From posts to protection: Ethical considerations regarding forensic psychiatrists and a duty to warn based on social media.

Increasing use of social media in forensic mental health evaluations will lead to new challenges that must be resolved by forensic practitioners and the legal system. One such dilemma is the discovery of information that would typically trigger a legal duty and professional ethics obligation for mental health professionals to breach doctor-patient confidentiality to promote public safety and prevent harm to vulnerable third parties. Although the law and professional organizations offer clear guidance for practitioners in the treatment role, there is currently no clarity from the law or instruction from professional organizations on what mental health professionals should do if they discover such information during a confidential forensic evaluation. For example, a forensic evaluator may find evidence on social media of an evaluee's threats to seriously harm others, abuse of children and the elderly, or severely impaired driving. There are no clear guidelines for how a forensic psychiatrist should respond in these complicated situations. We review the legal concepts and historical evolution of confidentiality, privilege, and mandated reporter duties that forensic practitioners should consider in these legally ambiguous situations. Finally, we discuss ethics frameworks practitioners can implement to determine their most ethical course of action when faced with such dilemmas.

Psychological distress and coping efficacy in children with disorders of gut-brain interaction.

BACKGROUND: Multiple psychological factors influence disorders of gut-brain interaction (DGBIs). We aimed to evaluate psychological distress in Colombian schoolchildren with and without DGBIs. METHODS: We included children ages 8-18 years without organic medical conditions from largest regional public schools in Colombia. Children completed Spanish versions of Rome III diagnostic questionnaire for DGBIs, State Trait Anxiety Inventory for Children (STAIC), Children's Somatization Inventory (CSI), and a measure of coping efficacy. These data, demographic and socioeconomic characteristics, were compared between children with DGBIs and healthy peers. Exploratory analyses investigated differences between youth with symptoms of functional abdominal pain disorders (FAPDs) compared with healthy peers. KEY RESULTS: Of 1496 children, 281 (mean age 12.9 ± 2.2 years, 49.8% females) self-reported criteria for DGBIs and 125 reported (44.5%) FAPDs. Children with DGBIs had higher trait anxiety, emotional sensitivity, somatization including GI, non-GI, pain-related, and non-pain-related subscales (p < 0.001 each) and lower coping efficacy (p = 0.02) compared to healthy peers. Females had higher trait anxiety and somatization (p = 0.04 and p = 0.005, respectively). State and trait anxiety and coping efficacy differed based on location in children with DGBIs (p = 0.02, p = 0.03, and p < 0.001, respectively). Children with FAPDs had higher trait anxiety (p = 0.02) and somatization (p < 0.001) compared to healthy youth. CONCLUSIONS & INFERENCES: Children with DGBIs had higher anxiety, emotional sensitivity, and somatization, and lower coping efficacy compared with healthy youth. This highlights the importance of appraising psychological distress characteristics as well as incorporating conflict resolution, assertiveness training, and resilience building during the treatment of DGBIs.

Vertebral Tortuosity Is Associated With Increased Rate of Cardiovascular Events in Vascular Ehlers-Danlos Syndrome.

