Medical events in SARS-Cov-2 infected psychiatric inpatients with and without pre-existing co-morbid medical conditions.

SARS-CoV-2 (COVID-19) infection can be associated with significant medical complications. This risk could be even higher in psychiatric patients due to an increased risk of medical co-morbidity. In addition, psychiatric patients are also vulnerable to acquiring SARS-CoV2 infection due to homelessness, living in crowded areas, and poor adherence to recommended preventive measures. This retrospective study aims to compare two groups of patients, namely COVID-19 positive inpatient psychiatric patients with and without preexisting medical comorbidity on specific clinical and socio-demographic features and more importantly how many patients in the two groups subsequently developed medical complications. All COVID-19 positive psychiatric patients who were admitted to acute psychiatric inpatient units over a one-year period during the peri-pandemic phase were included for this study. Data was collected from the electronic medical records of 174 patients admitted to the inpatient psychiatric facility between January and December 2020. Among the COVID-19 positive patients, twenty individuals out of eighty-nine in the WC (with pre-existing medical comorbidity) group and two individuals out of eighty-five in the WOC (without pre-existing medical comorbidity) group developed COVID-related pneumonia. Ten WC patients and two WOC patients required supplemental oxygen, while only one patient in the WC group developed critical illness and required ventilatory support. The WC group had longer stay in both psychiatric and medical units compared to the WOC group. Consistent with existing literature that patients with comorbid medical condition are higher risk of COVID-19 complications, this study replicates the finding that in psychiatric inpatients pre-existing comorbid medical conditions create a higher risk of experiencing COVID-19 related medical complications. More interestingly, however that increased risk of developing new medical complications was not significantly different from the published rates observed in the general population which is surprising given how vulnerable psychiatric patients are, both medical, psychiatrically and psychosocially. In fact, in some ways and for reasons as yet unclear, the medical complication rate was slightly better in the WC compared to published data in the general population groups.

Possible Role of Parvalbumin Interneurons in Meditation and Psychiatric Illness.

Parvalbumin (PV) interneurons are present in multiple brain regions and produce complex influences on brain functioning. An increasing number of research findings indicate that the function of these interneurons is more complex than solely to inhibit pyramidal neurons in the cortex. They generate feedback and feedforward inhibition of cortical neurons, and they are critically involved in the generation of neuronal network oscillation. These oscillations, generated by various brain regions, are linked to perceptions, thought processes, and cognitive functions, all of which, in turn, influence human emotions and behavior. Both animal and human studies consistently have found that meditation practice results in enhancement in the effects of alpha-, theta-, and gamma-frequency oscillations, which may correspond to positive changes in cognition, emotion, conscious awareness, and, subsequently, behavior. Although the study of meditation has moved into mainstream neuroscience research, the link between PV interneurons and any role they might play in meditative states remains elusive. This article is focused primarily on gamma-frequency oscillation, which is generated by PV interneurons, to develop insight and perspective into the role of PV interneurons in meditation. This article also points to new and emerging directions that address whether this role of PV interneurons in meditation extends to a beneficial, and potentially therapeutic, role in the treatment of common psychiatric disorders, including schizophrenia.

Does Perspective Taking Matter for Writing? Perspective Taking in Source-Based Analytical Writing of Secondary Students.

Perspective taking, one's knowledge of their own mental and emotional states and inferences about others' mental and emotional states, is an important skill for writing development. In the present study, we examined how perspective taking is expressed in writing and how it is related to overall writing quality. We analyzed seventh graders' source-based analytical essays (N = 195) to investigate (1) the extent to which students incorporated perspective taking in their essays, (2) how the extent of perspective taking in essays differ by students' sex and English learner status, and (3) the extent to which perspective taking in writing is associated with overall writing quality. Findings revealed that students wrote more from their own perspective than that of others. Moreover, the results of multi-level analyses suggested that female students exhibited more varied perspectives but there was no meaningful difference by English learner status. Lastly, greater extent of perspective taking, particularly that of higher level of perspectives (i.e., dual perspective), was associated with better writing quality, after accounting for students' demographic backgrounds (e.g., sex, poverty status, English learner status) and essay length. These results underscore the importance of writing from multiple perspectives on writing quality.

Creating a Multidisciplinary Placenta Accreta Program.

