Biopsychosocial factors associated with complications in patients with frostbite.

Cold weather injuries can be devastating and life changing. Biopsychosocial factors such as homelessness and mental illness (especially substance use disorders [SUDs]) are known risk factors for incurring frostbite. Based on clinical experience in an urban level 1 trauma center, we hypothesized that complications following frostbite injury would be influenced by homelessness, SUDs, and other forms of mental illness. The aim of this study was to examine the relationship between biopsychosocial factors and both amputations and unplanned hospital readmissions after cold injuries. Patients admitted with a diagnosis of frostbite between the winters of 2009 and 2018 were included in this retrospective cohort study. Descriptive statistics and multivariable regression assessed factors associated with outcomes of interest. Of the 148 patients in the study, 40 had unplanned readmissions within 1 year. Readmitted patients were significantly less likely to have a stable living situation (48.7% vs 75.0%, P = .005) and more likely to have an SUD (85.0% vs 60.2%, P = .005) or other psychiatric disorder (70.0% vs 50.9%, P = .042). Homelessness and SUDs were independent predictors of unplanned readmission. Overall, 18% of frostbite injuries resulted in amputation. Any history of drug and/or alcohol use independently predicted amputations. The study results suggest that additional hospital and community resources may need to be marshaled to prevent vulnerable patients with biopsychosocial risk factors from having complications after frostbite. Complications place a high downstream burden on healthcare systems. Clinicians caring for frostbite patients with comorbid conditions can use these findings to inform care and discharge decisions.

Case report: asenapine and anticholinergic toxicity.

While antipsychotic medications have long been associated with anticholinergic effects, asenapine has been purported to have no capacity for muscarinic cholinergic antagonism based on in vitro studies. Research in rat brain tissue has yielded different results, with one study finding more cholinergic M1-5 binding in the medial prefrontal cortex, dorsolateral frontal cortex and hippocampal CA1 and CA3 areas than would be predicted from in vitro findings. Moreover, it is structurally similar to other anticholinergic antipsychotics such as loxapine and, to a lesser degree, quetiapine, olanzapine and clozapine. This case report describes the anticholinergic toxidrome in a patient treated with benztropine and paroxetine at stable doses, with the emergence of the toxidrome after upward titration of asenapine. A broad differential was considered. With further consideration of the history, time-course, clinical features and physical examination, the presentation is most indicative of the anticholinergic toxidrome. Although not employed, physostigmine, the antidote for anticholinergic delirium, could help to differentiate this toxidrome and serve as a diagnostic and therapeutic intervention. We have presented this case to highlight the importance for clinicians to integrate history and bedside examination data with principles of pharmacology. In particular, asenapine should be added to the list of compounds with recognized anticholinergic potential.

American Association for Emergency Psychiatry Recommendations to Address Psychiatric Staff Shortages in Emergency Settings.

OBJECTIVE: The psychological sequelae of the COVID-19 crisis will increase demands for psychiatric care in already strained emergency and mental health systems. To address the shortage of psychiatrists (and nurse practitioners and physician assistants) in emergency settings (ESs), the American Association for Emergency Psychiatry (AAEP) has established recommendations for utilizing nonprescribing mental health professionals in the evaluation and management of psychiatric patients in these contexts. METHODS: Faced with limited research on the roles and competencies of nonprescribing psychiatric emergency clinicians (PECs), a multidisciplinary committee of members of AAEP was tasked with developing recommendations for use of PECs. RESULTS: The committee developed eight recommendations regarding the role of PECs in evaluation and management of patients who present to ESs with behavioral emergencies. PECs should have the following competencies: conducting independent psychiatric and substance abuse evaluations; managing behavioral emergencies; aiding in the recognition of confounding medical illnesses, intoxication and withdrawal states, and adverse drug reactions; developing appropriate treatment plans; recognizing when consultation from a psychiatrist or emergency physician is indicated; possessing self-awareness and recognizing clinician-patient dynamics; understanding medicolegal issues, such as involuntary holds and decision-making capacity; and collaborating with clinical teams in ESs. PECs are not meant to replace psychiatrists but to extend the psychiatrist's reach. Use of PECs has already been implemented in some areas of the country. CONCLUSIONS: On the basis of the AAEP recommendations, ESs can address staffing shortages while ensuring safe management of patients with behavioral emergencies. With appropriate orientation and training, the PEC can serve effectively and competently in an ES.

