OBJECTIVE: Randomized controlled trials (RCT) have shown supported employment (SE) to be an evidence-based practice (EBP) for people with psychiatric disabilities. Whether SE implemented under "real-world" conditions achieves outcomes comparable to RCTs is an important question for the psychiatric rehabilitation field. We examined employment outcomes achieved by SE programs in Massachusetts, and in particular examined whether fidelity to EBP standards was associated with outcomes.
METHOD: We examined outcomes for 3,474 clients served by 21 programs between 1997 and 2006, using multiple sources of data, including a client tracking database maintained by the SE programs as well as program site visits to assess fidelity to EBP standards. Using Generalized Estimating Equations, we modeled associations of client factors (demographics, diagnosis), program fidelity and other program factors to: (a) obtaining a job within 1 year of program enrollment; and among those obtaining jobs, (b) working 20 hours/week or more; and (c) earning $9/hr or more.
RESULTS: There were 51% of clients who obtained a job within 1 year of enrollment. Clients served by high fidelity programs were more likely to obtain jobs (OR = 1.45) and to work 20 hr/week or more (OR = 1.52); fidelity was unrelated to wages.
CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This study contributes to the evidence that real-world programs can implement SE with fidelity and achieve outcomes on par with those found in RCTs, and that fidelity makes a difference in the outcomes programs achieve. High fidelity programs may be most effective in helping clients acquire jobs and maximize the hours they work.
Sex differences in mental health and substance use disorders and treatment entry among justice-involved Veterans in the Veterans Health Administration
BACKGROUND: Over half of veterans in the criminal justice system have mental health or substance use disorders. However, there is a critical lack of information about female veterans in the criminal justice system and how diagnosis prevalence and treatment entry differ by sex.
OBJECTIVES: To document prevalence of mental health and substance use disorder diagnoses and treatment entry rates among female veterans compared with male veterans in the justice system.
RESEARCH DESIGN: Retrospective cohort study using national Veterans Health Administration clinical/administrative data from veterans seen by Veterans Justice Outreach Specialists in fiscal years 2010-2012.
SUBJECTS: A total of 1535 females and 30,478 male veterans were included.
MEASURES: Demographic characteristics (eg, sex, age, residence, homeless status), mental health disorders (eg, depression, post-traumatic stress disorder), substance use disorders (eg, alcohol and opioid use disorders), and treatment entry (eg, outpatient, residential, pharmacotherapy).
RESULTS: Among female veterans, prevalence of mental health and substance use disorders was 88% and 58%, respectively, compared with 76% and 72% among male veterans. Women had higher odds of being diagnosed with a mental health disorder [adjusted odds ratio (AOR)=1.98; 95% confidence interval (CI), 1.68-2.34] and lower odds of being diagnosed with a substance use disorder (AOR=0.50; 95% CI, 0.45-0.56) compared with men. Women had lower odds of entering mental health residential treatment (AOR=0.69; 95% CI, 0.57-0.83).
CONCLUSIONS: Female veterans involved in the justice system have a high burden of mental health disorders (88%) and more than half have substance use disorders (58%). Entry to mental health residential treatment for women is an important quality improvement target.
Cue-induced craving in patients with cocaine use disorder predicts cognitive control deficits toward cocaine cues
INTRODUCTION: Cue-induced craving is a clinically important aspect of cocaine addiction influencing ongoing use and sobriety. However, little is known about the relationship between cue-induced craving and cognitive control toward cocaine cues. While studies suggest that cocaine users have an attentional bias toward cocaine cues, the present study extends this research by testing if cocaine use disorder patients (CDPs) can control their eye movements toward cocaine cues and whether their response varied by cue-induced craving intensity.
METHODS: Thirty CDPs underwent a cue exposure procedure to dichotomize them into high and low craving groups followed by a modified antisaccade task in which subjects were asked to control their eye movements toward either a cocaine or neutral drug cue by looking away from the suddenly presented cue. The relationship between breakdowns in cognitive control (as measured by eye errors) and cue-induced craving (changes in self-reported craving following cocaine cue exposure) was investigated.