OBJECTIVE: To develop a formalized comprehensive placenta accreta (PA) program to improve maternal and neonatal outcomes associated with a PA birth. DESIGN: To develop a clinically innovative PA program, goals were identified and teams were created to collaboratively address best practices in each phase of clinical patient care, along with the financial and marketing aspects necessary for a sustainable program. SETTING/LOCAL PROBLEM: A Level 3 perinatal center in the Southwestern United States. IMPLEMENTATION: A diverse multidisciplinary team addressed each aspect of care associated with a PA birth, including team members from the main operating room; trauma surgery; blood bank; interventional radiology unit; NICU; and gynecology-oncology, anesthesia, and urology departments. MEASUREMENTS: Pre- and postprogram clinical outcome measures were examined including estimated blood loss at birth, postbirth ICU transfers and length of stay, and postpartum length of stay. RESULTS: Clinical outcomes after program implementation showed decreased blood loss at birth (from an estimated 6,350 ml to 1,300-1,400 ml), reduced postbirth ICU length of stay (from approximately 3 days to less than 1 day, with many women bypassing ICU transfer altogether), and shortened postpartum length of stay (from 8 days to 4 days). CONCLUSION: With implementation of this PA program, women receive a proactive approach to care that includes education, holistic care, and an organized team approach to birth made possible by the innovative care delivery model, structures, and processes. Standardized checklists and workflows help each clinician understand his or her role in the process, and resources are directed effectively and efficiently. Multidisciplinary, multispecialty collaboration results in decreased variation in care with associated improved patient outcomes.

Efficacy, Safety, and Dose of Pafuramidine, a New Oral Drug for Treatment of First Stage Sleeping Sickness, in a Phase 2a Clinical Study and Phase 2b Randomized Clinical Studies.

BACKGROUND: Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT. METHODS: The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent. FINDINGS/CONCLUSION: Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.

Efficacy and Safety of Pafuramidine versus Pentamidine Maleate for Treatment of First Stage Sleeping Sickness in a Randomized, Comparator-Controlled, International Phase 3 Clinical Trial.

BACKGROUND: Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently require parenteral administration. In previous studies, orally administered pafuramidine was well tolerated in healthy patients (for up to 21 days) and stage 1 HAT patients (for up to 10 days), and demonstrated efficacy comparable to pentamidine. METHODS: This was a Phase 3, multi-center, randomized, open-label, parallel-group, active control study where 273 male and female patients with first stage Trypanosoma brucei gambiense HAT were treated at six sites: one trypanosomiasis reference center in Angola, one hospital in South Sudan, and four hospitals in the Democratic Republic of the Congo between August 2005 and September 2009 to support the registration of pafuramidine for treatment of first stage HAT in collaboration with the United States Food and Drug Administration. Patients were treated with either 100 mg of pafuramidine orally twice a day for 10 days or 4 mg/kg pentamidine intramuscularly once daily for 7 days to assess the efficacy and safety of pafuramidine versus pentamidine. Pregnant and lactating women as well as adolescents were included. The primary efficacy endpoint was the combined rate of clinical and parasitological cure at 12 months. The primary safety outcome was the frequency and severity of adverse events. The study was registered on the International Clinical Trials Registry Platform at www.clinicaltrials.gov with the number ISRCTN85534673. FINDINGS/CONCLUSIONS: The overall cure rate at 12 months was 89% in the pafuramidine group and 95% in the pentamidine group; pafuramidine was non-inferior to pentamidine as the upper bound of the 95% confidence interval did not exceed 15%. The safety profile of pafuramidine was superior to pentamidine; however, 3 patients in the pafuramidine group had glomerulonephritis or nephropathy approximately 8 weeks post-treatment. Two of these events were judged as possibly related to pafuramidine. Despite good tolerability observed in preceding studies, the development program for pafuramidine was discontinued due to delayed post-treatment toxicity.

Avatar-based simulation in the evaluation of diagnosis and management of mental health disorders in primary care.

Major Depressive Disorder (MDD) and Posttraumatic Stress Disorder (PTSD) are highly prevalent illnesses, but the literature suggests they are under-detected and suboptimally managed by primary care practitioners (PCPs). In this paper, we propose and use an evaluation method, using digitally simulated patients (avatars) to evaluate the diagnostic and therapeutic reasoning of PCPs and compared it to the traditional use of paper-based cases. Verbal (think-aloud) protocols were captured in the context of a diagnostic and therapeutic reasoning task. Propositional and semantic representational analysis of simulation data during evaluation, showed specific deficiencies in PCP reasoning, suggesting a promise of this technology in training and evaluation in mental health. Avatars are flexible and easily modifiable and are also a cost-effective and easy-to-disseminate educational tool.

A semiphysiologically based pharmacokinetic modeling approach to predict the dose-exposure relationship of an antiparasitic prodrug/active metabolite pair.

