Michael J. Peluso

Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load.

Objective:To characterize HIV-infected patients with neurosymptomatic cerebrospinal fluid (CSF) ‘escape’, defined as detectable CSF HIV RNA in the setting of treatment-suppressed plasma levels or CSF RNA more than 1-log higher than plasma RNA. Design:Retrospective case series. Setting:Four urban medical centers in the United States and Europe. Participants:Virologically controlled HIV-infected patients on antiretroviral therapy (ART) with progressive neurologic abnormalities who were determined to have CSF ‘escape’. Intervention:Optimization of ART based upon drug susceptibility and presumed central nervous system exposure. Main outcome measures:Levels of CSF HIV RNA and inflammatory markers, clinical signs and symptoms, and MRI findings. Results:Ten patients presented with new neurologic abnormalities, which included sensory, motor, and cognitive manifestations. Median CSF HIV RNA was 3900 copies/ml (range 134–9056), whereas median plasma HIV RNA was 62 copies/ml (range <50 to 380). Median CD4+ T-cell count was 482 cells/&mgr;l (range 290–660). All patients had been controlled to less than 500 copies/ml for median 27.5 months (range 2–96) and five of 10 had been suppressed to less than 50 copies/ml for median 19.5 months (range 2–96). Patients had documentation of a stable ART regimen for median 21 months (range 9–60). All had CSF pleocytosis or elevated CSF protein; seven of eight had abnormalities on MRI; and six of seven harbored CSF resistance mutations. Following optimization of ART, eight of nine patients improved clinically. Conclusion:The development of neurologic symptoms in patients on ART with low or undetectable plasma HIV levels may be an indication of CSF ‘escape’. This study adds to a growing body of literature regarding this rare condition in well controlled HIV infection.

Prevalence of Depression, Depressive Symptoms, and Suicidal Ideation Among Medical Students: A Systematic Review and Meta-Analysis

Importance Medical students are at high risk for depression and suicidal ideation. However, the prevalence estimates of these disorders vary between studies. Objective To estimate the prevalence of depression, depressive symptoms, and suicidal ideation in medical students. Data Sources and Study Selection Systematic search of EMBASE, ERIC, MEDLINE, psycARTICLES, and psycINFO without language restriction for studies on the prevalence of depression, depressive symptoms, or suicidal ideation in medical students published before September 17, 2016. Studies that were published in the peer-reviewed literature and used validated assessment methods were included. Data Extraction and Synthesis Information on study characteristics; prevalence of depression or depressive symptoms and suicidal ideation; and whether students who screened positive for depression sought treatment was extracted independently by 3 investigators. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using stratified meta-analysis and meta-regression. Main Outcomes and Measures Point or period prevalence of depression, depressive symptoms, or suicidal ideation as assessed by validated questionnaire or structured interview. Results Depression or depressive symptom prevalence data were extracted from 167 cross-sectional studies (n = 116 628) and 16 longitudinal studies (n = 5728) from 43 countries. All but 1 study used self-report instruments. The overall pooled crude prevalence of depression or depressive symptoms was 27.2% (37 933/122 356 individuals; 95% CI, 24.7% to 29.9%, I2 = 98.9%). Summary prevalence estimates ranged across assessment modalities from 9.3% to 55.9%. Depressive symptom prevalence remained relatively constant over the period studied (baseline survey year range of 1982-2015; slope, 0.2% increase per year [95% CI, -0.2% to 0.7%]). In the 9 longitudinal studies that assessed depressive symptoms before and during medical school (n = 2432), the median absolute increase in symptoms was 13.5% (range, 0.6% to 35.3%). Prevalence estimates did not significantly differ between studies of only preclinical students and studies of only clinical students (23.7% [95% CI, 19.5% to 28.5%] vs 22.4% [95% CI, 17.6% to 28.2%]; P = .72). The percentage of medical students screening positive for depression who sought psychiatric treatment was 15.7% (110/954 individuals; 95% CI, 10.2% to 23.4%, I2 = 70.1%). Suicidal ideation prevalence data were extracted from 24 cross-sectional studies (n = 21 002) from 15 countries. All but 1 study used self-report instruments. The overall pooled crude prevalence of suicidal ideation was 11.1% (2043/21 002 individuals; 95% CI, 9.0% to 13.7%, I2 = 95.8%). Summary prevalence estimates ranged across assessment modalities from 7.4% to 24.2%. Conclusions and Relevance In this systematic review, the summary estimate of the prevalence of depression or depressive symptoms among medical students was 27.2% and that of suicidal ideation was 11.1%. Further research is needed to identify strategies for preventing and treating these disorders in this population.

Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs

BACKGROUND Second-generation antipsychotics have been thought to cause fewer extrapyramidal side-effects (EPS) than first-generation antipsychotics, but recent pragmatic trials have indicated equivalence. AIMS To determine whether second-generation antipsychotics had better outcomes in terms of EPS than first-generation drugs. METHOD We conducted an intention-to-treat, secondary analysis of data from an earlier randomised controlled trial (n = 227). A clinically significant difference was defined as double or half the symptoms in groups prescribed first- v. second-generation antipsychotics, represented by odds ratios greater than 2.0 (indicating advantage for first-generation drugs) or less than 0.5 (indicating advantage for the newer drugs). We also examined EPS in terms of symptoms emergent at 12 weeks and 52 weeks, and symptoms that had resolved at these time points. RESULTS At baseline those randomised to the first-generation antipsychotic group (n = 118) had similar EPS to the second-generation group (n = 109). Indications of resolved Parkinsonism (OR = 0.5) and akathisia (OR = 0.4) and increased tardive dyskinesia (OR = 2.2) in the second-generation drug group at 12 weeks were not statistically significant and the effects were not present by 52 weeks. Patients in the second-generation group were dramatically (30-fold) less likely to be prescribed adjunctive anticholinergic medication, despite equivalence in terms of EPS. CONCLUSIONS The expected improvement in EPS profiles for participants randomised to second-generation drugs was not found; the prognosis over 1 year of those in the first-generation arm was no worse in these terms. The place of careful prescription of first-generation drugs in contemporary practice remains to be defined, potentially improving clinical effectiveness and avoiding life-shortening metabolic disturbances in some patients currently treated with the narrow range of second-generation antipsychotics used in routine practice. This has educational implications because a generation of psychiatrists now has little or no experience with first-generation antipsychotic prescription.

Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection

BACKGROUND Cerebrospinal fluid (CSF) and neuroimaging abnormalities demonstrate neuronal injury during chronic AIDS, but data on these biomarkers during primary human immunodeficiency virus (HIV) infection is limited. METHODS We compared CSF concentrations of neurofilament light chain, t-tau, p-tau, amyloid precursor proteins, and amyloid-beta 42 in 92 subjects with primary HIV infection and 25 controls. We examined relationships with disease progression and neuroinflammation, neuropsychological testing, and proton-magnetic resonance spectroscopy (MRS)-based metabolites. RESULTS Neurofilament light chain was elevated in primary HIV infection compared with controls (P = .0004) and correlated with CSF neopterin (r = 0.38; P = .0005), interferon gamma-induced protein 10 (r = 0.39; P = .002), white blood cells (r = 0.32; P = .004), protein (r = 0.59; P < .0001), and CSF/plasma albumin ratio (r = 0.60; P < .0001). Neurofilament light chain correlated with decreased N-acteylaspartate/creatine and glutamate/creatine in the anterior cingulate (r = -0.35, P = .02; r = -0.40, P = .009, respectively), frontal white matter (r = -0.43, P = .003; r = -0.30, P = .048, respectively), and parietal gray matter (r = -0.43, P = .003; r = -0.47, P = .001, respectively). Beta-amyloid was elevated in the primary infection group (P = .0005) and correlated with time infected (r = 0.34; P = .003). Neither marker correlated with neuropsychological abnormalities. T-tau and soluble amyloid precursor proteins did not differ between groups. CONCLUSIONS Elevated neurofilament light chain and its correlation with MRS-based metabolites suggest early neuronal injury in a subset of participants with primary HIV infection through mechanisms involving central nervous system inflammation.