RESULTS: CDPs overall made significantly more errors toward cocaine cues compared to neutral cues, with higher cravers making significantly more errors than lower cravers even though they did not differ significantly in addiction severity, impulsivity, anxiety, or depression levels. Cue-induced craving was the only specific and significant predictor of subsequent errors toward cocaine cues.
CONCLUSION: Cue-induced craving directly and specifically relates to breakdowns of cognitive control toward cocaine cues in CDPs, with higher cravers being more susceptible. Hence, it may be useful identifying high cravers and target treatment toward curbing craving to decrease the likelihood of a subsequent breakdown in control.
Effective techniques to encourage colorectal cancer screening in underscreened populations have included social support interventions and e-mail reminders from physicians. Personalized e-mail messages to promote colorectal cancer screening within social networks could be even more effective but have not been studied. The authors interviewed 387 e-mail users, aged 42-73 years in Georgia, Hawaii, and Massachusetts. Participants were asked to edit a sample message in which the sender shares a recent colonoscopy experience and urges the recipient to discuss colorectal cancer screening with a doctor. For those reporting willingness to send this message, changes to the message and suggested subject lines were recorded. Edited text was analyzed for content and concordance with original message. The majority of participants (74.4%) were willing to e-mail a modifiable message. Of those willing, 63.5% edited the message. Common edits included deletion (17.7%) or modification (17.4%) of a negatively framed sentence on colon cancer risks and addition or modification of personalizing words (15.6%). Few edits changed the meaning of the message (5.6%), and even fewer introduced factual inaccuracies (1.7%). Modifiable e-mail messages offer a way for screened individuals to promote colorectal cancer screening to social network members. The accuracy and effects of such messages should be further studied.
Implementation of Mindfulness Training for Mental Health Staff: Organizational Context and Stakeholder Perspectives
Occupational stress and burnout adversely impacts mental health care staff well-being and patient outcomes. Mindfulness training reduces staff stress and may improve patient care. However, few studies explore mental health setting implementation. This qualitative study used focus groups to evaluate stakeholders' perceptions of organizational factors affecting implementation of an adapted version of Mindfulness-Based Stress Reduction (MBSR) for staff on adolescent mental health units. Common facilitators included leadership securing buy-in with staff, allocating staff time to participate, and quiet space for training and practice. Other facilitators were past staff knowledge of mindfulness, local champions, and acculturating staff with mindfulness through a non-mandatory training attendance policy. Common barriers were limited staff time to attend training sessions and insufficient training coverage for some staff. Staff also reported improved focus when interacting with adolescents and improved social cohesion on the units. We conclude that a mindfulness-based program for reducing occupational stress can be successfully implemented on adolescent mental health units. Implementation appeared to change the social context of the units, including staff and patient interactions. More broadly, our findings highlight the importance of environmental factors in shaping attitudes, diffusion of innovation, and acculturation of wellness program implementations.
Behavioral Health Care Needs, Detention-Based Care, and Criminal Recidivism at Community Reentry From Juvenile Detention: A Multisite Survival Curve Analysis
OBJECTIVES: We examined the provision of behavioral health services to youths detained in Indiana between 2008 and 2012 and the impact of services on recidivism.
METHOD: We obtained information about behavioral health needs, behavioral health treatment received, and recidivism within 12 months after release for 8363 adolescents (aged 12-18 years; 79.4% male). We conducted survival analyses to determine whether behavioral health services significantly affected time to recidivating.
RESULTS: Approximately 19.1% of youths had positive mental health screens, and 25.3% of all youths recidivated within 12 months after release. Of youths with positive screens, 29.2% saw a mental health clinician, 16.1% received behavioral health services during detention, and 30.0% received referrals for postdetention services. Survival analyses showed that being male, Black, and younger, and having higher scores on the substance use or irritability subscales of the screen predicted shorter time to recidivism. Receiving a behavior precaution, behavioral health services in detention, or an assessment in the community also predicted shorter time to recidivating.
CONCLUSIONS: Findings support previous research showing that behavioral health problems are related to recidivism and that Black males are disproportionately rearrested after detention.
Local recurrence and survival following stereotactic radiosurgery for brain metastases from small cell lung cancer
PURPOSE: Stereotactic radiosurgery (SRS) represents a treatment option for patients with brain metastases from small cell lung cancer (SCLC) following prior cranial radiation. Inferior local control has been described. We reviewed our failure patterns following SRS treatment to evaluate this concern.