Dose selection during antiparasitic drug development in animal models and humans traditionally has relied on correlations between plasma concentrations obtained at or below maximally tolerated doses that are efficacious. The objective of this study was to improve the understanding of the relationship between dose and plasma/tissue exposure of the model antiparasitic agent, pafuramidine, using a semiphysiologically based pharmacokinetic (semi-PBPK) modeling approach. Preclinical and clinical data generated during the development of pafuramidine, a prodrug of the active metabolite, furamidine, were used. A whole-body semi-PBPK model for rats was developed based on a whole-liver PBPK model using rat isolated perfused liver data. A whole-body semi-PBPK model for humans was developed on the basis of the whole-body rat model. Scaling factors were calculated using metabolic and transport clearance data generated from rat and human sandwich-cultured hepatocytes. Both whole-body models described pafuramidine and furamidine disposition in plasma and predicted furamidine tissue (liver and kidney) exposure and excretion profiles (biliary and renal). The whole-body models predicted that the intestine contributes significantly (30-40%) to presystemic furamidine formation in both rats and humans. The predicted terminal elimination half-life of furamidine in plasma was 3- to 4-fold longer than that of pafuramidine in rats (170 versus 47 h) and humans (64 versus 19 h). The dose-plasma/tissue exposure relationship for the prodrug/active metabolite pair was determined using the whole-body models. The human model proposed a dose regimen of pafuramidine (40 mg once daily) based on a predefined efficacy-safety index. A similar approach could be used to guide dose-ranging studies in humans for next-in-class compounds.

Diamidines for human African trypanosomiasis.

Aromatic diamidines are potent trypanocides. Pentamidine, a diamidine, has been used for more than 60 years to treat human African trypanosomiasis (HAT); however, the drug must be administered parenterally and is active against first-stage HAT only, prior to the parasites causing neurological deterioration through invasion of the CNS. A major research effort to design novel diamidines has led to the development of orally active prodrugs and, remarkably, a new generation of compounds that can penetrate the CNS. In this review, progress in the development of diamidines for the treatment of HAT is discussed.

Misclassification of drug failure in Plasmodium falciparum clinical trials in southeast Asia.

Most trials of antimalarials occur in areas in which reinfections are possible. For Plasmodium falciparum, reinfections are distinguished from recrudescences by polymerase chain reaction analysis of 3 polymorphic genes. However, the validity of this approach has never been rigorously tested. We tested for misclassification in 6 patients from clinical trials in Thailand and Cambodia who were classified as being reinfected by the standard polymerase chain reaction protocol. Using heteroduplex tracking assays and direct DNA sequencing, we found that 5 (83%) of 6 patients were misclassified. Misclassification in this manner overestimates the efficacy of antimalarials and delays the recognition of decreasing therapeutic efficacy, thus delaying potential changes in policy.

Cardiac alterations in human African trypanosomiasis (T.b. gambiense) with respect to the disease stage and antiparasitic treatment.

BACKGROUND: In Human African Trypanosomiasis, neurological symptoms dominate and cardiac involvement has been suggested. Because of increasing resistance to the available drugs for HAT, new compounds are desperately needed. Evaluation of cardiotoxicity is one parameter of drug safety, but without knowledge of the baseline heart involvement in HAT, cardiologic findings and drug-induced alterations will be difficult to interpret. The aims of the study were to assess the frequency and characteristics of electrocardiographic findings in the first stage of HAT, to compare these findings to those of second stage patients and healthy controls and to assess any potential effects of different therapeutic antiparasitic compounds with respect to ECG changes after treatment. METHODS: Four hundred and six patients with first stage HAT were recruited in the Democratic Republic of Congo, Angola and Sudan between 2002 and 2007 in a series of clinical trials comparing the efficacy and safety of the experimental treatment DB289 to the standard first stage treatment, pentamidine. These ECGs were compared to the ECGs of healthy volunteers (n = 61) and to those of second stage HAT patients (n = 56). RESULTS: In first and second stage HAT, a prolonged QTc interval, repolarization changes and low voltage were significantly more frequent than in healthy controls. Treatment in first stage was associated with repolarization changes in both the DB289 and the pentamidine group to a similar extent. The QTc interval did not change during treatment. CONCLUSIONS: Cardiac involvement in HAT, as demonstrated by ECG alterations, appears early in the evolution of the disease. The prolongation of the QTC interval comprises a risk of fatal arrhythmias if new drugs with an additional potential of QTC prolongation will be used. During treatment ECG abnormalities such as repolarization changes consistent with peri-myocarditis occur frequently and appear to be associated with the disease stage, but not with a specific drug.

Bio-inspired, side-on attachment of a ruthenium photosensitizer to an iron hydrogenase active site model.

