Combating Fentanyl: National Guard Physician Assistants on the Front Lines of America's War Against Synthetic Opioids.

There is a significant threat to global health security due to synthetic opioids, illicitly manufactured fentanyl (IMF), and nefarious uses of pharmaceutical based agents (PBA). Since 2014, increased distribution of synthetic opioids including IMF into the US through China, India, and Mexico has resulted in devastating consequences to the average street drug user. Additionally, clandestine lab operations for pill manufacturing and distribution have increased, along with unintentional drug overdoses due to drugs being laced with fentanyl or some other synthetic opioid derivative. Naloxone has been shown to be an effective and useful tool for reversing signs and symptoms of synthetic opioid overdose, though additional doses may be required depending on the analog. In addition to the risk of overdose in US civilians, other state actors have utilized fentanyl and its analogs as incapacitants resulting in significant numbers of casualties. The National Guard Weapons of Mass Destruction-Civil Support Teams (WMD-CST) have been on the front lines supporting federal law enforcement agencies with hazard identification and assessment. Physician Assistants (PA) are assigned to these units and provide the necessary skills and expertise to keep on scene personnel safe. This article aims to dispel some of the rumors and myths surrounding fentanyl in an effort to educate first receivers, first responders, and hospital providers. Lastly, this article provides a review of synthetic opioid production, overdose, hazards, treatment/countermeasures, decontamination for responders, and the potential use of synthetic opioids as WMDs.

Sterility Testing for Hematopoietic Stem Cells.

Over the last two decades, rapid technological advances have led to the wide adoption of cell and gene therapy products for the treatment of a variety of disease states. In this study, we reviewed the literature between 2003 and 2021 to provide a summary of overarching trends associated with microbial contamination in hematopoietic stem cells (HSCs) derived from peripheral blood, bone marrow, and cord blood. We provide a brief background on the regulatory context for human cells, tissues, and cellular and tissue-based products (HCT/Ps) as regulated by the US Food and Drug Administration (FDA), sterility testing expectations for autologous (Section 361) and allogeneic (Section 351) HSC products, and discuss clinical risks associated with the infusion of a contaminated HSC product. Finally, we discuss the expectations for current good tissue practices (cGTP) and current good manufacturing practices (cGMP) for the manufacturing and testing of HSC based on Section 361 and Section 351 categorization, respectively. We provide commentary on what is practiced in the field and discuss the critical need for updates to professional standards that keep pace with advancing technologies with an aim to clarify expectations for manufacturing and testing facilities to improve standardization across institutions.

Steam inhalation: More harm than good? Perspective from a UK burns centre.

INTRODUCTION: Steam inhalation is common practice in UK households for coryzal symptoms in adults and children. Steam inhalation has the potential to and has caused significant scald injuries, predominantly due to unintentional contact with the hot water used. METHODS: The authors used electronic health records to retrospectively identify all patients admitted with scald injuries secondary to steam inhalation over a 2-year period from January 2018-December 2019 at Chelsea and Westminster Hospital, a regional burns centre. Data collected included patient demographics, mechanism of burn, as well as burn size, depth, treatment and any associated complications. An International Burns Injury Database enquiry assessed the national prevalence steam inhalation scalds over the same time period. RESULTS: 19 adult and paediatric patients were identified in our centre over a 2-year period, with an age range of 2 weeks to 91 years old. The majority (16/19, 84%) of patients received burns to their lower body, with three patients receiving burns to their chest and/or upper limbs. Six patients underwent surgery, 98 clinic appointments were utilised and the total length of hospital stay was 83 days. The estimated total cost of treating these 19 patients was over £31,872. Nationally, 201 cases were identified between Jan 2018-Dec 2019. CONCLUSIONS: Scald injuries secondary to steam inhalation have a significant impact both in terms of hospital stay and cost. Since this study captured only patients admitted to hospital, the true negative impact of steam inhalation is likely to be much higher than calculated. Better public awareness on the risks of steam inhalation and primary prevention policies could reduce the frequency of such injuries.

Current and Future Cell Therapy Standards and Guidelines.

Cell biology researchers, cellular engineers, and clinicians are teaming together to create powerful drugs. The use of cell-derived products as biologics is rapidly advancing. These human cell-based products have great potential for treating serious conditions but may have unidentified risks. Manipulations, expansions, and gene modifications increase the risks of unexpected outcomes. Implementation of the 21st Century Cures Act is opening avenues for accelerated approvals of these drugs for use in clinical trials and licensure. Although overwhelming, collaboration between regulators, industry, and research and medical communities enables the field to safely meet the needs of critically ill patients.

A prospective RCT comparing combined chromoendoscopy with water exchange (CWE) vs water exchange (WE) vs air insufflation (AI) in adenoma detection in screening colonoscopy.