METHODS AND MATERIALS: Individuals with SCLC who received SRS for brain metastases from 2004 to 2011 were identified. Central nervous system (CNS) disease was detected and followed by gadolinium-enhanced, high-resolution magnetic resonance (MR) imaging. SRS dose was prescribed to the tumor periphery. Local recurrence was defined by increasing lesion size or enhancement, MR-spectroscopy, and perfusion changes consistent with recurrent disease or pathologic confirmation. Any new enhancing lesion not identified on the SRS planning scan was considered a regional failure. Overall survival (OS) and CNS control were evaluated using the Kaplan-Meier method. Factors predicted to influence outcome were tested by univariate log-rank analysis and Cox regression.
RESULTS: Fifteen males and 25 females (median age of 61 years [range, 36-79]) of which 39 received prior brain irradiation were identified. In all, 132 lesions (3.3 per patient) between 0.4 and 4.7 cm received a median dose of 16 Gy (12-22 Gy). Thirteen metastases (10%) ultimately recurred locally with 6- and 12-month control rates of 81% and 69%, respectively. Only 1 of 110 metastases < 2 cm recurred. Local failure was more likely for size > 2 cm (P < .001) and dose < 16 Gy (P < .001). The median OS was 6.5 months, and the time to regional CNS recurrence was 5.2 months. For patients with single brain metastases, both OS (P = .037) and regional CNS recurrence (P = .003) were improved. CNS control (P = .001), and survival (P = .057), were also longer for patients with controlled systemic disease.
CONCLUSIONS: Local control following SRS for SCLC metastases is achievable for lesions < 2 cm. For metastases > 2 cm, local failure is more common than expected. Patients with controlled systemic disease and limited CNS involvement would benefit most from aggressive treatment. Inc.
PURPOSE: The prognostic value of aberrant C-X-C chemokine receptor type 4 (CXCR4) levels in NSCLC has been described in empirical studies. This meta-analysis evaluates the value of CXCR4 as a prognostic marker for NSCLC and determines the relationship between CXCR4 and clinicopathological features of NSCLC.
METHODS: A comprehensive search of the English-language literature in PubMed, Embase, Google Scholar and Web of Science was performed. Articles containing sufficient published data to determine an estimate of the hazard ratio (HR) and a 95% confidence interval (95% CI) for over survival (OS) or disease-free survival (DFS) were selected. Of 417 potentially relevant studies, 10 eligible studies (1,334 NSCLC patients) met the inclusion criteria.
RESULTS: Overall, high CXCR4 expression was significantly associated with a poor OS rate (HR=1.59, 95% CI=1.36-1.87, P < 0.001) while the association with DFS was not statistically significant (HR=1.00, 95% CI=0.37-2.69, P=0.993). Stratified analysis by subcellular localization found that CXCR4 overexpression in the non-nucleus predicts poor OS (HR=1.65, 95% CI=1.40-1.95, P < 0.001) and DFS (HR=3.06, 95% CI=2.15-4.37, P < 0.001), but elevated CXCR4 expression in the nucleus was positively associated with DFS (HR=0.44, 95% CI=0.26-0.75, P=0.002). NSCLC patients with CXCR4 expression were more likely to be diagnosed with adenocarcinoma cancer (OR=1.45, 95% CI=1.07-1.95, P=0.016), lymph node involvement (OR=0.69, 95% CI=0.50-0.96, P=0.027), and distant metastasis (OR=0.36, 95% CI=0.14-0.93, P=0.035).
CONCLUSION: Aberrant overexpression of CXCR4 is associated with worse overall survival, adenocarcinoma histology, distant metastasis, lymph node involvement in NSCLC.
BACKGROUND: Radiation therapy (RT) is a treatment modality traditionally used in patients with multiple myeloma (MM), but little is known regarding the role and effectiveness of RT in the era of novel agents, i.e., immunomodulatory drugs and proteasome inhibitors.