Clozapine usage increases the incidence of pneumonia compared with risperidone and the general population: a retrospective comparison of clozapine, risperidone, and the general population in a single hospital over 25 months.

The aim of this study was to determine whether the incidence of pneumonia in patients taking clozapine was more frequent compared with those taking risperidone or no atypical antipsychotics at all before admission to a tertiary care medical center. This was a retrospective, case-matched study of 465 general medicine patients over a 25 month period from 1 July 2010 to 31 July 2012. Detailed electronic medical records were analyzed to explore the association between the use of two atypical antipsychotics and incidence of pneumonia. Of the 155 patients in the clozapine group, 54 (34.8%) had documented pneumonia compared with 22 (14.2%) in the risperidone group and 18 (11.6%) in the general population group. Clozapine, when compared with the untreated general population, was associated with an increased risk of pneumonia (odds ratio=4.07; 95% confidence interval=2.25-7.36). There was, however, no significant increase in the risk of pneumonia associated with the use of risperidone (odds ratio=1.26; 95% confidence interval=0.65-2.45). Clozapine use is associated with increased risk of pneumonia that may be related to immunologic factors or side effects of sedation and drooling that make aspiration more likely, although causative mechanisms require further investigation. These findings suggest that providers should use added caution in choosing candidates for clozapine therapy.

Updates in Psychosomatic Medicine: 2014.

BACKGROUND: The amount of literature published annually related to psychosomatic medicine is vast; this poses a challenge for practitioners to keep up-to-date in all but a small area of expertise. OBJECTIVES: To introduce how a group process using volunteer experts can be harnessed to provide clinicians with a manageable selection of important publications in psychosomatic medicine, organized by specialty area, for 2014. METHODS: We used quarterly annotated abstracts selected by experts from the Academy of Psychosomatic Medicine and the European Association of Psychosomatic Medicine in 15 subspecialties to create a list of important articles. RESULTS: In 2014, subspecialty experts selected 88 articles of interest for practitioners of psychosomatic medicine. For this review, 14 articles were chosen. CONCLUSIONS: A group process can be used to whittle down the vast literature in psychosomatic medicine and compile a list of important articles for individual practitioners. Such an approach is consistent with the idea of physicians as lifelong learners and educators.

Interferon stimulated exonuclease gene 20 kDa links psychiatric events to distinct hepatitis C virus responses in human immunodeficiency virus positive patients.

Hepatitis C Virus (HCV) infection occurs frequently in patients with preexisting mental illness. Treatment for chronic hepatitis C using interferon formulations often increases risk for neuro-psychiatric symptoms. Pegylated-Interferon-α (PegIFN-α) remains crucial for attaining sustained virologic response (SVR); however, PegIFN-α based treatment is associated with psychiatric adverse effects, which require dose reduction and/or interruption. This study's main objective was to identify genes induced by PegIFN-α and expressed in the central nervous system and immune system, which could mediate the development of psychiatric toxicity in association with antiviral outcome. Using peripheral blood mononuclear cells from Human Immunodeficiency Virus (HIV)/HCV co-infected donors (N = 28), DNA microarray analysis was performed and 21 differentially regulated genes were identified in patients with psychiatric toxicity versus those without. Using these 21 expression profiles a two-way-ANOVA was performed to select genes based on antiviral outcome and occurrence of neuro-psychiatric adverse events. Microarray analysis demonstrated that Interferon-stimulated-exonuclease-gene 20 kDa (ISG20) and Interferon-alpha-inducible-protein 27 (IFI27) were the most regulated genes (P < 0.05) between three groups that were built by combining antiviral outcome and neuro-psychiatric toxicity. Validation by bDNA assay confirmed that ISG20 expression levels were significantly associated with these outcomes (P < 0.035). Baseline levels and induction of ISG20 correlated independently with no occurrence of psychiatric adverse events and non-response to therapy (P < 0.001). Among the 21 genes that were associated with psychiatric adverse events and 20 Interferon-inducible genes (IFIGs) used as controls, only ISG20 expression was able to link PegIFN-α related neuro-psychiatric toxicity to distinct HCV-responses in patients co-infected with HIV and HCV in vivo.