Guiding principles for the development of global health education curricula in undergraduate medical education

Background: Global health education (GHE) at undergraduate medical institutions has expanded significantly over the last 30 years, but many questions remain regarding the best practices for the development and implementation of global health programs. Aim: To identify key themes essential to the development of GHE programs. Method: We discuss five themes relevant to GHE in the context of existing literature and practice. Results: The following themes are essential to the development of GHE programs: the definition and scope of GHE, student competencies in global health, the challenges and opportunities associated with inter-institutional relationships, principles for GHE student placements, and the evaluation of GHE programs. We place these themes in the context of current literature and practice, and provide practical guidance on how these themes might be successfully implemented by institutions seeking to develop or refine GHE programs. Conclusions: Institutions developing or evaluating GHE programs should focus on these themes as they build their global health curricula.

Structured global health programs in U.S. medical schools: a web-based review of certificates, tracks, and concentrations.

Purpose To determine the prevalence and requirements of structured, longitudinal, nondegree global health (GH) programs (e.g., certificates, tracks, concentrations) in U.S. MD-granting medical schools. Method In March 2011, two reviewers independently searched the Web sites of all 133 U.S. MD-granting medical schools and reviewed Google search results seeking evidence of, information about, and the requirements of structured GH programs. The authors excluded programs that were not open to medical students, granted a degree, and/or required medical students to extend training time. Results Of 133 institutions analyzed, 32 (24%) had evidence of a structured GH program. Of the 30 (94%) programs for which the authors could find further information online, 16/30 (53%) were administered by the medical school, whereas 13/30 (43%) were administered by a different entity within the university; 1/30 (3%) was jointly administered. All 30 of the programs required additional didactic course work. The median number of courses was 4 (range: 1–12). Of the 30 schools with GH programs, 22 (73%) required an international experiential component, but only 12/30 (40%) specifically required an international clinical experience. Only 1 school (3%) directly addressed language or cultural proficiency. Conclusions Although structured GH programs were offered at one-quarter of U.S. medical schools, little standardization across programs existed in terms of requirements for didactic, clinical, scholarly, and cultural components. Online GH program information is not easily accessible, but it may be valuable in the development of new structured programs, the refinement of programs that already exist, and students’ selection of medical schools.

Adherence reporting in randomized controlled trials

Background Treatment adherence may influence the therapeutic effect that is observed in a randomized controlled trial (RCT). Adherence may also be an indicator of research quality and treatment acceptance by participants. Despite the importance of adherence in RCT research, little is known about current practices for its measurement and reporting. Purpose The objective of this study was to determine and evaluate adherence measurement and reporting practices in RCTs involving oral pharmacologic interventions published in high impact factor journals. Methods We conducted a systematic review of RCTs involving oral pharmacotherapy published during 2010 in 10 high-impact general medicine and subspecialty journals. Two investigators independently abstracted data regarding trial characteristics, adherence monitoring, and adherence reporting. Differences were reconciled in conference. Descriptive statistics were calculated, statistical comparisons were made using chi-square analysis, and associations assessed using Spearman’s rank correlation coefficient. Results Of 111 RCT manuscripts included in the sample, 51 (45.9%) reported study-drug adherence among participants. Studies that reported adherence results were more likely to report negative findings (i.e., no significant treatment effect in a superiority trial, non-equivalence in an equivalence trial) (p = 0.032). The most common method for adherence monitoring was pill count-back on returned bottles. Among the studies that reported adherence, the median adherence was 88.4% (range: 48%−100%), and trials with longer follow-up time reported lower adherence (r = −0.45; p = 0.0015). A minority of the 51 studies described a strategy for calculating adherence that accounted for participants who were lost to follow-up (11/51 studies; 21.6%), discontinued the study medication temporarily (6/51 studies; 11.8%), or discontinued the study drug permanently (1/51 study; 2%). Limitations This study is limited by the inclusion of a small set of journals with the highest impact factors in specific fields of clinical medicine, including general medicine. Although the analysis pertains to studies published in 2010, no new guidelines in the field since the last Consolidated Standards of Reporting Trials (CONSORT) statement have been issued that would be expected to change practices for adherence monitoring, analysis, and reporting. Conclusions Adherence measurement methodology and results are underreported in published RCTs. In the minority of RCTs that provided adherence information, there was substantial heterogeneity in how adherence was defined, analyzed, and reported. Improved reporting of adherence may enhance the interpretation of study quality and results.