METHODS: We retrospectively reviewed data from 449 consecutive MM patients seen at our institute in 2010-2012 to assess indications for RT as well as its effectiveness. Pain response was scored similarly to RTOG 0631 and used the Numerical Rating Pain Scale.
RESULTS: Among 442 evaluable patients, 149 (34%) patients and 262 sites received RT. The most common indication for RT was palliation of bone pain (n = 109, 42%), followed by prevention/treatment of pathological fractures (n = 73, 28%), spinal cord compression (n = 26, 10%), and involvement of vital organs/extramedullary disease (n = 25, 10%). Of the 55 patients evaluable for pain relief, complete and partial responses were obtained in 76.4 and 7.2%, respectively. Prior RT did not significantly decrease the median number of peripheral blood stem cells collected for autologous transplant, even when prior RT was given to both the spine and pelvis. Inadequacy of stem cell collection for autologous stem cell transplant (ASCT) was not significantly different and it occurred in 9 and 15% of patients receiving no RT and spine/pelvic RT, respectively. None of the three cases of therapy-induced acute myelogenous leukemia/MDS occurred in the RT group.
CONCLUSION: Despite the introduction of novel effective agents in the treatment of MM, RT remains a major therapeutic component for the management in 34% of patients, and it effectively provides pain relief while not interfering with successful peripheral blood stem cell collection for ASCT.
Predictors for long-term survival free from whole brain radiation therapy in patients treated with radiosurgery for limited brain metastases
PURPOSE: To identify predictors for prolonged survival free from salvage whole brain radiation therapy (WBRT) in patients with brain metastases treated with stereotactic radiosurgery (SRS) as their initial radiotherapy approach.
MATERIALS AND METHODS: Patients with brain metastases treated with SRS from 2001 to 2013 at our institution were identified. SRS without WBRT was typically offered to patients with 1-4 brain metastases, Karnofsky performance status > /=70, and life expectancy > /=3 months. Three hundred and eight patients met inclusion criteria for analysis. Medical records were reviewed for patient, disease, and treatment information. Two comparison groups were identified: those with > /=1-year WBRT-free survival (N = 104), and those who died or required salvage WBRT within 3 months of SRS (N = 56). Differences between these groups were assessed by univariate and multivariate analyses.
RESULTS: Median survival for all patients was 11 months. Among patients with > /=1-year WBRT-free survival, median survival was 33 months (12-107 months) with only 21% requiring salvage WBRT. Factors significantly associated with prolonged WBRT-free survival on univariate analysis (p < 0.05) included younger age, asymptomatic presentation, RTOG RPA class I, fewer brain metastases, surgical resection, breast primary, new or controlled primary, absence of extracranial metastatic disease, and oligometastatic disease burden ( < /=5 metastatic lesions). After controlling for covariates, asymptomatic presentation, breast primary, single brain metastasis, absence of extracranial metastases, and oligometastatic disease burden remained independent predictors for favorable WBRT-free survival.
CONCLUSION: A subset of patients with brain metastases can achieve long-term survival after upfront SRS without the need for salvage WBRT. Predictors identified in this study can help select patients that might benefit most from a treatment strategy of SRS alone.
Nodal stage of surgically resected non-small cell lung cancer and its effect on recurrence patterns and overall survival
PURPOSE: Current National Comprehensive Cancer Network guidelines recommend postoperative radiation therapy (PORT) for patients with resected non-small cell lung cancer (NSCLC) with N2 involvement. We investigated the relationship between nodal stage and local-regional recurrence (LR), distant recurrence (DR) and overall survival (OS) for patients having an R0 resection.
METHODS AND MATERIALS: A multi-institutional database of consecutive patients undergoing R0 resection for stage I-IIIA NSCLC from 1995 to 2008 was used. Patients receiving any radiation therapy before relapse were excluded. A total of 1241, 202, and 125 patients were identified with N0, N1, and N2 involvement, respectively; 161 patients received chemotherapy. Cumulative incidence rates were calculated for LR and DR as first sites of failure, and Kaplan-Meier estimates were made for OS. Competing risk analysis and proportional hazards models were used to examine LR, DR, and OS. Independent variables included age, sex, surgical procedure, extent of lymph node sampling, histology, lymphatic or vascular invasion, tumor size, tumor grade, chemotherapy, nodal stage, and visceral pleural invasion.
