An Industry Proposal for a Cell and Gene Therapy Safety Data Sheet.

Introduction: A safety data sheet (SDS) is an established hazard communication tool for chemicals, for which no comparable document exists in the biotherapeutics industry. As the cell and gene therapy (CGT) field expands, industry leaders have identified a growing need to address this gap in communication of the unique occupational health and safety risks posed by CGT materials and products. Methods: Following the sections of a traditional chemical SDS, information was modified by industry subject matter experts, relevant to CGT biological materials. This guide was developed based on assumptions of a maximum biosafety level 2, and any chemical components present in the material were excluded from the hazard classification. Results: The guide contains necessary information to conduct a workplace risk assessment and communicate the unique workplace hazards posed by potential exposures to the material. The target audience is intended to be entities handling and producing these materials, plus collaborators, contractors, or operations sites receiving and handling the CGT material. An example of a CGT SDS is provided in Table 1. Discussion: The CGT SDS provides industry with a best practice to address an existing gap in hazard communication for CGT. We expect that, as the field evolves, so may the contents. The CGT SDS can be used as a reference for other biological modalities in the field. Conclusions: This initial CGT SDS communicates workplace hazards and assesses the unique risks posed by these biological materials and can assist in creating exposure control plans specific to the workplace hazards.

Dual mechanical valve thrombosis resolution through thrombolytics: a case series.

Background: Prosthetic valve thrombosis (PVT) is a severe complication of mechanical valve replacement. Simultaneous thrombosis of multiple prosthetic valves is rare and is associated with worse outcomes. Treatment options include anticoagulation, thrombolysis, and redo operative valve replacement, with rare reports of adjunctive balloon valvuloplasty. There is limited evidence to guide therapeutic selection, specifically dosing, timing, and duration of thrombolysis. The following case series highlights the importance of successful thrombolytic management in dual PVT with high bleeding risk defined as a coagulopathy with an elevated international normalized ratio greater than 3 and New York Heart Association (NYHA) Class III and IV heart failure. Case summary: We describe two patients with concomitant aortic and mitral PVT. Both patients presented in NYHA Class III and IV heart failure with different challenges to surgical treatments including high bleeding risk from coagulopathy and history of multiple prior sternotomies. After multi-disciplinary discussions, both patients underwent a combination of low-dose, slow, or ultra-slow infusion of tissue plasminogen activator, with a resolution of their dual PVT seen on cine-fluoroscopy imaging as freely moving mechanical leaflets and improvement of heart failure symptoms back to baseline NYHA Class II or lower. Discussion: Prosthetic valve thrombosis is a complex medical condition requiring a multi-disciplinary team to evaluate the best course of treatment. A trial of pharmacologic thrombolysis is often the first attempted treatment for obstructive PVT, although surgery is recommended for patients with NYHA IV symptoms, or with contraindications to thrombolysis, including high bleeding risk. However, in patients with high bleeding risk and NYHA Class III and IV heart failure, especially with surgical contraindications, low-dose thrombolytics, with slow or ultra-slow infusions, may still be safe and effective treatment strategies for multi-valve PVT. Further research is needed to guide thrombolysis in multi-valve PVT.

Cryptococcus neoformans endocarditis in an immunocompetentpatient a case report.

BACKGROUND: Cryptococcus neoformans is an invasive fungal infection commonly affecting immunocompromised patients as pneumonia or meningitis. More rarely, case reports describe Cryptococcus neoformans endocarditis, though nearly exclusively among patients with active immunosuppression, implanted cardiac devices or prosthetic valves. CASE PRESENTATION: We report the case of a patient with underlying substance abuse disorder and systolic heart failure presenting with fever, altered mental status, and shower emboli subsequently found to have native tricuspid valve vegetations and blood cultures positive for cryptococcus neoformans in the absence of immunosuppression. CONCLUSIONS: Historically, Cryptococcus neoformans fungemia manifests clinically as pneumonia or meningitis among the immunosuppressed. There have been rare reports of endocarditis in this population and even fewer reports of native valve endocarditis exist. The present case along with mortality reported in prior literature, suggest suspicion must be maintained in the absence of immunosuppression, even in patients with native valves.