The first ruthenium-diiron complex [(mu-pdt)Fe2(CO)5{PPh2(C6H4CCbpy)}Ru(bpy)2]2+ 1 (pdt = propyldithiolate, bpy = 2,2'-bipyridine) is described in which the photoactive ruthenium trisbipyridyl unit is linked to a model of the iron hydrogenase active site by a ligand directly attached to one of the iron centers. Electrochemical and photophysical studies show that the light-induced MLCT excited state of the title complex is localized towards the potential diiron acceptor unit. However, the relatively mild potential required for the reduction of the acetylenic bipyridine together with the easily oxidized diiron portion leads to a reductive quenching of the excited state, instead. This process results in a transiently oxidized diiron unit which may explain the surprisingly high light sensitivity of complex 1.

Charge accumulation and polarization in titanium dioxide electrodes.

Nanocrystalline TiO(2) electrodes were studied spectroelectrochemically by observing the simultaneous relaxation of the current and absorbance after applying a voltage step. The absorbance behaved differently in two time regimes: (1) ionic polarization in the oxide electrode, in which charged ions, such as Ti(3+) sites and/or interstitial Ti(4+) sites, move in response to the applied electric field, and (2) the diffusion of Li(+) ions into the TiO(2). These two behaviors were analyzed with equivalent circuit models. Li(+) ions reduce the resistance of the TiO(2) by approximately 90%, increase the capacitance by approximately 350%, and decrease the inductance by approximately 30%. Voltage cycling produces a buildup of intercalated Li(+) ions, lessening the electrode's response to the potential step, and causing it to become a more efficient inductor. The potential distribution in the nanoparticles is described by using a dielectric model in which roughly half the applied potential is dropped across the interface with a Li(+)-ion-containing electrolyte.

Influence of cation on charge recombination in dye-sensitized TiO2 electrodes.

The reaction of a dye cation recombining with an electron in TiO(2), in the presence of Li(+), Ca(2+), and TBA(+) cations, was studied with laser-induced transient absorption measurements. The active cations, Li(+) and Ca(2+), shorten the dye cation lifetime on sensitized TiO(2) but not ZnO electrodes. By combining the absorbance measurements of the dye cation with simultaneous measurements of the current transient, the contribution of the recombination reaction to the current is identified. Furthermore, classical porous electrode theory is used to quantify the behavior of the heterogeneous electrode, and in doing so, the processes contributing to photoinduced current are identified as Helmholtz layer charging, porous electrode charging, recombination reactions, and surface diffusion of the active cations. The rate of charge recombination is proportional to the concentration of initially deposited active cations. The effect of water on the recombination rate and the current is also observed.

Defect chemistry, surface structures, and lithium insertion in anatase TiO2.

Atomistic simulation techniques are used to investigate the defect properties of anatase TiO(2) and Li(x)TiO(2) both in the bulk and at the surfaces. Interatomic potential parameters are derived that reproduce the lattice constants of anatase, and the energies of bulk defects and surface structures are calculated. Reduction of anatase involving interstitial Ti is found to be the most favorable defect reaction in the bulk, with a lower energy than either Frenkel or Schottky reactions. The binding energies of selected defect clusters are also presented: for the Ti(3+)-Li(+) defect cluster, the binding energy is found to be approximately 0.5 eV, suggesting that intercalated Li ions stabilize conduction band electrons. The Li ion migration path is found to run between octahedral sites, with an activation energy of 0.45-0.65 eV for mole fractions of lithium in Li(x)TiO(2) of x < or = 0.1. The calculated surface energies are used to predict the crystal morphology, which is found to be a truncated bipyramid in which only the (101) and (001) surfaces are expressed, in accord with the available microscopy data. Calculations of defect energies at the (101) surface suggest that single Ti(3+) defects and neutral Ti(3+)-Li(+) pairs tend to segregate to the surface.

Community entry in conducting rural focus groups: process, legitimacy, and lessons learned.

This article explores the value of community collaboration in a qualitative study of diabetes. In 1999, the Appalachian Diabetes Coalition of West Virginia University's Prevention Research Center employed a statewide effort to conduct focus groups in West Virginia to elicit cultural perspectives on diabetes and its management. The success of this research depended on community participation at many levels, particularly because of the rural, often geographically isolated community structure of the state. The researchers' entry into small communities and the involvement of local residents in focus groups was possible with the collaboration of the West Virginia Rural Health Education Partnerships program and the West Virginia University Extension Service, both of which played primary roles as community gatekeepers in helping the research team access and involve rural areas. This collaboration reinforced the value of a two-tiered approach in enlisting local resources. These relationships resulted in beneficial outcomes to all partners. Researchers benefited by gaining entry to communities, and the community organizations benefited by gaining a better understanding of the diabetic population to assist in planning programs. Working with well-established community groups with strong community ties is crucial when gaining entry for research and interventions. The identification and involvement of trusted, accessible members of rural communities gives research local legitimacy, ensures adequate participation and effective data collection, and permits entry into remote communities.