Nutmeg Intoxication: A Case Report.

Nutmeg intoxication is an uncommon precipitant of hyperactive delirium with severe agitation (HDSA) with anticholinergic properties that require a high index of suspicion for diagnosis. We present a case of a young adult who presented to the emergency department (ED) with HDSA. The patient was intubated and transferred to the medical intensive care unit (MICU) due to increasing safety threats unresponsive to multimodal de-escalation. He ultimately self-extubated, reported excessive nutmeg ingestion, and was discharged home after a short period of observation. Improved detection and streamlined management pathways for nutmeg intoxication will minimize unnecessary invasive procedures and costs to the healthcare system.

Maveropepimut-S, a DPX-Based Immune-Educating Therapy, Shows Promising and Durable Clinical Benefit in Patients with Recurrent Ovarian Cancer, a Phase II Trial.

PURPOSE: Patients with platinum-resistant ovarian cancer respond poorly to existing therapies. Hence there is a need for more effective treatments. PATIENTS AND METHODS: The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase II study to evaluate the safety and effectiveness of maveropepimut-S with cyclophosphamide in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL maveropepimut-S 3 weeks apart, followed by one 0.1-mL doses, every 8 weeks up to progression. Oral cyclophosphamide, 50 mg twice daily, was administered in repeating weekly on and off cycles. RESULTS: Twenty-two patients were enrolled. Median age was 58 years (38-78 years). Among the evaluable population, the objective response rate (ORR) was 21% [90% confidence interval (CI), 7.5%-41.9%], with a disease control rate (DCR) of 63% (90% CI, 41.8%-81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four SD patients maintained clinical benefit up to 25 months. Most treatment-related adverse events (TRAE) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T-cell responses were observed in treated patients with clinical benefit. CONCLUSIONS: Maveropepimut-S with intermittent low-dose cyclophosphamide is well-tolerated, with clinical benefit for patients with recurrent ovarian cancer. Observed responses are irrespective of the platinum status.

Impact of Working From Home on Addressing Practitioner Burnout and Work-Life Balance in Mental Health.

While the demand for mental health services is growing, a practitioner shortage and high rates of burnout limit the capacity of the system to provide care. The COVID-19 pandemic led to a shift toward increased telehealth use, presenting an opportunity for mental health practitioners to adopt flexible workplace policies, such as working from home, that are more common in nonclinical environments. This article discusses the impact of working from home on practitioner burnout, satisfaction, and work-life balance, which may inform recruitment and retention strategies for health care organizations.

Institution-initiated text messaging can reduce unplanned emergency department visits after appendectomy.

BACKGROUND/PURPOSE: The purpose of this study was to reduce unplanned Emergency Department (ED) visits for minor complaints in children after appendectomy through proactive institution-driven communication and utilization of telehealth resources. METHODS: We developed a text messaging system to initiate communication with parents of postappendectomy patients and connect them with a telehealth visit or a phone call with a surgical provider as needed. Using descriptive statistics, chi square, and statistical process control analytics, we compared rates of postoperative ED visits for the 8 months pre- and post-implementation of the messaging system and summarized the feedback we received from patients. RESULTS: A total of 791 laparoscopic appendectomies were performed in two institutions (preintervention = 382, post-intervention = 409). The postoperative ED visit rate decreased from 5.8% preimplementation to 2.4% post-implementation (p = 0.02). Over one-fifth of families messaged (21.6%) had questions in the postoperative period. The majority expressed interest in a video visit (52.5%), while some preferred to speak with the surgeon's office (25%). Over 90% of respondents found the system helpful, and 4.9% opted out. CONCLUSION: Implementation of a hospital-initiated text messaging system has the potential to reduce ED visits in the immediate postoperative period after appendectomy. This system can be scaled to include different surgeries across multiple disciplines. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Clinical Retrospective Pre/Post Intervention Study.

Association between care delivery interventions to enhance access and patients' perceived access in the Comprehensive Primary Care Initiative.