Examining Interventions and Adverse Events After Nonfatal Opioid Overdoses in Veterans.

Background: Veterans are twice as likely to experience a fatal opioid overdose compared with their civilian counterparts. Recognition has increased that effective opioid overdose prevention likely requires a holistic approach that addresses the biopsychosocial factors contributing to opioid-related morbidity and mortality. Methods: This retrospective descriptive study includes veterans who were administered naloxone for treatment of opioid overdose in the emergency department at Veterans Affairs San Diego Healthcare System from July 1, 2013 through April 1, 2017. Subjects were excluded if they received palliative/hospice care or were lost to follow-up, if there was documented lack of response to naloxone administration, and if overdose occurred secondary to inpatient administration of opioids. Data were collected via chart review. Results: Thirty-five patients were included in this study. At the time of nonfatal opioid overdose, 29 (82.9%) had an active opioid prescription, and the mean morphine equivalent daily dose (MEDD) was 117 mg. Thirty-three (94.3%) had comorbid psychiatric disorders and 20 (57.1%) had substance use disorders. Within 6 months following overdose, subjects received care from mental health (45.5%), addiction treatment services (50.0%), and pain management (40.0%). Documented repeat overdose occurred in 4 patients. Conclusions: This study may aid in the identification of potential areas for improvement in the prevention of opioid overdose and opioid-related mortality among veterans. Interventions designed to improve access to, engagement, and retention in effective care are pivotal for addressing the opioid epidemic as it evolves.

Evaluation of a Pharmacist Managed Telephone Pain Clinic for Neuropathy Treatment.

Pain is prevalent in our society, affecting more than a quarter-million U.S. adults and leading to poor patient outcomes. At the Veteran's Affairs San Diego Healthcare System (VASDHS), a Telephone Pain Clinic (TPC) was developed to improve these outcomes. The purpose of this study was to evaluate the effectiveness of TPC in improving neuropathic pain. A retrospective cohort study was conducted at the VASDHS comparing pre- and post- self-rated Numeric Rating Scale (NRS-11), an 11-point scale from 0 to 10 with 0 equaling no pain and 10 equaling most severe pain. Patients were included if they were referred and enrolled to the TPC for neuropathic pain. They were excluded if they were co-managed by another pain provider or were referred for any other pain conditions. A total of 830 TPC patients were screened between January 2008 to December 2009 and 52 patients met criteria. Patients who participated in the clinic were found to have a significant 0.83 (p = 0.014) reduction in mean pain score from baseline (6.62, SD 1.96) to discharge (5.79, SD 2.49). At discharge, pain medications that were increased were use of serotonin and norepinephrine reuptake inhibitors (SNRIs), pregabalin, and capsaicin. Management by the TPC showed promise and trends toward reducing pain experienced by patients with diabetic neuropathy, fibromyalgia, or postherpetic neuralgia. The TPC also may be more effective in maximizing evidenced-based pharmacotherapy for neuropathic pain, suggesting expertise by pharmacist clinical specialists.

Endotracheal tube cuff pressures - the worrying reality: a comparative audit of intra-operative versus emergency intubations.