Absence of Cerebrospinal Fluid Signs of Neuronal Injury Before and After Immediate Antiretroviral Therapy in Acute HIV Infection

BACKGROUND It is unknown whether neuronal injury begins during acute human immunodeficiency virus (HIV) infection, and whether immediate initiation of combination antiretroviral therapy (cART) prevents neuronal injury. METHODS Cerebrospinal fluid (CSF) neurofilament light chain (NFL), a measure of axonal injury, was assessed before and after cART initiation in individuals starting treatment during acute or chronic HIV infection. Nonparametric statistics examined relationships between NFL and disease progression, neuroinflammation, and cognitive performance. RESULTS Before treatment, subjects with acute infection had lower CSF NFL levels, with elevations for their age in 1 of 32 subjects with acute infection (3.1%) and 10 of 32 with chronic infection (31%) (P = .006). This persisted after cART initiation, with 1 of 25 acute (4%) and 4 of 9 chronic subjects (44%) showing elevated NFL levels (P = .01). In acute infection, pre-cART NFL levels were inversely correlated with proton magnetic resonance spectroscopic findings of N-acetylaspartate/creatine in frontal gray matter (r = -0.40; P = .03), frontal white matter (r = -0.46; P = .01), and parietal gray matter (r = -0.47; P = .01); correlations persisted after treatment in the frontal white matter (r = -0.51; P = .02) and parietal gray matter (r = -0.46; P = .04). CONCLUSIONS CSF NFL levels are not elevated in untreated acute HIV infection or after 6 months of immediately initiated cART but are abnormal in chronic HIV infection before and after treatment. In acute HIV infection, CSF NFL levels are inversely associated with neuroimaging markers of neuronal health.

Treatment of HIV in the CNS: Effects of Antiretroviral Therapy and the Promise of Non-Antiretroviral Therapeutics

The growing recognition of the burden of neurologic disease associated with HIV infection in the last decade has led to renewed efforts to characterize the pathophysiology of the virus within the central nervous system (CNS). The concept of the AIDS-dementia complex is now better understood as a spectrum of HIV-associated neurocognitive disorders (HAND), which range from asymptomatic disease to severe impairment. Recent work has shown that even optimally treated patients can experience not only persistent HAND, but also the development of new neurologic abnormalities despite viral suppression. This has thrown into question what the impact of antiretroviral therapy has been on the incidence and prevalence of neurocognitive dysfunction. In this context, the last few years have seen a concentrated effort to identify the effects that antiretroviral therapy has on the neurologic manifestations of HIV and to develop therapeutic modalities that might specifically alter the trajectory of HIV within the CNS.

Age and space irradiation modulate tumor progression: implications for carcinogenesis risk.

Age plays a major role in tumor incidence and is an important consideration when modeling the carcinogenesis process or estimating cancer risks. Epidemiological data show that from adolescence through middle age, cancer incidence increases with age. This effect is commonly attributed to a lifetime accumulation of cellular, particularly DNA, damage. However, during middle age the incidence begins to decelerate and, for many tumor sites, it actually decreases at sufficiently advanced ages. We investigated if the observed deceleration and potential decrease in incidence could be attributed to a decreased capacity of older hosts to support tumor progression, and whether HZE [high atomic number (Z), high energy (E)] radiation differentially modulates tumor progression in young vs. middle-age hosts, issues that are relevant to estimating carcinogenesis risk for astronauts. Lewis lung carcinoma (LLC) cells were injected into syngeneic mice (143 and 551 days old), which were then subject to whole-body 56Fe irradiation (1 GeV/amu). Three findings emerged: (1) among unirradiated animals, substantial inhibition of tumor progression and significantly decreased tumor growth rates were seen for middle-aged mice compared to young mice, (2) whole-body 56Fe irradiation inhibited tumor progression in both young and middle-aged mice (with greater suppression seen in case of young animals), with little effect on tumor growth rates, and (3) 56Fe irradiation suppressed tumor progression in young mice to a degree that was not significantly different than transiting from young to middle-aged. Thus, 56Fe irradiation acted similar to aging with respect to tumor progression. We further investigated the molecular underpinnings driving the radiation modulation of tumor dynamics in young and middle-aged mice. Through global gene expression analysis, the key players, FASN, AKT1 and the CXCL12/CXCR4 complex, were determined to be contributory. In sum, these findings demonstrated a reduced capacity of middle-aged hosts to support the progression phase of carcinogenesis and identify molecular factors that contribute to HZE radiation modulation of tumor progression as a function of age.