The Comprehensive Primary Care (CPC) initiative was an alternative payment model implemented from 2012 to 2016 to strengthen primary care by enhancing core functions, including access to care. The association between interventions to enhance access and patients' perception of access is unknown. We performed a cross-sectional analysis of CPC practice surveys and CAHPS patient survey responses pertaining to access and timeliness in 2016. There were regional differences in both patients' perceptions of access and interventions to enhance access, but no association between interventions and patients' perceptions. Practices with fewer clinicians and whose patients had fewer chronic conditions had better perceived access.

Single dose of DPX-rPA, an enhanced-delivery anthrax vaccine formulation, protects against a lethal Bacillus anthracis spore inhalation challenge.

Anthrax is a serious biological threat caused by pulmonary exposure to aerosolized spores of Bacillus anthracis. Biothrax® (anthrax vaccine adsorbed (AVA)) is the only Food and Drug Administration-licensed vaccine and requires five administrations over 12 months with annual boosting to maintain pre-exposure prophylaxis. Here we report the evaluation of a single intramuscular injection of recombinant B. anthracis-protective antigen (rPA) formulated in the DPX delivery platform. Immune responses were compared to an alum-based formulation in mice and rabbits. Serological analysis of anti-rPA immunoglobulin G and toxin neutralization activity demonstrated higher responses induced by DPX-rPA when compared to rPA in alum. DPX-rPA was compared to AVA in rabbits and non-human primates (NHPs). In both species, DPX-rPA generated responses after a single immunization, whereas AVA required two immunizations. In rabbits, single injection of DPX-rPA or two injections of AVA conferred 100% protection from anthrax challenge. In NHPs, single-dose DPX-rPA was 100% protective against challenge, whereas one animal in the two-dose AVA group and all saline administered animals succumbed to infection. DPX-rPA was minimally reactogenic in all species tested. These data indicate that DPX-rPA may offer improvement over AVA by reducing the doses needed for protective immune responses and is a promising candidate as a new-generation anthrax vaccine.

A Respiratory Syncytial Virus Vaccine Based on the Small Hydrophobic Protein Ectodomain Presented With a Novel Lipid-Based Formulation Is Highly Immunogenic and Safe in Adults: A First-in-Humans Study.

Background: Respiratory syncytial virus infection can cause lower respiratory tract infection in older adults comparable to influenza, but no vaccines are available. Methods: This was a randomized, observer-blinded, first-in-humans study of a novel synthetic RSV antigen based on the ectodomain of the small hydrophobic glycoprotein (SHe) of RSV subgroup A, formulated with either the lipid and oil-based vaccine platform DepoVax (DPX-RSV[A]) or alum (RSV[A]-Alum), in healthy, 50-64-year-old individuals. Two dose levels (10 or 25 µg) of SHe with each formulation were compared to placebo. A booster dose was administered on day 56. Results: There was no indication that the vaccine was unsafe. Mild pain, drowsiness, and muscles aches were the most common solicited adverse events (AEs), and the frequencies of the AEs did not increase after dose 2. Robust anti-SHe-specific immune responses were demonstrated in the DPX-RSV(A) 10-µg and 25-µg groups (geometric mean titer, approximately 10-fold and 100-fold greater than that of placebo at days 56 and 236, respectively), and responses were sustained in the DPX-RSV(A) 25-µg group at day 421. Responses to the RSV(A)-Alum vaccines were very low. Conclusions: A novel antigen from the SH protein of RSV, formulated in a lipid and oil-based vaccine platform, was highly immunogenic, with sustained antigen-specific antibody responses, and had an acceptable safety profile.

Type III hypersensitivity reactions to a B cell epitope antigen are abrogated using a depot forming vaccine platform.

