Extreme Risk Protection Orders: Legislative Intent and Clinician Guidance.

In this second column of a 2-part series exploring extreme risk protections orders, we utilize recent events in Colorado, including legislative efforts to expand the list of eligible petitioners to include clinicians, as an opportunity to explore questions and challenges faced by mental health and medical professionals serving in this capacity. Clinicians are in need of more clear guidance, given an emerging role that comes without clear evidence or practice standards to inform individualized clinical decision-making, and which potentially pits public safety interests against patient care needs, especially those pertaining to therapeutic relationships. In the interim, clinicians will best serve their patients by continuing to practice in a fashion that is analogous to decision-making around other interventions with serious implications for patient autonomy such as involuntary hospitalization. Ongoing collaboration with legislators is needed to arrive at laws that are informed by the limitations inherent in clinical risk assessment and that can be translated into clinical practices that simultaneously support patient needs and community safety.

A Radical New Approach for Mental Health Diversion.

The criminalization of mental illness is a national tragedy. Over the past three decades there have been numerous programs and initiatives designed to reduce the number of people with mental illness incarcerated in jails and prisons. Despite such efforts, incarceration rates have not fallen and have actually climbed in many jurisdictions. One major consequence of the criminalization of mental illness has been a large increase in referrals for evaluation for competency to stand trial and, consequently, in the need for competency restoration services. Many states have been unable to keep up with the demand for such services, causing patients to languish in jails with their criminal proceedings suspended, awaiting transfer to a state hospital. Expedited Diversion to Court-Ordered Treatment (EDCOT) is a new model for diversion that has great potential to drastically improve the diversion process, bypass the competency restoration system, and reduce the criminalization of mental illness. Successful implementation of EDCOT would result in more humane treatment of people with mental illness, without jeopardizing public safety; furthermore, it would pay for itself with the savings from reductions in the use of competency restoration services.

Assessing the Role of Cyberbiosecurity in Agriculture: A Case Study.

Agriculture has adopted the use of smart technology to help meet growing food demands. This increased automation and associated connectivity increases the risk of farms being targeted by cyber-attacks. Increasing frequency of cybersecurity breaches in many industries illustrates the need for securing our food supply chain. The uniqueness of biological data, the complexity of integration across the food and agricultural system, and the importance of this system to the U.S. bioeconomy and public welfare suggests an urgency as well as unique challenges that are not common across all industries. To identify and address the gaps in awareness and knowledge as well as encourage collaborations, Virginia Tech hosted a virtual workshop consisting of professionals from agriculture, cybersecurity, government, and academia. During the workshop, thought leaders and influencers discussed 1) common food and agricultural system challenges, scenarios, outcomes and risks to various sectors of the system; 2) cyberbiosecurity strategies for the system, gaps in workforce and training, and research and policy needs. The meeting sessions were transcribed and analyzed using qualitative methodology. The most common themes that emerged were challenges, solutions, viewpoints, common vocabulary. From the results of the analysis, it is evident that none of the participating groups had available cybersecurity training and resources. Participants were uncertain about future pathways for training, implementation, and outreach related to cyberbiosecurity. Recommendations include creating training and education, continued interdisciplinary collaboration, and recruiting government involvement to speed up better security practices related to cyberbiosecurity.

Electrically Conductive CNT Composites at Loadings below Theoretical Percolation Values.