RESULTS: The median follow-up time was 28.7 months. Patients with N1 or N2 nodal stage had rates of LR similar to those of patients with N0 disease, but were at significantly increased risk for both DR (N1, hazard ratio [HR] = 1.84, 95% confidence interval [CI]: 1.30-2.59; P=.001; N2, HR = 2.32, 95% CI: 1.55-3.48; P < .001) and death (N1, HR = 1.46, 95% CI: 1.18-1.81; P < .001; N2, HR = 2.33, 95% CI: 1.78-3.04; P < .001). LR was associated with squamous histology, visceral pleural involvement, tumor size, age, wedge resection, and segmentectomy. The most frequent site of LR was the mediastinum.
CONCLUSIONS: Our investigation demonstrated that nodal stage is directly associated with DR and OS but not with LR. Thus, even some patients with, N0-N1 disease are at relatively high risk of local recurrence. Prospective identification of risk factors for local recurrence may aid in selecting an appropriate population for further study of postoperative radiation therapy.
PURPOSE: To accurately hypothesize the optimal frequency of psychosocial distress screening in patients undergoing radiation therapy using exploratory modeling of prospective data.
MATERIALS AND METHODS: Between October 2010 and May 2011, 71 RT patients underwent daily screening with the Distress Thermometer. Prevalences of Distress Thermometer scores > /= 4 were recorded. Optimal screening frequency was evaluated by planned post hoc comparison of prevalence rates and required screening events estimated by numerical modeling, consisting of data point omission to mimic weekly, every-other-week, monthly, and one-time screening intervals. Dependence on clinical variables and chronologic trends were assessed as secondary end points.
RESULTS: A total of 2,028 daily screening events identified that 37% of patients reported distress at least once during the course of treatment. Weekly, every-other-week, monthly, and one-time screening models estimated distress prevalences of 32%, 31%, 23%, and 17%, respectively, but required only 21%, 12%, 7%, and 4% of the assessments required for daily screening. No clinical parameter significantly predicted distress in univariable analysis, but "alone" living situation trended toward significance (P = .06). Physician-reported grade 3 toxicity predicted distress with 98% specificity, but only 19% sensitivity.
CONCLUSION: Thirty-seven percent of radiation oncology patients reported distress at least once during treatment. Screening at every-other-week intervals optimized efficiency and frequency, identifying nearly 90% of distressed patients with 12% of the screening events compared with daily screening.
Although brachytherapy had been established as a highly effective modality for the treatment of cancer, its application was threatened by mid-20th century due to appreciation of the radiation hazard to health care workers. This review examines how the introduction of afterloading eliminated exposure and ushered in a brachytherapy renaissance.
Prescription dose evaluation for APBI with noninvasive image-guided breast brachytherapy using equivalent uniform dose
PURPOSE: Noninvasive image-guided breast brachytherapy (NIBB) is an attractive novel approach to deliver accelerated partial breast irradiation (APBI). Calculations of equivalent uniform dose (EUD) were performed to identify the appropriate APBI dose for this technique.
METHODS AND MATERIALS: APBI plans were developed for 15 patients: five with three-dimensional conformal APBI (3D-CRT), five with multi-lumen intracavitary balloons (m-IBB), and five simulating NIBB treatment. Prescription doses of 34.0 and 38.5 Gy were delivered in 10 fractions for m-IBB and 3D-CRT, respectively. Prescription doses ranging from 34.0 to 38.5 Gy were considered for NIBB. Dose-volume histogram data from all 3D-CRT, m-IBB, and NIBB plans were used to calculate the biologically effective EUD and corresponding EUD to the PTV_eval using the following equation: EUD = EUBED/(n [1 + EUD/alpha/beta]). An alpha/beta value of 4.6 Gy was assumed for breast tumor. EUD for varying NIBB prescription doses were compared with EUD values for the other APBI techniques.
RESULTS: Mean PTV_eval volume was largest for 3D-CRT (372.9 cm(3)) and was similar for NIBB and m-IBB (88.7 and 87.2 cm(3), respectively). The EUD value obtained by prescribing 38.5 Gy with 3D-CRT APBI was 38.6 Gy. The EUD value of 34.0 Gy prescribed with m-IBB was 34.4 Gy. EUD values for NIBB ranged from 33.9 to 38.2 Gy for prescription doses ranging from 34.0 to 38.5 Gy.
