STI). THe protease mutations K101E and K103N were detected at the end of the second or third STI. We concluded that the repeated abrupt termination and resumption of certain antiretroviral drug regimens during STI therapy may lead to the development of drug resistance in chronically HIV-infected individuals.

A cytostatic drug improves control of HIV-1 replication during structured treatment interruptions: a randomized study.

OBJECTIVE: To study the effect of highly active antiretroviral therapy (HAART) with and without hydroxyurea (HU) on changes in plasma viral load (VL) set-point, and on HIV-1-specific responses, after five cycles of structured treatment interruptions (STI). METHODS: A group of 20 patients taking HAART for chronic HIV infection with VL < 20 copies/ml were randomized to continue HAART or HAART plus HU for 24 weeks followed by five STI cycles. HU was also stopped in cycles 1-3 but continued in cycles 4 and 5. The number of individuals maintaining a VL set-point < 5000 copies/ml during the fifth interruption were determined. RESULTS: VL remained < 5000 copies/ml in eight out of nine patients in the HU group and in four out of ten patients in the HAART group after a median 48 weeks of follow-up after the fifth interruption ( P=0.039). By STI cycle 5, there was a significant increase in the neutralizing activity (NA), in both magnitude and breadth of the total cytotoxic T lymphocyte (CTL) response and in lymphoproliferative response (LPR) from baseline. No significant differences were observed between HAART and HU groups in NA, CTL and LPR at any time-point. There were no differences in the NA titers at any time-point between responder and non-responder patients. There was a trend for higher CTL and LPR levels in responder patients (P= 0.10). CONCLUSIONS: In this randomized, controlled study of STI with cycles of HAART or HAART plus HU, a lower peak VL rebound and a lower VL set-point was achieved in patients continuing HU while other drugs were discontinued. HU did not blunt anti-HIV-1-specific responses; however, control of VL did not correlate with anti-HIV-1-specific cellular immune responses.

Higher CD27+CD8+ T cells percentages during suppressive antiretroviral therapy predict greater subsequent CD4+ T cell recovery in treated HIV infection.

HIV-mediated immune dysfunction may influence CD4(+) T cell recovery during suppressive antiretroviral therapy (ART). We analyzed cellular biomarkers of immunological inflammation, maturation, and senescence in HIV-infected subjects on early suppressive ART. We performed longitudinal analyses of peripheral immunological biomarkers of subjects on suppressive ART (n = 24) from early treatment (median 6.4 months, interquartile range [IQR] 4.8-13.9 months) to 1-2 years of follow-up (median 19.8 months, IQR 18.3-24.6 months). We performed multivariate regression to determine which biomarkers were associated with and/or predictive of CD4(+) T cell recovery. After adjusting for the pre-ART CD4(+) T cell count, age, proximal CD4(+) T cell count, and length of ART medication, the percentage of CD27(+)CD8(+) T cells remained significantly associated with the CD4(+) T cell recovery rate (ß = 0.092 cells/ul/month, P = 0.028). In HIV-infected subjects starting suppressive ART, patients with the highest percentage of CD8(+) T cells expressing CD27 had the greatest rate of CD4(+) T cell recovery.

Residual viral replication during antiretroviral therapy boosts human immunodeficiency virus type 1-specific CD8+ T-cell responses in subjects treated early after infection.

Human immunodeficiency virus type 1 (HIV-1)-infected subjects treated early after infection have preserved HIV-1-specific CD4+ T-cell function. We studied the effect of highly active antiretroviral therapy (HAART) on the frequency of HIV-1-specific CD8+ T cells in patients treated during early (n = 31) or chronic (n = 23) infection. The degree of viral suppression and time of initiation of treatment influenced the magnitude of the CD8+ T-cell response. HIV-1-specific CD8+ T cells can increase in number after HAART in subjects treated early after infection who have episodes of transient viremia.

Changes in CD4+ T-cell differentiation phenotype during structured treatment interruption in patients with chronic HIV-1 infection.

Markers of maturation and activation were measured on peripheral CD4+ T cells in chronically HIV-1-infected patients in a randomized, controlled pilot study of structured treatment interruption (STI). Eight subjects underwent 2 cycles of 1 month off and 1 month on highly active antiretroviral therapy (HAART), followed by a final 3-month interruption. During STI, CD4+ T-cell percentage remained relatively stable in 4 of 8 subjects. The remaining 4 STI subjects had significant rapid decline in CD4+ T-cell percentage during STI, followed by return to pre-STI baseline while on HAART. Changes in overall CD4+ T-cell percentage corresponded with fluctuations in the CD45RA+CCR7+ naive and CD45RA-CCR7+ central memory subsets. Subjects with variable CD4+ T-cell percentages tended to have higher pre-HAART plasma HIV-1 RNA set-points and experienced higher levels of plasma HIV-1 RNA rebound during STI. These results suggest that interruptions should be avoided whenever possible in patients on HAART with high plasma HIV-1 RNA set-points.

Relevance of HIV-1-specific CD4+ helper T-cell responses during structured treatment interruptions in patients with CD4+ T-cell nadir above 400/mm3.

OBJECTIVES: To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved. METHODS: Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years. RESULTS: VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P < 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P < 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88). CONCLUSIONS: STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated.

Dual pressure from antiretroviral therapy and cell-mediated immune response on the human immunodeficiency virus type 1 protease gene.

Human immunodeficiency virus (HIV)-specific CD8(+) T-lymphocyte pressure can lead to the development of viral escape mutants, with consequent loss of immune control. Antiretroviral drugs also exert selection pressures on HIV, leading to the emergence of drug resistance mutations and increased levels of viral replication. We have determined a minimal epitope of HIV protease, amino acids 76 to 84, towards which a CD8(+) T-lymphocyte response is directed. This epitope, which is HLA-A2 restricted, includes two amino acids that commonly mutate (V82A and I84V) in the face of protease inhibitor therapy. Among 29 HIV-infected patients who were treated with protease inhibitors and who had developed resistance to these drugs, we show that the wild-type PR82V(76-84) epitope is commonly recognized by cytotoxic T lymphocytes (CTL) in HLA-A2-positive patients and that the CTL directed to this epitope are of high avidity. In contrast, the mutant PR82A(76-84) epitope is generally not recognized by wild-type-specific CTL, or when recognized it is of low to moderate avidity, suggesting that the protease inhibitor-selected V82A mutation acts both as a CTL and protease inhibitor escape mutant. Paradoxically, the absence of a mutation at position 82 was associated with the presence of a high-avidity CD8(+) T-cell response to the wild-type virus sequence. Our results indicate that both HIV type 1-specific CD8(+) T cells and antiretroviral drugs provide complex pressures on the same amino acid sequence of the HIV protease gene and, thus, can influence viral sequence evolution.