Peptide antigens are combined with an adjuvant in order to increase immunogenicity in vivo. The immunogenicity and safety of a RSV vaccine formulated in a novel oil-based platform, DepoVax™ (DPX), was compared to an alum formulation. A peptide B cell epitope derived from RSV small hydrophobic ectodomain (SHe) served as the antigen. Both vaccines induced SHe-specific antibodies after immunization of mice. A single dose of the DPX-based formulation resulted in anti-SHe titres for up to 20 weeks. Boosting with Alum-SHe, but not with DPX-SHe, led to unexpected clinical signs such as decreased activity, cyanosis and drop in body temperature in mice but not in rabbits. The severity of adverse reactions correlated with magnitude of SHe-specific IgG immune responses and decreased complement component 3 plasma levels, indicating a type III hypersensitivity reaction. By RP-HPLC analysis, we found that only 8-20% of the antigen was found to be adsorbed to alum in vitro, indicating that this antigen is likely released systemically upon injection in vivo. Clinical signs were not observed in rabbits, indicating the response correlates with peptide dose relative to size of animal. These results suggest that peptide antigens targeted to produce B cell mediated response may result in increased incidence of type III hypersensitivity reactions when delivered in non-depot forming vaccines. The DPX formulation induced strong antibody titres to the antigen without causing adverse events, likely due to the strength of the depot in vivo, and demonstrates the potential safety and immunogenicity of this platform for B cell peptide antigens.

Combination of poly I:C and Pam3CSK4 enhances activation of B cells in vitro and boosts antibody responses to protein vaccines in vivo.

Vaccines that can rapidly induce strong and robust antibody-mediated immunity could improve protection from certain infectious diseases for which current vaccine formulations are inefficient. For indications such as anthrax and influenza, antibody production in vivo is a correlate of efficacy. Toll-like receptor (TLR) agonists are frequently studied for their role as vaccine adjuvants, largely because of their ability to enhance initiation of immune responses to antigens by activating dendritic cells. However, TLRs are also expressed on B cells and may contribute to effective B cell activation and promote differentiation into antigen-specific antibody producing plasma cells in vivo. We sought to discover an adjuvant system that could be used to augment antibody responses to influenza and anthrax vaccines. We first characterized an adjuvant system in vitro which consisted of two TLR ligands, poly I:C (TLR3) and Pam3CSK4 (TLR2), by evaluating its effects on B cell activation. Each agonist enhanced B cell activation through increased expression of surface receptors, cytokine secretion and proliferation. However, when B cells were stimulated with poly I:C and Pam3CSK4 in combination, further enhancement to cell activation was observed. Using B cells isolated from knockout mice we confirmed that poly I:C and Pam3CSK4 were signaling through TLR3 and TLR2, respectively. B cells activated with Poly I:C and Pam3CSK4 displayed enhanced capacity to stimulate allogeneic CD4+ T cell activation and differentiate into antibody-producing plasma cells in vitro. Mice vaccinated with influenza or anthrax antigens formulated with poly I:C and Pam3CSK4 in DepoVax™ vaccine platform developed a rapid and strong antigen-specific serum antibody titer that persisted for at least 12 weeks after a single immunization. These results demonstrate that combinations of TLR adjuvants promote more effective B cell activation in vitro and can be used to augment antibody responses to vaccines in vivo.

Preventive Ethics Through Expanding Education.

Healthcare institutions have been making increasing efforts to standardize consultation methodology and to accredit both bioethics training programs and the consultants accordingly. The focus has traditionally been on the ethics consultation as the relevant unit of ethics intervention. Outcome measures are studied in relation to consultations, and the hidden assumption is that consultations are the preferred or best way to address day-to-day ethical dilemmas. Reflecting on the data from an internal quality improvement survey and the literature, we argue that having general ethics education as a key function of ethics services may be more important in meeting the contemporaneous needs of acute care settings. An expanded and varied ethics education, with attention to the time constraints of healthcare workers' schedules, was a key recommendation brought forward by survey respondents. Promoting ethical reflection and creating a culture of ethics may serve to prevent ethical dilemmas or mitigate their effects.

Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients.

