Single Dose of Recombinant Chimeric Horsepox Virus (TNX-801) Vaccination Protects Macaques from Lethal Monkeypox Challenge.

The ongoing global Monkeypox outbreak that started in the spring of 2022 has reinforced the importance of protecting the population using live virus vaccines based on the vaccinia virus (VACV). Smallpox also remains a biothreat and although some U.S. military personnel are immunized with VACV, safety concerns limit its use in other vulnerable groups. Consequently, there is a need for an effective and safer, single dose, live replicating vaccine against both viruses. One potential approach is to use the horsepox virus (HPXV) as a vaccine. Contemporary VACV shares a common ancestor with HPXV, which from the time of Edward Jenner and through the 19th century, was extensively used to vaccinate against smallpox. However, it is unknown if early HPXV-based vaccines exhibited different safety and efficacy profiles compared to modern VACV. A deeper understanding of HPXV as a vaccine platform may allow the construction of safer and more effective vaccines against the poxvirus family. In a proof-of-concept study, we vaccinated cynomolgus macaques with TNX-801, a recombinant chimeric horsepox virus (rcHPXV), and showed that the vaccine elicited protective immune responses against a lethal challenge with monkeypox virus (MPXV), strain Zaire. The vaccine was well tolerated and protected animals from the development of lesions and severe disease. These encouraging data support the further development of TNX-801.

Day-One Pain Reductions After Hip and Knee Replacement When Buprenorphine-Clonidine-Dexamethasone Is Added to Bupivacaine Nerve/Plexus Blocks: A Randomized Clinical Trial.

OBJECTIVE: To compare pain outcome reports of patients undergoing hip or knee replacement who received single-injection nerve/plexus blocks with plain bupivacaine (BPV) with those of patients who received injections of buprenorphine-clonidine-dexamethasone (BCD) admixed with BPV. DESIGN: Prospective, parallel-arm, randomized, double-blind trial. SETTING: A single veterans' hospital. SUBJECTS: Ninety-eight veterans scheduled for total hip or knee replacement surgery with spinal as the primary anesthetic. METHODS: Participants were randomized to BPV-BCD or plain BPV groups. They underwent nerve/plexus blocks in the L2-L4 and L4-S3 distributions in advance of joint replacement surgery. The primary outcome was change in pain from baseline during the postoperative day, as assessed by the total pain score on the short-form McGill Pain Questionnaire-v2 (SF-MPQ-2). Secondary outcomes were pain during movement, pain interference, range of motion, mobility, and quality of recovery. RESULTS: On postoperative day one, the SF-MPQ-2 total score for the BPV-BCD group demonstrated greater pain reduction than that of the plain BPV group (mean difference 1.8 points, 95% confidence interval 0.6 to 3.0, P = 0.003). The BPV-BCD group also had larger reductions in pain during movement in the surgical joint and less pain interference, along with increased range of hip and knee flexion, compared with the plain BPV group. Outcomes of mobility and quality of recovery were not different between groups. CONCLUSIONS: Preoperative BPV-BCD blocks in the L2-L4 and L4-S3 nerve distributions for hip and knee replacements led to less pain on postoperative day one and increased knee and hip range of motion, compared with plain BPV blocks. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02891798.

Extended Perineural Analgesia After Hip and Knee Replacement When Buprenorphine-Clonidine-Dexamethasone Is Added to Bupivacaine: Preliminary Report from a Randomized Clinical Trial.