CONCLUSIONS: Using EUD calculations to compare APBI techniques and treatment doses, a prescription dose of 36.0 Gy in 10 fractions using NIBB has a comparable biologic equivalent dose to other established brachytherapy techniques.
We evaluated patient outcomes following stereotactic radiosurgery (SRS)-treatment of large brain metastasis (3cm) at our institution. SRS is an established treatment for limited brain metastases. However, large tumors pose a challenge for this approach. For this study, 343 patients with 754 total brain metastases were treated with SRS, of which 93 had large tumors. The tumor size was 3-3.5, 3.5-4, and 4cm in 29%, 32%, and 39% of these patients. Surgical resection was performed prior to SRS in 68% of patients, and 53% achieved a gross total resection. The local control of large metastases was inferior compared to smaller tumors, with 1 year local control of 68 versus 86%, respectively (p < 0.001). Among the patients with large metastases, no correlation between local control and surgical resection (p=0.747), or extent of surgery (gross total versus subtotal resection; p=0.120), was identified. Histology (p=0.939), tumor size (3-4 versus > 4cm; p=0.551), and SRS dose (16 versus > 16Gy; p=0.539) also showed no correlation with local failure. The overall survival at 1, 2, and 5years was 46%, 29% and 5%, respectively. Prolonged survival was seen in patients with age < 65years (p=0.009), primary treatment compared with salvage (p=0.077), and controlled primary tumors (p=0.022). Radiation necrosis developed in 10 patients (11.8%). For patients with large brain metastases, SRS is well tolerated and can achieve local central nervous system disease control in the majority of patients, and extended survival in some, though the local control rate is suboptimal. Further strategies to improve the outcomes in this subgroup of patients are needed.
Is it a primary or metastatic melanocytic neoplasm of the central nervous system?: A molecular based approach
Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon and must be distinguished from metastatic lesions as patients with metastatic disease carry a worse prognosis. Therefore, tools to aid in the diagnosis of a primary CNS melanocytic neoplasm would be of clinical utility. Primary CNS melanocytic neoplasms, including uveal melanomas have frequent mutations in GNAQ and GNA11, but are rare in cutaneous and mucosal melanomas. Additionally, primary uveal melanomas often exhibit monosomy 3 conferring an elevated risk of metastasis. We present a 63 year-old male with a melanocytic neoplasm in the thoracic spinal cord. Molecular studies revealed the tumor contained a GNAQ mutation and four-color fluorescent in situ hybridization (FISH) composed of chromosome enumeration probes for 3, 7, 17 and a locus specific probe for 9p21/CDKN2A yielded a normal result (i.e. two copies per cell), favoring a primary versus metastatic melanocytic neoplasm of the CNS. We report a case in which the combination of mutational analysis and FISH aided in identifying the origin of the neoplasm.
Patterns in immunohistochemical usage in extended core prostate biopsies: comparisons among genitourinary pathologists and nongenitourinary pathologists
CONTEXT: Immunohistochemical (IHC) stains have known utility in prostate biopsies and are widely used to augment routine staining in difficult cases. Patterns in IHC utilization and differences based on pathologist training and experience is understudied in the peer-reviewed literature.
OBJECTIVES: To compare the rates of IHC usage between specialized (genitourinary; [GU]) and nonspecialized (non-GU) pathologists in extended core prostate biopsies (ECPBs) and the effects of diagnosis; and in cancer cases Gleason grade, disease extent, and perineural invasion on the rate.
DESIGN: Consecutive ECPBs from 2009-2011 were identified and billing data were used to determine the number of biopsies and IHC stains per case. Diagnoses were mapped and in cancer cases, Gleason grade, extent of disease, and perineural invasion were recorded. Pathologists were classified as GU or non-GU on the basis of training and experience.