NEUROBIOLOGICAL ASPECTS OF SUICIDE AND SUICIDE ATTEMPTS IN BIPOLAR DISORDER.

Suicide and bipolar disorder (BD) are challenging, complex, and intertwined areas of study in contemporary psychiatry. Indeed, BD is associated with the highest lifetime risk for suicide attempt and completion of all the psychiatric conditions. Given that several clinical risk factors for both suicide and BD have been well noted in the literature, exploring the neurobiological aspects of suicide in BD may provide insights into both preventive measures and future novel treatments. This review synthesizes findings regarding the neurobiological aspects of suicide and, when applicable, their link to BD. Neurochemical findings, genes/epigenetics, and potential molecular targets for current or future treatments are discussed. The role of endophenotypes and related proximal and distal risk factors underlying suicidal behavior are also explored. Lastly, we discuss the manner in which preclinical work on aggression and impulsivity may provide additional insights for the future development of novel treatments.

The rising incidence of intentional ingestion of ethanol-containing hand sanitizers.

OBJECTIVE: To describe a case of intentional ingestion of hand sanitizer in our hospital and to review published cases and those reported to the American Association of Poison Control Centers' National Poison Data System. DESIGN: A case report, a literature review of published cases, and a query of the National Poison Data System. SETTING: Medical intensive care unit. PATIENT: Seventeen-yr-old male 37-kg with an intentional ingestion of a hand sanitizer product into his gastrostomy tube. INTERVENTIONS: Intubation, ventilation, and hemodialysis. MEASUREMENTS AND MAIN RESULTS: Incidence and outcome of reported cases of unintentional and intentional ethanol containing-hand sanitizer ingestion in the United States from 2005 through 2009. A literature search found 14 detailed case reports of intentional alcohol-based hand sanitizer ingestions with one death. From 2005 to 2009, the National Poison Data System received reports of 68,712 exposures to 96 ethanol-based hand sanitizers. The number of new cases increased by an average of 1,894 (95% confidence interval [CI] 1266-2521) cases per year (p =.002). In 2005, the rate of exposures, per year, per million U.S. residents was 33.7 (95% CI 28.4-39.1); from 2005 to 2009, this rate increased on average by 5.87 per year (95% CI 3.70-8.04; p = .003). In 2005, the rate of intentional exposures, per year, per million U.S. residents, was 0.68 (95% CI 0.17-1.20); from 2005 to 2009, this rate increased on average by 0.32 per year (95% CI 0.11-0.53; p = .02). CONCLUSIONS: The number of new cases per year of intentional hand sanitizer ingestion significantly increased during this 5-yr period. Although the majority of cases of hand sanitizer ingestion have a favorable outcome, 288 moderate and 12 major medical outcomes were reported in this National Poison Data System cohort. Increased awareness of the risks associated with intentional ingestion is warranted, particularly among healthcare providers caring for persons with a history of substance abuse, risk-taking behavior, or suicidal ideation.

HIV/Hepatitis C virus-coinfected virologic responders to pegylated interferon and ribavirin therapy more frequently incur interferon-related adverse events than nonresponders do.