OBJECTIVE: We tested the hypothesis that buprenorphine-clonidine-dexamethasone (BCD) extends perineural analgesia compared with plain bupivacaine (BPV) nerve blocks used for hip and knee replacement surgery. DESIGN: Prospective, parallel-arms, randomized, double-blind trial. SETTING: A single veterans' hospital. SUBJECTS: Seventy-eight veterans scheduled for total hip or knee replacement with plans for spinal as the primary anesthetic. METHODS: Participants underwent nerve/plexus blocks at L2-L4 and L4-S3 in advance of hip or knee joint replacement surgery. Patients were randomized to receive BPV-BCD or plain BPV in a 4:1 allocation ratio. Patients answered four block duration questions (listed below). Time differences between treatments were analyzed using the t test. RESULTS: Significant (P < 0.001) prolongation of the time parameters was reported by patients after the BPV-BCD blocks (N = 62) vs plain BPV (N = 16). The time until start of postoperative pain was 26 vs 11 hours (mean difference = 15 hours, 95% CI = 8 to 21). The time until no pain relief from the blocks was 32 vs 15 hours (mean difference = 17 hours, 95% CI = 10 to 24). The time until the numbness wore off was 37 vs 21 hours (mean difference = 16 hours, 95% CI = 8 to 23). The time until the worst postoperative pain was 39 vs 20 hours (mean difference = 19 hours, 95% CI = 11 to 27). CONCLUSIONS: BPV-BCD provided 26-39 hours of perineural analgesia in the L2-L4 and L4-S3 nerve distributions after hip/knee replacement surgery, compared with 11-21 hours for plain BPV.

Cognitive and Functional Status of Persons Newly Enrolled at Dementia-Specific Adult Day Centers and Burden of Their Caregivers.

BACKGROUND AND OBJECTIVES: Recognizing the important role that dementia-specific adult day centers have in maintaining persons with a neurocognitive disorder in their home, this article examines three critical indicators at the time when people first enroll in such a center: cognitive and functional impairment of the enrollee, and burden reported by their family caregivers. We also considered variations in these 3 indicators by race/ethnicity and by the relationship of caregiver to the new enrollee. RESEARCH DESIGN AND METHODS: We conducted a secondary analysis of data collected by a nonprofit organization operating 11 dementia-specific adult day centers located on the east coast of Florida. Nursing staff conducted intake interviews with enrollees and their caregivers, and assessed functional status within one month of admission. Instruments included the Zarit Burden Scale and components of the Minimum Data Set: the Brief Interview for Mental Status (BIMS) and 4 measures of functional status. RESULTS: On average the cognitive scores of newly enrollees were well-within the range indicated for severe impairment, and these levels did not differ by race/ethnicity. Burden reported by caregivers however differed significantly, with Latinx caregivers reporting the greatest burden and African American/Black caregivers reporting the least. Further, while daughters generally reported higher levels of burden than other family caregivers, Black daughters reported the least. DISCUSSION AND IMPLICATIONS: Results suggest a need for greater dissemination efforts about adult day programs to the Latinx community, as well as attention to the disparate burden placed upon differing family relationships of caregivers to enrollees.

Standards for Nutrition Support: Adult Hospitalized Patients.

The American Society for Parenteral and Enteral Nutrition defines standards as benchmarks representing a range of performance of competent care that should be provided to assure safe and efficacious nutrition care in most circumstances. Standards are documents that define the structure needed to provide competent care. These Standards for Nutrition Support for Adult Hospitalized Patients are an update of the 2010 Standards. These practice-based standards are intended for use by healthcare professionals charged with the care of adult hospitalized patients receiving nutrition support therapy in any hospital with or without a formal nutrition support service or team. These Standards address professional responsibilities as they relate to patient assessment, diagnosis, education, care plan development, implementation, clinical monitoring, evaluation, and professional issues around nutrition support.

Intradialytic Laughter Yoga therapy for haemodialysis patients: a pre-post intervention feasibility study.