RESULTS: A total of 618 ECPBs were included in the study. Genitourinary pathologists ordered significantly fewer IHC tests per case and per biopsy than non-GU pathologists. The rate of ordering was most disparate for biopsies of cancerous and benign lesions. For biopsies of cancerous lesions, high-grade cancer, bilateral disease, and perineural invasion decreased the rate of ordering in both groups. In cancer cases, GU pathologists ordered significantly fewer stain tests for highest Gleason grade of 3 + 3 = 6, for patients with focal disease and for patients with multiple positive bilateral cores. The effect of the various predictors on IHC ordering rates was similar in both groups.
CONCLUSIONS: Genitourinary pathologists ordered significantly fewer IHC stain tests than non-GU pathologists in ECPBs. Guidelines to define when IHC workup is necessary and not necessary may be helpful to guide workups.
Long-lasting T cell-independent IgG responses require MyD88-mediated pathways and are maintained by high levels of virus persistence
Many viruses induce acute T cell-independent (TI) B cell responses due to their repetitive epitopes and the induction of innate cytokines. Nevertheless, T cell help is thought necessary for the development of long-lasting antiviral antibody responses in the form of long-lived plasma cells and memory B cells. We found that T cell-deficient (T cell receptor beta and delta chain [TCRbetadelta] knockout [KO]) mice persistently infected with polyomavirus (PyV) had long-lasting antiviral serum IgG, and we questioned whether they could generate TI B cell memory. TCRbetadelta KO mice did not form germinal centers after PyV infection, lacked long-lived IgG-secreting plasma cells in bone marrow, and did not have detectable memory B cell responses. Mice deficient in CD4(+) T cells had a lower persisting virus load than TCRbetadelta KO mice, and these mice had short-lived antiviral IgG responses, suggesting that a high virus load is required to activate naive B cells continuously, and maintain the long-lasting serum IgG levels. Developing B cells in bone marrow encounter high levels of viral antigens, which can cross-link both their B cell receptor (BCR) and Toll-like receptors (TLRs), and this dual engagement may lead to a loss of their tolerance. Consistent with this hypothesis, antiviral serum IgG levels were greatly diminished in TCRbetadelta KO/MyD88(-/-) mice. We conclude that high persisting antigen levels and innate signaling can lead to the maintenance of long-lasting IgG responses even in the absence of T cell help.
IMPORTANCE: Lifelong control of persistent virus infections is essential for host survival. Several members of the polyomavirus family are prevalent in humans, persisting at low levels in most people without clinical manifestations, but causing rare morbidity/mortality in the severely immune compromised. Studying the multiple mechanisms that control viral persistence in a mouse model, we previously found that murine polyomavirus (PyV) induces protective T cell-independent (TI) antiviral IgG. TI antibody (Ab) responses are usually short-lived, but T cell-deficient PyV-infected mice can live for many months. This study investigates how protective IgG is maintained under these circumstances and shows that these mice lack both forms of B cell memory, but they still have sustained antiviral IgG responses if they have high levels of persisting virus and intact MyD88-mediated pathways. These requirements may ensure life-saving protection against pathogens even in the absence of T cells, but they prevent the continuous generation of TI IgG against harmless antigens.
Disparate epitopes mediating protective heterologous immunity to unrelated viruses share peptide-MHC structural features recognized by cross-reactive T cells
Closely related peptide epitopes can be recognized by the same T cells and contribute to the immune response against pathogens encoding those epitopes, but sometimes cross-reactive epitopes share little homology. The degree of structural homology required for such disparate ligands to be recognized by cross-reactive TCRs remains unclear. In this study, we examined the mechanistic basis for cross-reactive T cell responses between epitopes from unrelated and pathogenic viruses, lymphocytic choriomeningitis virus (LCMV) and vaccinia virus. Our results show that the LCMV cross-reactive T cell response toward vaccinia virus is dominated by a shared asparagine residue, together with other shared structural elements conserved in the crystal structures of K(b)-VV-A11R and K(b)-LCMV-gp34. Based on analysis of the crystal structures and the specificity determinants for the cross-reactive T cell response, we were able to manipulate the degree of cross-reactivity of the T cell response, and to predict and generate a LCMV cross-reactive response toward a variant of a null OVA-derived peptide. These results indicate that protective heterologous immune responses can occur for disparate epitopes from unrelated viruses.