DepoVax™ is an innovative and strongly immunogenic vaccine platform. Survivin is highly expressed in many tumor types and has reported prognostic value. To generate tumor-specific immune response, a novel cancer vaccine was formulated in DepoVax platform (DPX-Survivac) using survivin HLA class I peptides. Safety and immune potency of DPX-Survivac was tested in combination with immune-modulator metronomic cyclophosphamide in ovarian cancer patients. All the patients receiving the therapy produced antigen-specific immune responses; higher dose vaccine and cyclophosphamide treatment generating significantly higher magnitude responses. Strong T cell responses were associated with differentiation of naïve T cells into central/effector memory (CM/EM) and late differentiated (LD) polyfunctional antigen-specific CD4+ and CD8+ T cells. This approach enabled rapid de novo activation/expansion of vaccine antigen-specific CD8+ T cells and provided a strong rationale for further testing to determine clinical benefits associated with this immune activation. These data represent vaccine-induced T cell activation in a clinical setting to a self-tumor antigen previously described only in animal models.

Acute Sensorineural Hearing Loss After Abuse of an Inhaled, Crushed Oxymorphone Extended-Release Tablet.

Oxymorphone, a semisynthetic µ-opioid receptor agonist, is the major active metabolite of oxycodone. It is a highly potent narcotic analgesic due to its high lipid solubility, which allows it to readily cross the blood-brain barrier and enter the central nervous system. It is available as both an immediate-release and extended-release (ER) formulation. Oxymorphone can be abused by injection or inhalation of crushed tablets; thus, in 2011, the manufacturer of ER oxymorphone reformulated the drug with crush-resistant technology to deter its misuse and abuse. We describe the case of a previously healthy, 24-year-old male who experienced reproducible acute subjective bilateral temporary hearing loss that occurred after inhalation of oxymorphone. He presented to the emergency department complaining of acute bilateral hearing loss after he reported snorting a crushed oxymorphone ER 30-mg tablet. Emergency department evaluation revealed obvious bilateral hearing loss as well as coincidental aspiration pneumonia. The patient's medical history revealed that he had experienced a similar episode of hearing loss after a previous episode of oxymorphone inhalation. His hearing loss began to improve 3 hours after presentation to the emergency department and was completely resolved by the following day. Use of the Naranjo adverse drug reaction probability scale revealed oxymorphone to be a probable cause of this patient's acute hearing loss (score of 6). The mechanism of action of opioid-associated hearing loss (OAHL) is not completely understood, but it is thought to be due to disturbances within the cochlea, such as cochlear ischemia. To our knowledge, this is only the second published case report of acute reversible hearing loss following oxymorphone inhalation and the first published case report of reproducible OAHL. Since opioid misuse continues to be prevalent despite attempts at reformulations to make the drugs crush resistant, a high degree of clinical suspicion is needed to evaluate and treat patients who present with unique findings after episodes of substance abuse, especially those related to tamper-resistant formulations.

Using quality indicators to evaluate the effect of implementing an enhanced collaborative care model among a community, primary healthcare practice population.

Over the past decade, Nova Scotia has been making important changes to strengthen its primary healthcare (PHC) system. Here we present the results from an observational, retrospective study evaluating the effect of an enhanced collaborative care model, which included team building and the addition of a nurse practitioner (NP) to the team, on the quality of healthcare delivery among a community, PHC population. To guide the evaluation, we used a broad range of national and provincially identified clinical quality-of-care indicators targeting a wide range of preventive and chronic disease management care (targeting process of care, and immediate and secondary outcomes). A total of 392 patient charts were audited (197 pre-period; 195 post-period). Patients included the full spectrum of the practice population - the young, the old, those with chronic conditions and others without. Results support the increasing body of evidence, which indicates improved chronic disease management among patients with targeted chronic conditions, particularly patients diagnosed with diabetes, who receive care through a collaborative practice where a NP is part of the team. In addition, these results also demonstrate the beginning of better preventive care among all patients.

First-in-man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi-functional T cell responses in ovarian, breast and prostate cancer patients.