It is well established that dramatic increases in conductivity occur upon the addition of conductive filler materials to highly resistive polymeric matrices in experimental settings. However, the mechanisms responsible for the observed behavior at low filler loadings, below theoretical percolation limits, of even high aspect ratio fillers such as carbon nanotubes (CNT) are not completely understood. In this study, conductive composites were fabricated using CNT bundles dispersed in epoxy resins at diverse loadings, using different dispersion and curing protocols. Based on electron microscopy observation of the CNTs strands distribution in the polymeric matrices and the corresponding electrical conductivities of those specimens, we concluded that no single electron transfer model can accurately explain the conductive behavior for all the loading values. We propose the existence of two different conductive mechanisms; one that exists close to the percolation limit, from 'low loadings' to higher CNT contents (CNT % wt > 0.1) and a second for 'extremely low loadings', near the percolation threshold (CNT % wt < 0.1). The high conductivity observed for composites at low CNT loading values can be explained by the existence of a percolative CNT network that coexists with micron size regions of non-conductive material. In contrast, samples with extremely low CNT loading values, which present no connectivity or close proximity between CNT bundles, show an electrical conductivity characterized by a current/voltage dependence. Data suggests that at these loadings, conduction may occur via a material breakdown mechanism, similar to dielectric breakdown in a capacitor. The lessons learned from the data gathered in here could guide future experimental research aimed to control the conductivity of CNT composites.

Real-World Effectiveness of Chemotherapy in Elderly Patients With Metastatic Bladder Cancer in the United States.

BACKGROUND: Outcomes for patients with metastatic bladder cancer (mBC) are generally poor and progressively worse following first-line (1L) chemotherapy. OBJECTIVE: To evaluate treatment patterns, survival outcomes, and characteristics of a large, real-world US population of elderly patients with advanced mBC receiving 1L and second-line (2L) treatment retrospectively. METHODS: We identified patients with advanced mBC (aged ≥66 years)-newly diagnosed between January 1, 2004, and December 31, 2011-in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program-Medicare linked database and assessed their palliative systemic chemotherapy treatments and survival outcomes. RESULTS: Of 1703 eligible patients, 42% received 1L chemotherapy; 1L-treated patients tended to be younger and healthier than nontreated patients. Only 27% of 1L-treated patients received cisplatin-based chemotherapy, most commonly cisplatin-gemcitabine. Cisplatin-treated patients were younger and had fewer comorbidities than non-cisplatin-treated patients. Thirty-five percent of 1L-treated patients subsequently received 2L chemotherapy. Patients received a variety of 2L agents as combination chemotherapy (52%) or single-agent chemotherapy (39%). Median overall survival durations in 1L-treated and 2L-treated patients were 8.5 and 7.9 months, respectively. CONCLUSIONS: Results from this retrospective SEER-Medicare database analysis underscore the historical inadequacies of 1L and 2L treatments in elderly patients with advanced mBC. Few patients were treated with 1L chemotherapy, a minority of whom received 1L cisplatin-based chemotherapy, and even fewer received 2L chemotherapy. These findings highlight the disconnect between 1L treatment in clinical trials and treatment in the real-world setting and the lack of standard approaches to 2L treatment in the United States.

When Restoration Fails: One State's Answer to the Dilemma of Permanent Incompetence.

The landmark 1972 U.S. Supreme Court decision in Jackson v. Indiana prohibited the indefinite commitment of criminal defendants on grounds of incompetence to stand trial if there was no substantial probability of restoration to competency in the foreseeable future. Such defendants are still subject to ordinary civil commitment; however, not all will meet civil commitment criteria, given that the criteria for a finding of incompetency to stand trial do not map directly onto the general criteria for involuntary psychiatric hospitalization. If a person charged with a serious crime, such as murder, has no substantial probability of being restored to competency, but does not meet standard civil commitment criteria, compliance with Jackson would seem to require release into the community. This article describes a legislative response to this possibility that became law in California four decades ago, as well as the outcome of its main legal challenge a few years later. Although the law has received harsh criticism from some quarters, it has survived, and provides a legally straightforward, if ethically controversial, means of answering the question of what to do with a permanently incompetent defendant who is charged with a serious violent offense and does not meet traditional civil commitment criteria.

Radiation Therapy for Residual or Recurrent Atypical Meningioma: The Effects of Modality, Timing, and Tumor Pathology on Long-Term Outcomes.