BACKGROUND: Laughter Yoga consists of physical exercise, relaxation techniques and simulated vigorous laughter. It has been associated with physical and psychological benefits for people in diverse clinical and non-clinical settings, but has not yet been tested in a haemodialysis setting. The study had three aims: 1) to examine the feasibility of conducting Laughter Yoga for patients with end stage kidney disease in a dialysis setting; 2) to explore the psychological and physiological impact of Laughter Yoga for these patients; and 3) to estimate the sample size required for future research. METHODS: Pre/post intervention feasibility study. Eighteen participants were recruited into the study and Laughter Yoga therapists provided a four week intradialytic program (30-min intervention three times per week). Primary outcomes were psychological items measured at the first and last Laughter Yoga session, including: quality of life; subjective wellbeing; mood; optimism; control; self-esteem; depression, anxiety and stress. Secondary outcomes were: blood pressure, intradialytic hypotensive episodes and lung function (forced expiratory volume). Dialysis nurses exposed to the intervention completed a Laughter Yoga attitudes and perceptions survey (n = 11). Data were analysed using IBM SPSS Statistics v22, including descriptive and inferential statistics, and sample size estimates were calculated using G*Power. RESULTS: One participant withdrew from the study for medical reasons that were unrelated to the study during the first week (94 % retention rate). There were non-significant increases in happiness, mood, and optimism and a decrease in stress. Episodes of intradialytic hypotension decreased from 19 pre and 19 during Laughter Yoga to 4 post Laughter Yoga. There was no change in lung function or blood pressure. All nurses agreed or strongly agreed that Laughter Yoga had a positive impact on patients' mood, it was a feasible intervention and they would recommend Laughter Yoga to their patients. Sample size calculations for future research indicated that a minimum of 207 participants would be required to provide sufficient power to detect change in key psychological variables. CONCLUSIONS: This study provides evidence that Laughter Yoga is a safe, low-intensity form of intradialytic physical activity that can be successfully implemented for patients in dialysis settings. Larger studies are required, however, to determine the effect of Laughter Yoga on key psychological variables. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry - ACTRN12614001130651 . Registered 23 October 2014.

A.S.P.E.N. clinical guidelines: parenteral nutrition ordering, order review, compounding, labeling, and dispensing.

BACKGROUND: Parenteral nutrition (PN) is a high-alert medication available for patient care within a complex clinical process. Beyond application of best practice recommendations to guide safe use and optimize clinical outcome, several issues are better addressed through evidence-based policies, procedures, and practices. This document provides evidence-based guidance for clinical practices involving PN prescribing, order review, and preparation. METHOD: A systematic review of the best available evidence was used by an expert work group to answer a series of questions about PN prescribing, order review, compounding, labeling, and dispensing. Concepts from the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) format were applied as appropriate. The specific clinical guideline recommendations were developed using consensus prior to review and approval by the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. The following questions were addressed: (1) Does education of prescribers improve PN ordering? (2) What is the maximum safe osmolarity of PN admixtures intended for peripheral vein administration? (3) What are the appropriate calcium intake and calcium-phosphate ratios in PN for optimal neonatal bone mineralization? (4) What are the clinical advantages or disadvantages of commercially available premade ("premixed") multichambered PN formulations compared with traditional/customized PN formulations? (5) What are the clinical (infection, catheter occlusion) advantages or disadvantages of 2-in-1 compared with 3-in-1 PN admixtures? (6) What macronutrient dosing limits are expected to provide for the most stable 3-in-1 admixtures? (7) What are the most appropriate recommendations for optimizing calcium (gluconate) and (Na- or K-) phosphate compatibility in PN admixtures? (8) What micronutrient contamination is present in parenteral stock solutions currently used to compound PN admixtures? (9) Is it safe to use the PN admixture as a vehicle for non-nutrient medication delivery? (10) Should heparin be included in the PN admixture to reduce the risk of central vein thrombosis? (11) What methods of repackaging intravenous fat emulsion (IVFE) into smaller patient-specific volumes are safe? (12) What beyond-use date should be used for (a) IVFE dispensed for separate infusion in the original container and (b) repackaged IVFE?

Laughter and humor therapy in dialysis.

Laughter and humor therapy have been used in health care to achieve physiological and psychological health-related benefits. The application of these therapies to the dialysis context remains unclear. This paper reviews the evidence related to laughter and humor therapy as a medical therapy relevant to the dialysis patient population. Studies from other groups such as children, the elderly, and persons with mental health, cancer, and other chronic conditions are included to inform potential applications of laughter therapy to the dialysis population. Therapeutic interventions could range from humorous videos, stories, laughter clowns through to raucous simulated laughter and Laughter Yoga. The effect of laughter and humor on depression, anxiety, pain, immunity, fatigue, sleep quality, respiratory function and blood glucose may have applications to the dialysis context and require further research.