BACKGROUND: DepoVax is a novel non-emulsion depot-forming vaccine platform with the capacity to significantly enhance the immunogenicity of peptide cancer antigens. Naturally processed HLA-A2 restricted peptides presented by breast, ovarian and prostate cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907. METHODS: A phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose/volume cohorts in a three immunization protocol. RESULTS: DPX-0907 was shown to be safe with injection site reactions being the most commonly reported adverse event. All breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients exhibited detectable immune responses, resulting in a 61% immunological response rate. Immune responses were generally observed in patients with better disease control after their last prior treatment. Antigen-specific responses were detected in 73% of immune responders (44% of evaluable patients) after the first vaccination. In 83% of immune responders (50% of evaluable patients), peptide-specific T cell responses were detected at ≥2 time points post vaccination with 64% of the responders (39% of evaluable patients) showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T cell memory with the ability to secrete multiple Type 1 cytokines. CONCLUSIONS: The novel DepoVax formulation promotes multifunctional effector memory responses to peptide-based tumor associated antigens. The data supports the capacity of DPX-0907 to elicit Type-1 biased immune responses, warranting further clinical development of the vaccine. This study underscores the importance of applying vaccines in clinical settings in which patients are more likely to be immune competent. TRIAL REGISTRATION: ClinicalTrials.gov NCT01095848.

Efficacy of a single dose hepatitis B depot vaccine.

A single dose formulation of a novel hepatitis B vaccine, consisting of an adjuvant emulsion of liposomes in oil was produced at a manufacturing scale and delivered to rabbits. This single dose vaccine generated a significantly higher antibody response than two doses of an alum-adjuvanted control vaccine in the short term, and was as effective as three doses of the control vaccine in the long term.

A novel breast/ovarian cancer peptide vaccine platform that promotes specific type-1 but not Treg/Tr1-type responses.

In light of lack of efficacy associated with current cancer vaccines, we aimed to develop a novel vaccine platform called DepoVax as a therapeutic vaccine for breast/ovarian cancer. This study was designed to examine the efficacy of this novel platform over conventional emulsion vaccine using human class I MHC transgenic mice. We have developed a water-free depot vaccine formulation (DPX-0907) with high immune activating potential. Naturally processed peptides bound to HLA-A2 molecules isolated from independent breast and ovarian tumor cell lines, but not normal cells, were isolated and used as antigens in DPX-0907 along with a proprietary adjuvant and a T helper peptide epitope. Efficacy of vaccine was tested in immunized HLA-A*0201/H2Dd transgenic mice by measuring the frequency of IFN-gamma secreting cells in the draining lymph nodes, and regulatory T-cell frequencies in the spleen. Compared with a water-in-oil emulsion vaccine, DPX-0907 enhanced IFN-gamma+CD8+ T cells in vaccine site-draining lymph nodes, as seen by immunofluorescence staining and increased the frequency of IFN-gamma+ lymph node cells as seen by enzyme-linked immunosorbent spot assay. Notably, while conventional vaccine formulations elicited elevated levels of splenic Foxp3+CD4+ and IL10-secreting T cells, this was not the case for DPX-0907-based vaccines, with treated animals exhibiting normal levels of regulatory T cells. These data support the unique capabilities of a vaccine formulation containing novel tumor peptides and DPX-0907 to elicit type-1 dominated, specific immunity that may represent a potent clinical therapeutic modality for patients with breast or ovarian carcinoma.

Improper hydrogen-bonding CH x Y interactions in binary methanol systems as studied by FTIR and Raman spectroscopy.

Fourier Transform infrared spectroscopy and Raman spectroscopy have been used to investigate hydrogen bonding of methanol in different solvents with an aim to explore potential experimental evidence for improper hydrogen bonding involving the methyl group of methanol as suggested by various computational studies. Pure methanol and solutions of methanol in water, acetonitrile, carbon tetrachloride, deuterium oxide, and deuterated acetonitrile have been studied over a range of concentrations. Wavenumber shifts of the CH stretching vibrations were examined to determine if the CH from methanol participates in hydrogen bonding. New concepts of the vibrational wavenumber and integrated intensity at infinite dilution are proposed and given the respective symbols nu(CH(o)) and C(j,CH)*(o). Using the results obtained for methanol in carbon tetrachloride as a reference, shifts in nu(CH(o)) of methanol to higher wavenumbers (blue shifts) were observed in each of the other solvents studied, with the shifts being greatest for the methanol-water interactions. The shifts in vibrational wavenumber suggest possible improper hydrogen bonding, although at this stage a definitive conclusion is not possible. The C(j,CH)*(o) results show that there is no distinguishable change in the methanol CH stretch integrated intensity in carbon tetrachloride and acetonitrile, while there is a significant decrease in the methanol CH stretch integrated intensity in the water solutions.