Background Arterial tortuosity is associated with adverse events in Marfan and Loeys-Dietz syndromes but remains understudied in Vascular Ehlers-Danlos syndrome. Methods and Results Subjects with a pathogenic COL3A1 variant diagnosed at age <50 years were included from 2 institutions and the GenTAC Registry (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions). Height-adjusted vertebral artery tortuosity index (VTI-h) using magnetic resonance or computed tomography angiography was calculated. Associations between VTI-h and outcomes of (1) cardiovascular events (arterial dissection/rupture, aneurysm requiring intervention, stroke), or (2) hollow organ collapse/rupture at age <50 years were evaluated using receiver operator curve analysis (using outcome by age 30 years) and mixed-effects Poisson regression for incidence rate ratios. Of 65 subjects (54% male), median VTI-h was 12 (interquartile range, 8-16). Variants were missense in 46%, splice site in 31%, and null/gene deletion in 14%. Thirty-two subjects (49%) had 59 events, including 28 dissections, 5 arterial ruptures, 4 aneurysms requiring intervention, 4 strokes, 11 hollow organ ruptures, and 7 pneumothoraces. Receiver operator curve analysis suggested optimal discrimination at VTI-h ≥15.5 for cardiovascular events (sensitivity 70%, specificity 76%) and no association with noncardiovascular events (area under the curve, 0.49 [95% CI, 0.22-0.78]). By multivariable analysis, older age was associated with increased cardiovascular event rate while VTI-h ≥15.5 was not (incidence rate ratios, 1.79 [95% CI, 0.76-4.24], P=0.185). However, VTI-h ≥15.5 was associated with events among those with high-risk variants <40 years (incidence rate ratios, 4.14 [95% CI, 1.13-15.10], P=0.032), suggesting effect modification by genotype and age. Conclusions Increased arterial tortuosity is associated with a higher incidence rate of cardiovascular events in Vascular Ehlers-Danlos syndrome. Vertebral tortuosity index may be a useful biomarker for prognosis when evaluated in conjunction with genotype and age.

Safety of exercise for adults with thoracic aortic aneurysms and dissections.

Background: Current guidelines for patients with thoracic aortic aneurysms or dissections (TAD) restrict vigorous exertion with the intention to prevent acute aortic dissections. However, a safe threshold for exercise intensity has not been established for TAD patients. In this study, we measured exertional changes in systolic and diastolic blood pressure during isometric and dynamic exercises in a cohort of TAD patients to determine safety of moderate intensity exercise. Methods: Thirty-one adults with TAD and 14 controls were recruited from UTHealth outpatient clinics. All participants completed an exercise protocol consisting of two circuits of five moderate intensity exercises: hand grips, leg raises, bicep curls, stationary cycling, and wall sits. Blood pressure values were recorded during exercise using Spacelabs OnTrak Ambulatory Blood Pressure monitors. Perceived exertion during each exercise was measured using the Borg CR-10 scale. Results: No significant differences in the maximum exertional systolic pressure, diastolic pressure, or change from baseline was found between the TAD and control groups. Higher amounts of self-reported weekly moderate activity level (MAL) in TAD correlated with lower exertional SBP during exercise. Higher Borg scores were associated with a greater change in systolic pressure. Conclusion: Moderate intensity exercise is safe and feasible for many TAD patients. Our data confirms that the Borg score may be a useful proxy for exercise intensity. In this study, we establish a reproducible exercise protocol that can be adapted to create individualized exercise regimens for TAD patients as part of a care plan to improve long-term cardiovascular health.

Validation of the Ottawa Troponin Pathway.

BACKGROUND: The Ottawa Troponin Pathway (OTP) was developed to improve Non-ST elevation myocardial infarction (NSTEMI) diagnosis accuracy using 3-h serial conventional troponin I (TnI) measurements. We sought to validate the OTP in patients with TnI values >99th percentile upper reference limit (>45 ng/L). METHODS: We conducted a health records review in adult patients with NSTEMI symptoms with at least two serial TnI and at least one >45 ng/L at two emergency departments (EDs). We collected baseline characteristics, ED management and disposition. 30-day outcomes included death due to cardiac ischemia, an unknown cause, or NSTEMI. RESULTS: 635 patients were included, and 107 patients were diagnosed with NSTEMI within 30-days. 217 patients had at least one TnI value >45 ng/L but <100 ng/L, of whom 4 patients were diagnosed with NSTEMI. 418 patients had at least one TnI value ≥100 ng/L, and 103 were diagnosed with NSTEMI. The OTP accurately identified all 107 patients with NSTEMI: sensitivity and specificity was 100% (95% CI 96.6%-100%) and 32.2% (95% CI 28.2%-36.4) respectively. CONCLUSIONS: The OTP is validated among patients with TnI values above the 99th percentile with symptoms concerning for ACS. Using OTP will allow for early referral and discharge home and improve ED crowding. REB NUMBER: 20180393-01H.