BACKGROUND: Optimal use of stereotactic radiosurgery (SRS) vs external beam radiation therapy (EBRT) for treatment of residual/recurrent atypical meningioma is unclear. OBJECTIVE: To analyze features associated with progression after radiation therapy. METHODS: Fifty radiation-naive patients who received SRS or EBRT for residual and/or recurrent atypical meningioma were examined for predictors of progression using Cox regression and Kaplan-Meier analyses. RESULTS: Thirty-two patients (64%) received adjuvant radiation after subtotal resection, 12 patients (24%) received salvage radiation after progression following subtotal resection, and 6 patients (12%) received salvage radiation after recurrence following gross total resection. Twenty-one patients (42%) received SRS (median 18 Gy), and 7 (33%) had tumor progression. Twenty-nine patients (58%) received EBRT (median 54 Gy), and 13 (45%) had tumor progression. Whereas tumor volume (P = .53), SRS vs EBRT (P = .45), and adjuvant vs salvage (P = .34) were not associated with progression after radiation therapy, spontaneous necrosis (hazard ratio [HR] = 82.3, P < .001), embolization necrosis (HR = 15.6, P = .03), and brain invasion (HR = 3.8, P = .008) predicted progression in univariate and multivariate analyses. Tumors treated with SRS/EBRT had 2- and 5-year actuarial locoregional control rates of 91%/88% and 71%/69%, respectively. Tumors with spontaneous necrosis, embolization necrosis, and no necrosis had 2- and 5-year locoregional control rates of 76%, 92%, and 100% and 36%, 73%, and 100%, respectively (P < .001). CONCLUSION: This study suggests that necrosis may be a negative predictor of radiation response regardless of radiation timing or modality. ABBREVIATIONS: AM, atypical meningiomaEBRT, external beam radiation therapyGTR, gross total resectionLC, locoregional controlOS, overall survivalPOE, preoperative embolizationRT, radiation therapySRS, stereotactic radiosurgerySTR, subtotal resection.

Clinical and Dosimetric Predictors of Acute Severe Lymphopenia During Radiation Therapy and Concurrent Temozolomide for High-Grade Glioma.

PURPOSE: Acute severe lymphopenia (ASL) frequently develops during radiation therapy (RT) and concurrent temozolomide (TMZ) for high-grade glioma (HGG) and is associated with decreased survival. The current study was designed to identify potential predictors of ASL, with a focus on actionable RT-specific dosimetric parameters. METHODS AND MATERIALS: From January 2007 to December 2012, 183 patients with HGG were treated with RT+TMZ and had available data including total lymphocyte count (TLC) and radiation dose-volume histogram parameters. ASL was defined as TLC of <500/µL within the first 3 months from the start of RT. Stepwise logistic regression analysis was used to determine the most important predictors of ASL. RESULTS: Fifty-three patients (29%) developed ASL. Patients with ASL had significantly worse overall survival than those without (median: 12.5 vs 20.2 months, respectively, P<.001). Stepwise logistic regression analysis identified female sex (odds ratio [OR]: 5.30; 95% confidence interval [CI]: 2.46-11.41), older age (OR: 1.05; 95% CI: 1.02-1.09), lower baseline TLC (OR: 0.92; 95% CI: 0.87-0.98), and higher brain volume receiving 25 Gy (V25Gy) (OR: 1.03; 95% CI: 1.003-1.05) as the most significant predictors for ASL. Brain V25Gy <56% appeared to be the optimal threshold (OR: 2.36; 95% CI: 1.11-5.01), with an ASL rate of 38% versus 20% above and below this threshold, respectively (P=.006). CONCLUSIONS: Female sex, older age, lower baseline TLC, and higher brain V25Gy are significant predictors of ASL during RT+TMZ therapy for HGG. Maintaining the V25Gy of brain below 56% may reduce the risk of ASL.

Impact of 1p/19q codeletion and histology on outcomes of anaplastic gliomas treated with radiation therapy and temozolomide.