Rejection of large HPV-16 expressing tumors in aged mice by a single immunization of VacciMax encapsulated CTL/T helper peptides.

The incidence of cancer increases significantly in later life, yet few pre-clinical studies of cancer immunotherapy use mice of advanced age. A novel vaccine delivery platform (VacciMax,VM) is described that encapsulates antigens and adjuvants in multilamellar liposomes in a water-in-oil emulsion. The therapeutic potential of VM-based vaccines administered as a single dose was tested in HLA-A2 transgenic mice of advanced age (48-58 weeks old) bearing large palpable TC1/A2 tumors. The VM-based vaccines contained one or more peptides having human CTL epitopes derived from HPV 16 E6 and E7. VM formulations contained a single peptide, a mixture of four peptides or the same four peptides linked together in a single long peptide. All VM formulations contained PADRE and CpG as adjuvants and ISA51 as the hydrophobic component of the water-in-oil emulsion. VM-formulated vaccines containing the four peptides as a mixture or linked together in one long peptide eradicated 19-day old established tumors within 21 days of immunization. Peptide-specific cytotoxic cellular responses were confirmed by ELISPOT and intracellular staining for IFN-gamma producing CD8+ T cells. Mice rendered tumor-free by vaccination were re-challenged in the opposite flank with 10 million HLF-16 tumor cells, another HLA-A2/E6/E7 expressing tumor cell line. None of these mice developed tumors following the re-challenge. In summary, this report describes a VM-formulated therapeutic vaccine with the following unprecedented outcome: a) eradication of large tumors (> 700 mm3) b) in mice of advanced age c) in less than three weeks post-immunization d) following a single vaccination.

A C-terminal glycine suppresses production of pleurocidin as a fusion peptide in Escherichia coli.

The winter flounder (Pseudopleuronectes americanus) antimicrobial peptide pleurocidin was produced in Escherichia coli using a synthetic gene constructed by PCR. The gene expresses pleurocidin from pET21a fused to the C-terminus of an insoluble carrier peptide. Once expressed, the fusion peptide formed inclusion bodies in the cytoplasm that were collected, solubilized in guanidine-HCl, and chemically cleaved using hydroxylamine at a unique asparaginyl-glycyl dipeptide. This released recombinant pleurocidin (r-pleurocidin), which was purified using ultrafiltration followed by reverse phase chromatography. The r-pleurocidin peptide resolved as a single band (2.7 kDa) when analyzed by Tris-Tricine buffered SDS-PAGE, and its amino acid sequence was confirmed using tandem mass spectrometry. Extending the pleurocidin sequence with a C-terminal glycine (r-pleurocidin-G) suppressed production of the fusion peptide 15-fold. When pleurocidin was extended further to include aspartate (r-pleurocidin-GD), the same effect was observed, and when pleurocidin was extended with aspartate alone, no effect was observed. Expression of fusion peptide containing either r-pleurocidin-G or r-pleurocidin-GD with low concentrations of inductant caused E. coli to enter stationary phase prematurely, but did not affect overall growth rates. A partial production recovery of r-pleurocidin-G was achieved by inducing expression in stationary phase cells. We observed r-pleurocidin-G to have enhanced antimicrobial activity compared with r-pleurocidin, and we propose that this activity interferes with E. coli metabolism during expression. This antimicrobial effect is probably facilitated by residual solubility of the fusion peptide and by a C-terminal cap structure, which stabilizes the r-pleurocidin-G alpha-helix that is thought to be important for activity.