Voluntary intoxication, homicide, and mens rea: Past, present, and future.

Voluntary, or intentional, acute intoxication does not qualify for an insanity defense. However, in many jurisdictions, voluntary intoxication can create a diminished capacity to form a specific intent necessary for a criminal offense. This is a type of mens rea defense. Homicide provides a clear example where the absence of a required specific intent can lead to a lesser included crime that does not require that specific intent. Thereby, a mens rea defense may lessen a first-degree murder charge to a lesser degree or even manslaughter, depending on the jurisdiction. After reviewing the history of mens rea defenses and voluntary intoxication, we performed a search of LexisNexis for state statutes and case law regulating the use of voluntary intoxication in mens rea defenses, focusing on homicide-related offenses. In this article, we compare the different approaches that have developed to address this complex issue. We discuss why knowledge of these different approaches is essential to the practicing forensic examiner in relevant jurisdictions and explore developing issues in the area.

Efficient Delivery of Nerve Growth Factors to the Central Nervous System for Neural Regeneration.

The central nervous system (CNS) plays a central role in the control of sensory and motor functions, and the disruption of its barriers can result in severe and debilitating neurological disorders. Neurotrophins are promising therapeutic agents for neural regeneration in the damaged CNS. However, their penetration across the blood-brain barrier remains a formidable challenge, representing a bottleneck for brain and spinal cord therapy. Herein, a nanocapsule-based delivery system is reported that enables intravenously injected nerve growth factor (NGF) to enter the CNS in healthy mice and nonhuman primates. Under pathological conditions, the delivery of NGF enables neural regeneration, tissue remodeling, and functional recovery in mice with spinal cord injury. This technology can be utilized to deliver other neurotrophins and growth factors to the CNS, opening a new avenue for tissue engineering and the treatment of CNS disorders and neurodegenerative diseases.

The Effect of Ketorolac on Thoracolumbar Posterolateral Fusion: A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: The purpose of this study was to evaluate the effect of postoperative ketorolac administration (ie, dosage and duration of use) on pseudarthrosis following thoracolumbar posterolateral spinal fusions. SUMMARY OF BACKGROUND DATA: Ketorolac is a nonsteroidal anti-inflammatory drug often administered for pain control after spine surgery. The main concern with ketorolac is the risk of pseudarthrosis following fusion. MATERIALS AND METHODS: A systematic search of multiple medical reference databases was conducted for studies detailing postoperative ketorolac use in lumbar fusion and scoliosis surgery in adult and pediatric patients, respectively. Meta-analysis was performed using the random-effects model for heterogeneity as this study analyzes heterogenous patient populations undergoing variable approaches to fusion and variable numbers of levels with variable means of detection of pseudarthrosis. Outcome measure was pseudarthrosis. RESULTS: Overall, 6 studies totaling 1558 patients were reviewed. Pseudarthrosis was observed in 119 (7.6%) patients. Pseudarthrosis were observed in adults with ketorolac administered for >2 days [odds ratio (OR), 3.44, 95% confidence interval (95% CI), 1.87-6.36; P<0.001], adults with doses of ≥120 mg/d (OR, 2.93, 95% CI, 1.06-8.12; P=0.039), and adults with ketorolac administered for >2 days and at doses ≥120 mg/d (OR, 4.75, 95% CI, 2.34-9.62; P<0.001). Ketorolac use in smokers was associated with pseudarthrosis (OR, 8.71, 95% CI, 2.23-34.0; P=0.002). CONCLUSION: Ketorolac, when administered for >2 days and/or at a dose of ≥120 mg/d, is associated with pseudarthrosis in adults after posterolateral lumbar fusion. Ketorolac use in smokers is also associated with pseudarthrosis.

Effectiveness of Reoperations for Adjacent Segment Disease Following Lumbar Spinal Fusion.