OBJECTIVES: The primary aim was to assess the need for objective cuff pressure monitoring in the theatre complex and trauma centre at Groote Schuur Hospital, Cape Town, South Africa. Secondary aims were to determine whether the tube size, tube make or place of intubation affected cuff pressure. METHOD: Endotracheal tube cuff pressures of 91 patients in the trauma centre and 100 patients in the theatre complex were randomly measured using a Mallinckrodt cuff pressure gauge. The measurements were recorded on a standardised data sheet and transferred to an electronic database for analysis. RESULTS: There was a significant difference between cuff pressures in the trauma centre and those in the theatre complex (p<0.001), the means being 55 cmH2O and 25 cmH2O, respectively. The site of intubation had a significant (p=0.001) effect on cuff pressures, with mean pressures as follows: on scene - 71 cmH2O; referral hospital - 57 cmH2O; and Groote Schuur trauma centre - 42 cmH2O. Only 30% of cuff pressures measured in the trauma centre were below 30 cmH2O, and, alarmingly, 17% were between 91 and 120 cmH2O. In the theatre complex, 77% of cuff pressures were in the acceptable range. Digital balloon palpation corresponded poorly (correlation coefficient 0.47) with measured cuff pressure, and statistical analysis showed that it tended to underestimate the pressure at higher cuff pressures. CONCLUSION: The risk of a high cuff pressure is roughly two- to threefold higher in emergency patients than in theatre patients. These unacceptably high cuff pressures are especially concerning in view of the fact that many trauma patients are hypotensive and therefore more susceptible to mucosal ischaemia.

Outcome of laparoscopic inguinal hernia repair in a South African private practice setting.

OBJECTIVE: The aim of this study was to determine the recurrence and complication rates of laparoscopic inguinal hernia repair performed in a private practice in Cape Town. DESIGN AND SUBJECTS: An unselected cohort of 507 patients who underwent laparoscopic totally extraperitoneal (TEP) inguinal hernia repair before September 2005 were included in this study, thus ensuring a minimum 5-year follow-up. Patient demographic data, clinical notes, operating notes and outpatient follow-up notes were studied. Patients were interviewed telephonically regarding hernia recurrence, chronic pain and technique preference if they had previously undergone an open repair. All data collected were recorded on an electronic spreadsheet. The primary outcome parameter was recurrence. The secondary outcome parameters were postoperative and long-term complications. RESULTS: Of the 507 patients, 267 were contactable telephonically. There were 384 hernia repairs with a mean follow-up of 8.8 years. There were 9 recurrences (2.3%). The overall complication rate was 7.9%. Two per cent of patients suffered from chronic groin pain with gradual improvement since surgery. Sixteen per cent of patients had had previous open repair of an inguinal hernia, either on the ipsilateral or the contralateral side, and all judged the open repair to have been more painful. CONCLUSIONS: The recurrence and complication rates for laparoscopic TEP inguinal hernia repair in this practice are low and comparable to the best reported series. There is a low incidence of persistent postoperative pain with the laparoscopic technique, and it is the technique preferred by patients who previously underwent an open repair.

Clinical efficacy of vorinostat in a patient with leiomyosarcoma.

Leiomyosarcoma is a heterogeneous tumor group, representing <1% of all new cancers diagnosed in United States. Treatment choice is based upon site, grade, and extent of disease. However, prognosis for metastatic or unresectable sarcoma is very poor with reported median survival of 12 months. Response to chemotherapy has been approximately 8% to 39% based upon the chemotherapeutic agent and whether used alone or in combination. Vorinostat is an orally active, potent, and competitive inhibitor of histone deacetylases approved for cutaneous T-cell lymphoma. There are limited preclinical data illustrating the activity of histone deacetylase inhibitors in sarcoma. Here is a case of a lady with leiomyosarcoma who has progressed through multiple chemotherapeutic agent who has achieved a partial response to vorinostat treatment.

pH-dependent spectral properties of para-aminobenzoic acid and its derivatives.

The local environment dictates the structural and functional properties of many important chemical and biological systems. The impact of pH on the photophysical properties of a series of para-aminobenzoic acids is examined using a combination of experimental spectroscopy and quantum chemical calculations. Following photoexcitation, PABA derivatives may undergo an intramolecular charge transfer (ICT) resulting in the formation of a zwitterionic species. The thermodynamics of the excited state reaction and temperature-dependence of the radiative emission processes are evaluated through variable temperature fluorescence spectroscopy carried out in a range of aqueous buffers. Quantum chemical calculations are used to analyze structural changes with modifications at the amine position and different protonation states. The ICT is only observed in the tertiary amine, which calculations show has more sp(2) character than the primary or secondary amines. Thermodynamic analysis indicates the ICT reaction is driven by entropy.