Long-term seizure, cognitive, and psychiatric outcome following trans-middle temporal gyrus amygdalohippocampectomy and standard temporal lobectomy.

OBJECT: Previous comparisons of standard temporal lobectomy (STL) and selective amygdalohippocampectomy (SelAH) have been limited by inadequate long-term follow-up, variable definitions of favorable outcome, and inadequate consideration of psychiatric comorbidities. METHODS: The authors performed a retrospective analysis of seizure, cognitive, and psychiatric outcomes in a noncontemporaneous cohort of 69 patients with unilateral refractory temporal lobe epilepsy and MRI evidence of mesial temporal sclerosis after either an STL or an SelAH and examined seizure, cognitive, and psychiatric outcomes. RESULTS: The mean duration of follow-up for STL was 9.7 years (range 1-18 years), and for trans-middle temporal gyrus SelAH (mtg-SelAH) it was 6.85 years (range 1-15 years). There was no significant difference in seizure outcome when "favorable" was defined as time to loss of Engel Class I or II status; better seizure outcome was seen in the STL group when "favorable" was defined as time to loss of Engel Class IA status (p=0.034). Further analysis revealed a higher occurrence of seizures solely during attempted medication withdrawal in the mtg-SelAH group than in the STL group (p=0.016). The authors found no significant difference in the effect of surgery type on any cognitive and most psychiatric variables. Standard temporal lobectomy was associated with significantly higher scores on assessment of postsurgical paranoia (p=0.048). CONCLUSIONS: Overall, few differences in seizure, cognitive, and psychiatric outcome were found between STL and mtg-SelAH on long-term follow-up. Longer exposure to medication side effects after mtg-SelAH may adversely affect quality of life but is unlikely to cause additional functional impairment. In patients with high levels of presurgical psychiatric disease, mtg-SelAH may be the preferred surgery type.

Interictal PET and ictal subtraction SPECT: sensitivity in the detection of seizure foci in patients with medically intractable epilepsy.

PURPOSE: Interictal positron emission tomography (PET) and ictal subtraction single photon emission computed tomography (SPECT) of the brain have been shown to be valuable tests in the presurgical evaluation of epilepsy. To determine the relative utility of these methods in the localization of seizure foci, we compared interictal PET and ictal subtraction SPECT to subdural and depth electrode recordings in patients with medically intractable epilepsy. METHODS: Between 2003 and 2009, clinical information on all patients at our institution undergoing intracranial electroencephalography (EEG) monitoring was charted in a prospectively recorded database. Patients who underwent preoperative interictal PET and ictal subtraction SPECT were selected from this database. Patient characteristics and the findings on preoperative interictal PET and ictal subtraction SPECT were analyzed. Sensitivity of detection of seizure foci for each modality, as compared to intracranial EEG monitoring, was calculated. KEY FINDINGS: Fifty-three patients underwent intracranial EEG monitoring with preoperative interictal PET and ictal subtraction SPECT scans. The average patient age was 32.7 years (median 32 years, range 1-60 years). Twenty-seven patients had findings of reduced metabolism on interictal PET scan, whereas all 53 patients studied demonstrated a region of relative hyperperfusion on ictal subtraction SPECT suggestive of an epileptogenic zone. Intracranial EEG monitoring identified a single seizure focus in 45 patients, with 39 eventually undergoing resective surgery. Of the 45 patients in whom a seizure focus was localized, PET scan identified the same region in 25 cases (56% sensitivity) and SPECT in 39 cases (87% sensitivity). Intracranial EEG was concordant with at least one study in 41 cases (91%) and both studies in 23 cases (51%). In 16 (80%) of 20 cases where PET did not correlate with intracranial EEG, the SPECT study was concordant. Conversely, PET and intracranial EEG were concordant in two (33%) of the six cases where the SPECT did not demonstrate the seizure focus outlined by intracranial EEG. Thirty-three patients had surgical resection and >2 years of follow-up, and 21 of these (64%) had Engel class 1 outcome. No significant effect of imaging concordance on seizure outcome was seen. SIGNIFICANCE: Interictal PET and ictal subtraction SPECT studies can provide important information in the preoperative evaluation of medically intractable epilepsy. Of the two studies, ictal subtraction SPECT appears to be the more sensitive. When both studies are used together, however, they can provide complementary information.