PURPOSE: Anaplastic gliomas represent a heterogeneous group of primary high-grade brain tumors, and the optimal postoperative treatment remains controversial. In this report, we present our institutional data on the clinical outcomes of radiation therapy (RT) plus temozolomide (RT + TMZ) for anaplastic gliomas, stratified by histology and 1p/19q codeletion. METHODS AND MATERIALS: A single-institution retrospective review was conducted of patients with supratentorial anaplastic oligodendroglioma (AO), mixed anaplastic oligoastrocytoma (AOA), and anaplastic astrocytoma (AA). After surgery, RT was delivered at a median total dose of 60 Gy (range, 31.6-63 Gy) in daily fractions. All patients received standard concurrent TMZ, with or without adjuvant TMZ. Histological/molecular subtypes were defined as codeleted AO/AOA, non-codeleted AO/AOA, and AA. RESULTS: From 2000 to 2012, 111 cases met study criteria and were evaluable. Codeleted AO/AOA had superior overall survival (OS) to non-codeleted AO/AOA (91% vs 68% at 5 years, respectively, P=.02), whereas progression-free survival (PFS) was not significantly different (70% vs 46% at 5 years, respectively, P=.10). AA had inferior OS to non-codeleted AO/AOA (37% vs 68% at 5 years, respectively, P=.007) and inferior PFS (27% vs 46%, respectively, P=.03). On multivariate analysis, age, performance status, and histological or molecular subtype were independent predictors for both PFS and OS. Compared to historical controls, RT + TMZ provided comparable OS to RT with procarbazine, lomustine, and vincristine (RT + PCV) for codeleted AO/AOA, superior OS to RT alone for non-codeleted AO/AOA, and similar OS to RT alone for AA. CONCLUSIONS: RT + TMZ may be a promising treatment for both codeleted and non-codeleted AO/AOA, but its role for AA remains unclear.

Long-term changes in attitudes toward premarital sex in the United States: reexamining the role of cohort replacement.

Attitudes toward premarital sex in the United States have changed considerably since the 1970s. However, it is unclear whether these changes are due to cohort replacement, broader changes within cohorts, or a combination of the two processes. We examined within- and between-cohort changes in attitudes toward premarital sex in the United States from 1975 to 2008 using hierarchical age-period-cohort models based on data from the General Social Survey. We used a religious plausibility structure framework to examine several possible mechanisms for within- and between-cohort variation in premarital sex attitudes over time, including changes in religious participation, marital patterns, and family structure. The results provided mixed support for our hypotheses. Attitudes toward premarital sex became more permissive over time in the United States in part because of the process of cohort replacement, but the level of permissiveness peaked with the baby boomer cohorts. This cohort effect is due in part to differences in rates of religious service attendance and educational attainment. However, the overall increase in permissive attitudes toward premarital sex is also due to period effects that are not captured by the measures included in our analyses.

Radiation therapy dose escalation for glioblastoma multiforme in the era of temozolomide.

PURPOSE: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). METHODS AND MATERIALS: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/ß ratio of 5.6 for GBM. RESULTS: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dose at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR. CONCLUSION: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.

Predictors of individual tumor local control after stereotactic radiosurgery for non-small cell lung cancer brain metastases.