Although several options are available to address adjacent segment disease (ASD), the most effective surgical treatment has not been determined. In addition, it is important to subdivide ASD into stenosis with or without instability to determine if a decompression alone vs an extension of fusion is necessary. A systematic search of multiple medical reference databases was conducted for studies on surgical treatment of ASD. The primary outcome measures used were radiographic and clinical success rates. Meta-analysis was completed to determine effect summary values, 95% confidence intervals, and Q statistic and I2 values, using the random effects model for heterogeneity. The search yielded 662 studies, of which 657 were excluded. A total of 5 (level IV) studies with a total of 118 patients were included in this review. In 2 studies (46 patients), stenosis without instability was the indication for reoperation for ASD. However, extension of fusion was the modality of choice for the treatment of ASD in all studies. Overall clinical improvement (in back and/or leg pain scores) was noted in 71.3% of patients (95% confidence interval, 37.4-100), while radiographic fusion was noted in 89.3% of patients (95% confidence interval, 51.2-100). Following reoperation for ASD, revision surgery rates ranged from 4.5% to 23.1% at last clinical follow-up. There is variability in the clinical improvement following lumbar fusion for ASD. In addition, little literature exists regarding the optimal treatment options for patients with ASD for stenosis with or without instability. [Orthopedics. 2018; 41(2):e161-e167.].

Intraoperative Neuromonitoring for Anterior Cervical Spine Surgery: What Is the Evidence?

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: The goal of this study was to (i) assess the risk of neurological injury after anterior cervical spine surgery (ACSS) with and without intraoperative neuromonitoring (ION) and (ii) evaluate differences in the sensitivity and specificity of ION for ACSS. SUMMARY OF BACKGROUND DATA: Although ION is used to detect impending neurological injuries in deformity surgery, it's utility in ACSS remains controversial. METHODS: A systematic search of multiple medical reference databases was conducted for studies on ION use for ACSS. Studies that included posterior cervical surgery were excluded. Meta-analysis was performed using the random-effects model for heterogeneity. Outcome measure was postoperative neurological injury. RESULTS: The search yielded 10 studies totaling 26,357 patients. The weighted risk of neurological injury after ACSS was 0.64% (0.23-1.25). The weighted risk of neurological injury was 0.20% (0.05-0.47) for ACDFs compared with 1.02% (0.10-2.88) for corpectomies. For ACDFs, there was no difference in the risk of neurological injury with or without ION (odds ratio, 0.726; confidence interval, CI, 0.287-1.833; P = 0.498). The pooled sensitivities and specificities of ION for ACSS are 71% (CI: 48%-87%) and 98% (CI: 92%-100%), respectively. Unimodal ION has a higher specificity than multimodal ION [unimodal: 99% (CI: 97%-100%), multimodal: 92% (CI: 81%-96%), P = 0.0218]. There was no statistically significant difference in sensitivities between unimodal and multimodal [68% vs. 88%, respectively, P = 0.949]. CONCLUSION: The risk of neurological injury after ACSS is low although procedures involving a corpectomy may carry a higher risk. For ACDFs, there is no difference in the risk of neurological injury with or without ION use. Unimodal ION has a higher specificity than multimodal ION and may minimize "subclinical" intraoperative alerts in ACSS. LEVEL OF EVIDENCE: 3.

Starter unit flexibility for engineered product synthesis by the nonreducing polyketide synthase PksA.

Nonreducing polyketide synthases (NR-PKSs) are unique among PKSs in their domain structure, notably including a starter unit:acyl-carrier protein (ACP) transacylase (SAT) domain that selects an acyl group as the primer for biosynthesis, most commonly acetyl-CoA from central metabolism. This clan of mega-enzymes resembles fatty acid synthases (FASs) by sharing both their central chain elongation steps and their capacity for iterative catalysis. In this mode of synthesis, catalytic domains involved in chain extension exhibit substrate plasticity to accommodate growing chains as small as two carbons to 20 or more. PksA is the NR-PKS central to the biosynthesis of the mycotoxin aflatoxin B1 whose SAT domain accepts an unusual hexanoyl starter from a dedicated yeast-like FAS. Explored in this paper is the ability of PksA to utilize a selection of potential starter units as substrates to initiate and sustain extension and cyclization to on-target, programmed polyketide synthesis. Most of these starter units were successfully accepted and properly processed by PksA to achieve biosynthesis of the predicted naphthopyrone product. Analysis of the on-target and derailment products revealed trends of tolerance by individual PksA domains to alternative starter units. In addition, natural and un-natural variants of the active site cysteine were examined and found to be capable of biosynthesis, suggesting possible direct loading of starter units onto the ß-ketoacyl synthase (KS) domain. In light of the data assembled here, the predictable synthesis of unnatural products by NR-PKSs is more fully defined.

Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis.

Lovastatin is an important statin prescribed for the treatment and prevention of cardiovascular diseases. Biosynthesis of lovastatin uses an iterative type I polyketide synthase (PKS). LovC is a trans-acting enoyl reductase (ER) that specifically reduces three out of eight possible polyketide intermediates during lovastatin biosynthesis. Such trans-acting ERs have been reported across a variety of other fungal PKS enzymes as a strategy in nature to diversify polyketides. How LovC achieves such specificity is unknown. The 1.9-Å structure of LovC reveals that LovC possesses a medium-chain dehydrogenase/reductase (MDR) fold with a unique monomeric assembly. Two LovC cocrystal structures and enzymological studies help elucidate the molecular basis of LovC specificity, define stereochemistry, and identify active-site residues. Sequence alignment indicates a general applicability to trans-acting ERs of fungal PKSs, as well as their potential application to directing biosynthesis.

Medical student/student doctor access to patients in an emergency department.

OBJECTIVES: To determine the proportion of patients in a teaching hospital ED who are available to medical students; identify barriers to student access to patients; and determine whether patients are more likely to be accessible if the term student doctor is used rather than medical student. METHODS: Repeated cross-sectional study of the ED of a tertiary teaching hospital. Interviews were attempted with all patients in the ED during six 4 h periods. Outcome measures included: number of patients present and accessible to students; present but inaccessible, absent or unfit to be seen for clinical reasons; number of patients consenting to history, physical examination and certain procedures; and difference in patient consent between the terms 'medical student' and 'student doctor'. RESULTS: Overall, 180 of 450 (40.0%) patients completed the interview, 72 (16.0%) were able to be observed only, and 198 (44.0%) were not suitable for interview or observation. The common reasons for patient unsuitability were: physically not available (60%), being assessed by a health professional or undergoing a procedure (13.0%) altered mental status (7.4%), unstable or terminally ill (5.2%); refusal to participate in the study (4.8%), or dangerous or under arrest (4.1%). No significant differences were found in patient willingness to undergo clinical skills from 'student doctors' compared with 'medical students'. CONCLUSION: A minimum 40% of patients in a tertiary ED are accessible for student learning, with high proportions of patients accepting of students practising supervised history-taking, physical examination, and most less-invasive procedural skills.

Double oxidation of the cyclic nonaketide dihydromonacolin L to monacolin J by a single cytochrome P450 monooxygenase, LovA.

Lovastatin, a cyclic nonaketide from Aspergillus terreus, is a hypercholesterolemic agent and a precursor to simvastatin, a semi-synthetic cholesterol-lowering drug. The biosynthesis of the lovastatin backbone (dihydromonacolin L) and the final 2-methylbutyryl decoration have been fully characterized. However, it remains unclear how two central reactions are catalyzed, namely, introduction of the 4a,5-double bond and hydroxylation at C-8. A cytochrome P450 gene, lovA, clustered with polyketide synthase lovB, has been a prime candidate for these reactions, but inability to obtain LovA recombinant enzyme has impeded detailed biochemical analyses. The synthetic codon optimization and/or N-terminal peptide replacement of lovA allowed the lovA expression in yeast (Saccharomyces cerevisiae). Both in vivo feeding and in vitro enzyme assays showed that LovA catalyzed the conversion of dihydromonacolin L acid to monacolin L acid and monacolin J acid, two proposed pathway intermediates in the biosynthesis of lovastatin. LovA was demonstrated to catalyze the regio- and stereo-specific hydroxylation of monacolin L acid to yield monacolin J acid. These results demonstrate that LovA is the single enzyme that performs both of the two elusive oxidative reactions in the lovastatin biosynthesis.