Preclinical antitumor activity of thiarabine in human leukemia and lymphoma xenograft models.

Thiarabine was evaluated for antitumor activity in seven human leukemia, lymphoma, and myeloma xenograft models to explore the activity in hematological malignancies. Thiarabine was active against all of the human leukemia and lymphoma lines tested, being curative against HL-60 leukemia and AS283 lymphoma and effecting tumor regressions in CCRF-CEM, MOLT-4, and K-562 leukemia and RL lymphoma models, but did not exhibit any appreciable activity against RPMI-8226 myeloma. For the leukemia/lymphoma models, thiarabine was more efficacious than ara-C/palmO-ara-C (four models), clofarabine (three models), fludarabine monophosphate (five models), cladribine (four models), and gemcitabine (six models). Thiarabine warrants future clinical trials with leukemias/lymphomas.

Preclinical combination therapy of clofarabine plus radiation.

Clofarabine, an approved anticancer drug, was evaluated in combination with radiation in six subcutaneously implanted human tumor xenograft models. Clofarabine had no effect on the growth of SF-295 glioblastoma, which was not enhanced by radiation. There was no difference between clofarabine with and without radiation in the DU-145 prostate model. The combined effect on NCI-H460 lung tumors appeared to be additive. SR475 head and neck, PANC-1 pancreatic, and HCT-116 colon tumors were radiomodified by clofarabine. The radiomodifying capacity of clofarabine was superior to that for gemcitabine in two models (PANC-1 and HCT-116) and was comparable in the other four models.

Preclinical combination therapy of thiarabine plus various clinical anticancer agents.

Thiarabine is undergoing clinical trials. In support of that effort combination therapy of thiarabine plus six clinical anticancer agents was evaluated using various human tumor xenograft models. The antitumor activity of thiarabine in combination appeared to be greater than additive with irinotecan (DLD-1 colon), paclitaxel (PC-3 prostate), cisplatin (PC-3 prostate), or cyclophosphamide (RL lymphoma), additive with irinotecan (NCI-H460 NSCLC), cisplatin (NCI-H460 NSCLC) or methotrexate (CCRF-CEM leukemia), and less than additive with irinotecan (HT29 colon), paclitaxel (NCI-H460 NSCLC) or cisplatin (NCI-H23 NSCLC). Combining thiarabine with irinotecan, paclitaxel, cisplatin, or cyclophosphamide should receive consideration in the clinical treatment of cancer.

Outcome of frontal lobe epilepsy surgery.

PURPOSE: There is still controversy in deciding which patients with frontal lobe epilepsy (FLE) should undergo resective surgery, even though it is a well-established therapy. The aim of this study is to define multiple outcome measures and determine whether there are certain subpopulations of preferred surgical candidates that have a more favorable seizure prognosis. METHODS: Fifty-eight patients underwent resective FLE surgery with a mean follow-up period of 79.3 months (range 12-208 months). Patient demographics, clinical seizure characteristics, seizure-onset zone within the frontal lobes, and diagnostic tests were tabulated. Engel class, International League Against Epilepsy (ILAE) class, postoperative seizure patterns, time to first recurrent seizure, and seizures and employment during the last year of follow-up were used as outcome measures. Neuropsychological performance and Beck Depression Inventory (BDI) scores were used to define neuropsychological outcome and examined as predictors of seizure outcome. KEY FINDINGS: Thirty-three (57%) patients with resective surgery had an Engel class I outcome and 29 (50%) had an ILAE class I outcome. Mean time to first seizure after surgery was 33.3 months (range 0-208). Only 14 patients (24%) were completely seizure-free without auras (Engel IA) throughout the entire follow-up period. The most common pattern of seizure recurrence was mixed, with prolonged periods of seizure freedom intermixed with recurrences. In addition, 32% of patients made gains in employment and 52% were able to reduce use of antiepileptic drugs (AEDs), although only 9% discontinued AEDs. No significant association was found between class I or class IA outcome and the presence of a focal magnetic resonance imaging (MRI) abnormality, any specific localization of seizure focus within the frontal lobe, or neuropsychological change. SIGNIFICANCE: Findings indicate that that long-term outcome is generally favorable in FLE resective surgery, and support the need for considering multiple outcome measures to more fully characterize clinically relevant postsurgical changes. Outcome can be favorable even in MRI-negative patients.