PURPOSE: To evaluate local control rates and predictors of individual tumor local control for brain metastases from non-small cell lung cancer (NSCLC) treated with stereotactic radiosurgery (SRS). METHODS AND MATERIALS: Between June 1998 and May 2011, 401 brain metastases in 228 patients were treated with Gamma Knife single-fraction SRS. Local failure was defined as an increase in lesion size after SRS. Local control was estimated using the Kaplan-Meier method. The Cox proportional hazards model was used for univariate and multivariate analysis. Receiver operating characteristic analysis was used to identify an optimal cutpoint for conformality index relative to local control. A P value <.05 was considered statistically significant. RESULTS: Median age was 60 years (range, 27-84 years). There were 66 cerebellar metastases (16%) and 335 supratentorial metastases (84%). The median prescription dose was 20 Gy (range, 14-24 Gy). Median overall survival from time of SRS was 12.1 months. The estimated local control at 12 months was 74%. On multivariate analysis, cerebellar location (hazard ratio [HR] 1.94, P=.009), larger tumor volume (HR 1.09, P<.001), and lower conformality (HR 0.700, P=.044) were significant independent predictors of local failure. Conformality index cutpoints of 1.4-1.9 were predictive of local control, whereas a cutpoint of 1.75 was the most predictive (P=.001). The adjusted Kaplan-Meier 1-year local control for conformality index ≥ 1.75 was 84% versus 69% for conformality index <1.75, controlling for tumor volume and location. The 1-year adjusted local control for cerebellar lesions was 60%, compared with 77% for supratentorial lesions, controlling for tumor volume and conformality index. CONCLUSIONS: Cerebellar tumor location, lower conformality index, and larger tumor volume were significant independent predictors of local failure after SRS for brain metastases from NSCLC. These results warrant further investigation in a prospective setting.

DSM-5 and neurocognitive disorders.

The newest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) introduces several changes in the diagnostic criteria for dementia and other cognitive disorders. Some of these changes may prove helpful for clinical and forensic practitioners, particularly when evaluating less severe cognitive impairments. The most substantial change is that the cognitive disorder-not otherwise specified category found in prior editions has been eliminated. Those disorders that do not cause sufficient impairment to qualify for a diagnosis of dementia are now defined as neurocognitive disorders and placed on a spectrum with the more severe conditions. The concept of social cognition is also introduced as one of the core functional domains that can be affected by a neurocognitive disorder. This concept may be particularly significant in the evaluation of patients with non-Alzheimer's dementias, such as frontotemporal dementia. With the aging of the population and the increasing recognition of the possibility of long-lasting cognitive deficits after traumatic brain injury, the need for assessment of cognitive disorders in medicolegal contexts is certain to increase. Forensic psychiatrists who perform these evaluations should understand the conceptualization of Neurocognitive Disorders as presented in DSM-5 and how it differs from prior diagnostic systems.

Management of atypical cranial meningiomas, part 1: predictors of recurrence and the role of adjuvant radiation after gross total resection.

BACKGROUND: Indications for external beam radiation therapy (EBRT) for atypical meningiomas (AMs) remain unclear. OBJECTIVE: To analyze features associated with recurrence in AM patients after gross total resection (GTR) and to assess the relative benefit of EBRT in a retrospective cohort study. METHODS: One hundred fifty-one primary AMs after GTR (88 female patients; median follow-up, 45.0 months) were examined for possible predictors of recurrence (age, sex, location, volume, bone involvement, brain invasion). The Fisher exact and Wilcoxon rank-sum tests were used to analyze the association between these predictors and use of EBRT. The impact on recurrence for these predictors and EBRT was analyzed with Kaplan-Meier and Cox regression. RESULTS: Of 151 patients, 13 (8.6%) experienced recurrence after GTR (median, 47.0 months). Multivariate analysis identified elevated mitotic index (P = .007) and brain invasion (P = .002) as predictors of recurrence. Larger volume (P = .96) was not associated with recurrence but was more likely to prompt EBRT (P = .001). Recurrences occurred in 11 of 112 with GTR (9.8%; median, 44 months) and 2 of 39 with GTR/EBRT (5.1%; median, 133 months). The 2-, 5-, and 10-year progression-free survival rates after GTR vs GTR/EBRT were 97%, 86%, and 68% vs 100%, 100%, and 78%. Kaplan-Meier analysis demonstrated no difference in progression-free survival or overall survival after GTR vs GTR/EBRT (P = .8, P > .99). CONCLUSION: Brain invasion and high mitotic rates may predict recurrence. After GTR of AMs, EBRT appears not to affect progression-free survival and overall survival, suggesting that observation rather than EBRT may be indicated after GTR.

Management of atypical cranial meningiomas, part 2: predictors of progression and the role of adjuvant radiation after subtotal resection.