Forensic Psychiatry in the People's Republic of China.

Forensic psychiatry is practiced somewhat differently in the People's Republic of China (PRC) than in the United States. In the United States, psychiatrists and psychologists often work at the interface of mental health and criminal, civil, family, correctional, and law enforcement matters. Their roles in the United States are sometimes consultative and sometimes more direct, sometimes as agency or government employees but often as private forensic practitioners. In China, forensic roles have only recently expanded from the criminal law context. Forensic psychiatrists are almost always government agents/employees, and evaluations usually address only criminal responsibility. One of the authors (Dr. Gao), after spending almost a year in the United States working with Dr. Reid and other professionals, introduced several new forensic concepts to Kangning Hospital in the coastal city of Shenzhen. Many of those concepts have changed forensic procedures in the Guangdong region and are spreading more broadly in China.

Enzymatic synthesis of resorcylic acid lactones by cooperation of fungal iterative polyketide synthases involved in hypothemycin biosynthesis.

Hypothemycin is a macrolide protein kinase inhibitor from the fungus Hypomyces subiculosus. During biosynthesis, its carbon framework is assembled by two iterative polyketide synthases (PKSs), Hpm8 (highly reducing) and Hpm3 (nonreducing). These were heterologously expressed in Saccharomyces cerevisiae BJ5464-NpgA, purified to near homogeneity, and reconstituted in vitro to produce (6'S,10'S)-trans-7',8'-dehydrozearalenol (1) from malonyl-CoA and NADPH. The structure of 1 was determined by X-ray crystallographic analysis. In the absence of functional Hpm3, the reducing PKS Hpm8 produces and offloads truncated pyrone products instead of the expected hexaketide. The nonreducing Hpm3 is able to accept an N-acetylcysteamine thioester of a correctly functionalized hexaketide to form 1, but it is unable to initiate polyketide formation from malonyl-CoA. We show that the starter-unit:ACP transacylase (SAT) of Hpm3 is critical for crosstalk between the two enzymes and that the rate of biosynthesis of 1 is determined by the rate of hexaketide formation by Hpm8.

Complete reconstitution of a highly reducing iterative polyketide synthase.

Highly reducing iterative polyketide synthases are large, multifunctional enzymes that make important metabolites in fungi, such as lovastatin, a cholesterol-lowering drug from Aspergillus terreus. We report efficient expression of the lovastatin nonaketide synthase (LovB) from an engineered strain of Saccharomyces cerevisiae, as well as complete reconstitution of its catalytic function in the presence and absence of cofactors (the reduced form of nicotinamide adenine dinucleotide phosphate and S-adenosylmethionine) and its partner enzyme, the enoyl reductase LovC. Our results demonstrate that LovB retains correct intermediates until completion of synthesis of dihydromonacolin L, but off-loads incorrectly processed compounds as pyrones or hydrolytic products. Experiments replacing LovC with analogous MlcG from compactin biosynthesis demonstrate a gate-keeping function for this partner enzyme. This study represents a key step in the understanding of the functions and structures of this family of enzymes.

Drug discovery and natural products: end of an era or an endless frontier?

Historically, the majority of new drugs have been generated from natural products (secondary metabolites) and from compounds derived from natural products. During the past 15 years, pharmaceutical industry research into natural products has declined, in part because of an emphasis on high-throughput screening of synthetic libraries. Currently there is substantial decline in new drug approvals and impending loss of patent protection for important medicines. However, untapped biological resources, "smart screening" methods, robotic separation with structural analysis, metabolic engineering, and synthetic biology offer exciting technologies for new natural product drug discovery. Advances in rapid genetic sequencing, coupled with manipulation of biosynthetic pathways, may provide a vast resource for the future discovery of pharmaceutical agents.