BACKGROUND: This study aimed to assess the relationship between interferon (IFN)-related adverse effects and Hepatitis C virus (HCV) virologic response in HIV/HCV-coinfected individuals treated with pegylated interferon and ribavirin. METHODS: We conducted 2 prospective, open-label trials treating HIV/HCV-coinfected individuals with pegylated interferon alpha-2b or alpha-2a and ribavirin for 48 weeks. Safety laboratories, HCV RNA, psychiatric, and ophthalmologic evaluations were performed at baseline and monthly until week 72. RESULTS: Responders were defined as those with HCV RNA decline of > or = 2-log drop from baseline and nonresponders were those who did not. Remarkably, of the 27 patients (50%) who developed psychiatric toxicities, 26 patients were responders, although only 1 of 14 virologic nonresponders experienced psychiatric toxicity. Other adverse effects, such as anemia and ophthalmologic toxicities, were also more frequent in responders compared with nonresponders. Decline in CD4 T-cell counts strongly correlated with HCV viral decline. CONCLUSIONS: Our study demonstrates coupling of antiviral effect and occurrence of adverse events in HIV/HCV-coinfected patients. These patients with IFN-related adverse effects need a multidisciplinary treatment approach, hence, they are more likely to achieve sustained virologic response. Future studies are needed to evaluate the factors that predict the development of IFN-alpha-dependent adverse events before therapy.

Topologies of complexes containing O6-alkylguanine-DNA alkyltransferase and DNA.

The mutagenic and cytotoxic effects of many alkylating agents are reduced by O(6)-alkylguanine-DNA alkyltransferase (AGT). In humans, this protein not only protects the integrity of the genome, but also contributes to the resistance of tumors to DNA-alkylating chemotherapeutic agents. Here we describe and test models for cooperative multiprotein complexes of AGT with single-stranded and duplex DNAs that are based on in vitro binding data and the crystal structure of a 1:1 AGT-DNA complex. These models predict that cooperative assemblies contain a three-start helical array of proteins with dominant protein-protein interactions between the amino-terminal face of protein n and the carboxy-terminal face of protein n+3, and they predict that binding duplex DNA does not require large changes in B-form DNA geometry. Experimental tests using protein cross-linking analyzed by mass spectrometry, electrophoretic and analytical ultracentrifugation binding assays, and topological analyses with closed circular DNA show that the properties of multiprotein AGT-DNA complexes are consistent with these predictions.

Interactions of human O(6)-alkylguanine-DNA alkyltransferase (AGT) with short double-stranded DNAs.

O(6)-alkylguanine-DNA alkyltransferase (AGT) is a ubiquitous enzyme with an amino acid sequence that is conserved in Eubacteria, Archaea, and Eukarya. It repairs O(6)-alkylguanine and O(4)-alkylthymine adducts in single-stranded and duplex DNAs. In performing these functions, AGT must partition between adduct-containing sites and the large excess of adduct-free DNA distributed throughout the genome. Here, we characterize the binding of human AGT to linear double-stranded, adduct-free DNAs ranging in length from 11 bp to 2686 bp. Moderately cooperative binding (22.6 +/- 3.7 < or = omega < or = 145.0 +/- 37.0) results in an all-or-nothing association pattern on short templates. The apparent binding site size S(app) (mean = 4.39 +/- 0.02 bp) oscillates with increasing template length. Oscillations in cooperativity factor omega have the same frequency but are of opposite phase to S(app), with the result that the most stable protein-protein and protein-DNA interactions occur at the highest packing densities. The oscillation period (4.05 +/- 0.02 bp/protein) is nearly identical to the occluded binding site size obtained at the highest measured binding density (4 bp/protein) and is significantly smaller than the contour length ( approximately 8 bp) occupied in crystalline complexes. A model in which protein molecules overlap along the DNA contour is proposed to account for these features. High AGT densities resulting from cooperative binding may allow efficient search for lesions in the context of chromatin remodeling and DNA replication.

Seizure length in electroconvulsive therapy as a function of age, sex, and treatment number.

Most electroconvulsive therapy (ECT) research indicates that seizure length does not correlate with clinical efficacy. However, it is common in practice for clinicians to undertake measures to prolong seizures if the duration seems to be too short, although there is no universally agreed upon minimum seizure duration for ECT. We felt it would be informative for the ECT field to report mean seizure durations over the course of treatments based on age and sex in a very large cohort to provide norms for reference. We studied 519 patients' courses of ECT and recorded treatment number, sex, and age along with motor and electroencephalogram seizure duration. We found that women have longer seizures, but only at the first treatment session. There is a strong inverse correlation between age and seizure length. The biggest drop in seizure duration along a course of treatments occurs between the first and second treatments; beyond that, seizure duration remains relatively constant.