BACKGROUND: The efficacies of adjuvant stereotactic radiosurgery (SRS) and external beam radiation therapy (EBRT) for atypical meningiomas (AMs) after subtotal resection (STR) remain unclear. OBJECTIVE: To analyze the clinical, histopathological, and radiographic features associated with progression in AM patients after STR. METHODS: Fifty-nine primary AMs after STR were examined for predictors of progression, including the impact of SRS and EBRT, in a retrospective cohort study. RESULTS: Twenty-seven patients (46%) progressed after STR (median, 30 months). On univariate analysis, spontaneous necrosis positively (hazard ratio = 5.2; P = .006) and adjuvant radiation negatively (hazard ratio = 0.3; P = .009) correlated with progression; on multivariate analysis, only adjuvant radiation remained independently significant (hazard ratio = 0.3; P = .006). SRS and EBRT were associated with greater local control (LC; P = .02) and progression-free survival (P = .007). The 2-, 5-, and 10-year actuarial LC rates after STR vs STR/EBRT were 60%, 34%, and 34% vs 96%, 65%, and 45%. The 2-, 5-, and 10-year actuarial progression-free survival rates after STR vs STR/EBRT were 60%, 30%, and 26% vs 96%, 65%, and 45%. Compared with STR alone, adjuvant radiation therapy significantly improved LC in AMs that lack spontaneous necrosis (P = .003) but did not improve LC in AMs with spontaneous necrosis (P = .6). CONCLUSION: Adjuvant SRS or EBRT improved LC of AMs after STR but only for tumors without spontaneous necrosis. Spontaneous necrosis may aid in decisions to administer adjuvant SRS or EBRT after STR of AMs.

A retrospective analysis of survival and prognostic factors after stereotactic radiosurgery for aggressive meningiomas.

BACKGROUND: While most meningiomas are benign, aggressive meningiomas are associated with high levels of recurrence and mortality. A single institution's Gamma Knife radiosurgical experience with atypical and malignant meningiomas is presented, stratified by the most recent WHO classification. METHODS: Thirty-one patients with atypical and 4 patients with malignant meningiomas treated with Gamma Knife radiosurgery between July 2000 and July 2011 were retrospectively reviewed. All patients underwent prior surgical resection. Overall survival was the primary endpoint and rate of disease recurrence in the brain was a secondary endpoint. Patients who had previous radiotherapy or prior surgical resection were included. Kaplan-Meier and Cox proportional hazards models were used to estimate survival and identify factors predictive of recurrence and survival. RESULTS: Post-Gamma Knife recurrence was identified in 11 patients (31.4%) with a median overall survival of 36 months and progression-free survival of 25.8 months. Nine patients (25.7%) had died. Three-year overall survival (OS) and progression-free survival (PFS) rates were 78.0% and 65.0%, respectively. WHO grade II 3-year OS and PFS were 83.4% and 70.1%, while WHO grade III 3-year OS and PFS were 33.3% and 0%. Recurrence rate was significantly higher in patients with a prior history of benign meningioma, nuclear atypia, high mitotic rate, spontaneous necrosis, and WHO grade III diagnosis on univariate analysis; only WHO grade III diagnosis was significant on multivariate analysis. Overall survival was adversely affected in patients with WHO grade III diagnosis, prior history of benign meningioma, prior fractionated radiotherapy, larger tumor volume, and higher isocenter number on univariate analysis; WHO grade III diagnosis and larger treated tumor volume were significant on multivariate analysis. CONCLUSION: Atypical and anaplastic meningiomas remain difficult tumors to treat. WHO grade III diagnosis and treated tumor volume were significantly predictive of recurrence and survival on multivariate analysis in aggressive meningioma patients treated with radiosurgery. Larger tumor size predicts poor survival, while nuclear atypia, necrosis, and increased mitotic rate are risk factors for recurrence. Clinical and pathologic predictors may help identify patients that are at higher risk for recurrence.