Parenteral nutrition: risks, complications, and management.

Parenteral nutrition is a life-saving modality, but one that also carries risks for potentially life-threatening complications. Comprehensive management of patients receiving parenteral nutrition includes careful selection of candidates, individualizing formulas to meet patients' unique needs, monitoring response to therapy, and implementing strategies designed to avoid complications. Measures to mitigate the risk of central line-associated bloodstream infections are particularly important. As with all complex therapies, a collaborative, multidisciplinary approach promotes optimal outcomes.

Isolation and characterization of a murine P388 leukemia line resistant to thiarabine.

A murine P388 leukemia line fully resistant to thiarabine was obtained after five courses of intraperitoneal treatment (daily for nine consecutive days). The subline was sensitive as was the parental P388/0 line to 5-fluorouracil, gemcitabine, cyclophosphamide, cisplatin, melphalan, BCNU, mitomycin C, doxorubicin, mitoxantrone, etoposide, irinotecan, vincristine, and paclitaxel, but was cross resistant (at least marginally) to three antimetabolites: palmO-ara-C, fludarabine phosphate, and methotrexate. The deoxycytidine kinase activity in the subline was comparable to that for P388/0, whereas the dCMP deaminase activity was 43% of that for P388/0. No deoxycytidine deaminase activity was detected in either of the leukemias. There appeared to be little, if any, difference in the metabolism of deoxycytidine, cytidine, or thiarabine in the two leukemias.

Isolation and characterization of a murine P388 leukemia line resistant to clofarabine.

A murine P388 leukemia line fully resistant to clofarabine was obtained after only two courses of intraperitoneal treatment (three times a day for nine consecutive days). The resistance was stable for at least 13 weeks without treatment. The subline was as sensitive to 5-fluorouracil, methotrexate, cyclophosphamide, cisplatin, melphalan, BCNU, doxorubicin, etoposide, irinotecan, vincristine, and docetaxel as was the parental P388/0 line but was cross-resistant to five antimetabolites [palmO-ara-C, 4'-thio-ara-C, fludarabine phosphate, cladribine, and gemcitabine-all of which require deoxycytidine kinase for activation] and paclitaxel. The subline had less than 1% of the deoxycytidine kinase activity in comparison to P388/0.

Efficacy of vagus nerve stimulation for refractory epilepsy among patient subgroups: a re-analysis using the Engel classification.

Optimal candidates for VNS as a treatment for refractory epilepsy have not been identified. In this retrospective two-center study, we used the Engel classification for evaluating seizure outcome, and tried to identify predictive factors for outcome by means of subgroup analysis. The medical records of patients who have been treated with VNS for at least one year at Dartmouth-Hitchcock Medical Center and Ghent University Hospital were evaluated. Seizure frequency outcome was assessed using the Engel classification for the study population as a whole, and for patient subgroups with regard to mental functioning, seizure type, predisposing factors for developing epilepsy, age at time of VNS implantation and epilepsy duration. 189 patients (102M/87F) were included in the study (mean FU: 41 months). 6% had a class I outcome (seizure-free), 13% a class II outcome (almost seizure-free), 49% a class III outcome (worthwhile improvement) and 32% had a class IV outcome (no improvement). When patients were divided into specific subgroups, a statistically significant better outcome was found patients with normal mental functioning (p=0.029). In our series, results for VNS are clearly inferior to resective surgery, but comparable to other treatment modalities for refractory epilepsy. With combined class I and II outcomes around 20%, and another 50% of patients having worthwhile improvement, VNS is a viable alternative when resective surgery is not feasible.