Interactions of human O6-alkylguanine-DNA alkyltransferase (AGT) with short single-stranded DNAs.

The O6-alkylguanine-DNA alkyltransferase (AGT) repairs O6-alkylguanine and O4-alkylthymine adducts in single-stranded and duplex DNAs. Here we characterize the binding of AGT to single-stranded DNAs ranging in length from 5 to 78 nucleotides (nt). Binding is moderately cooperative (37.9 +/- 3.0

Active-site alkylation destabilizes human O6-alkylguanine DNA alkyltransferase.

O(6)-alkylguanine-DNA alkyltransferase (AGT) repairs pro-mutagenic O(6)-alkylguanine and O(4)-alkylthymine lesions in DNA. The alkylated form of the protein is not reactivated; instead, it is rapidly ubiquitinated and degraded. Here, we show that alkylation destabilizes the native fold of the protein by 0.5-1.2 kcal/mole and the DNA-binding function by 0.8-1.4 kcal/mole. On this basis, we propose that destabilization of the native conformational ensemble acts as a signal for ubiquitination.

Effects of zinc occupancy on human O6-alkylguanine-DNA alkyltransferase.

A recent crystallographic study of recombinant human O(6)-alkylguanine-DNA alkyltransferase (hAGT) revealed a previously unknown zinc atom [Daniels et al., (2000) EMBO J. 19, 1719-1730]. The effects of zinc on the properties of hAGT are reported here. In bacterial expression systems, recombinant hAGT was produced in increasingly larger quantities when growth media are supplemented with up to 0.1 mM ZnCl(2). Metal-enriched hAGT samples had a 5-fold increase in repair rate constant over conventionally purified protein samples and a 60-fold increase over metal-stripped hAGT. In addition, mutants of the zinc-binding residues had decreases in zinc occupancy that correlated with reductions in repair rate. Zinc modulation did not abolish the repair capacity of a fraction of the hAGT population, as evidenced by the stoichiometric reaction with an oligodeoxyribonucleotide substrate. Zinc occupancy had a similar effect on the rate of reaction with O(6)-benzylguanine, a free base substrate, as on the repair of methylated DNA. Differentially zinc-treated hAGTs showed the same affinity for binding to native DNA and substrate oligodeoxyribonucleotides. Metal content manipulations had little effect upon the CD spectrum of hAGT, but fluorescence studies revealed a small conformational change based upon metal binding, and zinc occupancy correlated with enhanced hAGT stability as evidenced by resistance to the denaturing effects of urea. These results indicate that the presence of zinc confers a mechanistic enhancement to repair activity that does not result from an increase in substrate binding affinity. Zinc also provides conformational stability to hAGT that may influence its regulation.

DNA-binding mechanism of O6-alkylguanine-DNA alkyltransferase. Effects of protein and DNA alkylation on complex stability.

The mutagenic and cytotoxic effects of many endogenous and exogenous alkylating agents are mitigated by the actions of O(6)-alkylguanine-DNA alkyltransferase (AGT). In humans this protein protects the integrity of the genome, but it also contributes to the resistance of tumors to DNA-alkylating chemotherapeutic agents. Here we report properties of the interaction between AGT and short DNA oligonucleotides. We show that although AGT sediments as a monomer in the absence of DNA, it binds cooperatively to both single-stranded and double-stranded deoxyribonucleotides. This strong cooperative interaction is only slightly perturbed by active site mutation of AGT or by alkylation of either AGT or DNA. The stoichiometry of complex formation with 16-mer oligonucleotides, assessed by analytical ultracentrifugation and electrophoretic mobility shift assays, is 4:1 on single-stranded and duplex DNA and is unchanged by several active site mutations or by protein or DNA alkylation. These results have significant implications for the mechanisms by which AGT locates and interacts with repairable alkyl lesions to effect DNA repair.