Background: A low adenoma detection rate (ADR) increases risks of interval cancers (ICs). Proximal colon flat polyps, e.g. serrated lesions (SLs), are difficult to find. Missed proximal colon flat lesions likely contribute to IC. Aims: We compared chromoendoscopy with water exchange (CWE), water exchange (WE) and air insufflation (AI) in detecting adenomas in screening colonoscopy. Methods: After split-dose preparation, 480 veterans were randomized to AI, WE and CWE. Results: Primary outcome of proximal ADR (55.6% vs 53.4% vs 52.2%, respectively) were similar in all groups. Adenoma per colonoscopy (APC) and adenoma per positive colonoscopy (APPC) were comparable. Detection rate of proximal colon SLs was significantly higher for CWE and WE than AI (26.3%, 23.6% and 11.3%, respectively, p = 0.002). Limitations: single operator; SLs only surrogate markers of but not IC. Conclusions: When an endoscopist achieves high-quality AI examinations with overall ADR twice (61.6%) the recommended standard (30%), use of WE and CWE does not produce further improvement in proximal or overall ADR. Comparable APC and APPC confirm equivalent withdrawal inspection techniques. WE alone is sufficient to significantly improve detection of proximal SLs. The impact of increased detection of proximal SLs by WE on prevention of IC deserves to be studied. This study is registered at ClinicalTrial.gov (NCT#01607255).

S100ß in newborns after C-section with general vs. epidural anesthesia: a prospective observational study.

BACKGROUND: Preclinical evidence suggests that general anesthetics can dose dependently induce neurodegeneration in the developing brains of animals which can be reliably determined by measurement of blood S100ß, but this correlation remains unclear in humans. We hypothesized that S100ß would not be increased in cord arterial blood of fetuses exposed briefly to general anesthetics during a C-section, compared with epidural anesthesia. METHODS: A prospective observational clinical study comparatively measured changes of brain damage biomarker S100ß ratio of umbilical artery over vein (changes after fetus circulation) immediately after delivery under C-section with either epidural or general anesthesia. Newborn blood gas measurements, APGAR scores, and maternal well-being were also compared. RESULTS: Compared with epidural anesthesia, general anesthesia resulted in the lower S100ß ratio of umbilical artery over the vein (medium 2.64 [quartiles 1.39, 3.45] vs. medium 1.59 [quartiles 0.88, 2.01], P = 0.031), without changing the S100ß level in the vein of the mother. There was no significant difference between general and epidural anesthesia when comparing other maternal and newborn parameters. CONCLUSION: S100ß levels in newborn after C-section is lower with general anesthesia than epidural anesthesia, with unclear mechanisms.

Investigating the importance of the local food environment for fruit and vegetable intake in older men and women in 20 UK towns: a cross-sectional analysis of two national cohorts using novel methods.

BACKGROUND: Local neighbourhood environments can influence dietary behavior. There is limited evidence focused on older people who are likely to have greater dependence on local areas and may suffer functional limitations that amplify any neighbourhood impact. METHODS: Using multi-level ordinal regression analysis we investigated the association between multiple dimensions of neighbourhood food environments (captured by fine-detail, foot-based environmental audits and secondary data) and self-reported frequency of fruit and vegetable intake. The study was a cross-sectional analysis nested within two nationally representative cohorts in the UK: the British Regional Heart Study and the British Women's Heart and Health Study. Main exposures of interest were density of food retail outlets selling fruits and vegetables, the density of fast food outlets and a novel measure of diversity of the food retail environment. RESULTS: A total of 1124 men and 883 women, aged 69 - 92 years, living in 20 British towns were included in the analysis. There was strong evidence of an association between area income deprivation and fruit and vegetable consumption, with study members in the most deprived areas estimated to have 27% (95% CI: 7, 42) lower odds of being in a higher fruit and vegetable consumption category relative to those in the least deprived areas. We found no consistent evidence for an association between fruit and vegetable consumption and a range of other food environment domains, including density of shops selling fruits and vegetables, density of premises selling fast food, the area food retail diversity, area walkability, transport accessibility, or the local food marketing environment. For example, individuals living in areas with greatest fruit and vegetable outlet density had 2% (95% CI: -22, 21) lower odds of being in a higher fruit and vegetable consumption category relative to those in areas with no shops. CONCLUSIONS: Although small effect sizes in environment-diet relationships cannot be discounted, this study suggests that older people are less influenced by physical characteristics of neighbourhood food environments than is suggested in the literature. The association between area income deprivation and diet may be capturing an important social aspect of neighbourhoods that influence food intake in older adults and warrants further research.

"And DPSIR begat DAPSI(W)R(M)!" - A unifying framework for marine environmental management.

The marine environment is a complex system formed by interactions between ecological structure and functioning, physico-chemical processes and socio-economic systems. An increase in competing marine uses and users requires a holistic approach to marine management which considers the environmental, economic and societal impacts of all activities. If managed sustainably, the marine environment will deliver a range of ecosystem services which lead to benefits for society. In order to understand the complexity of the system, the DPSIR (Driver-Pressure-State-Impact-Response) approach has long been a valuable problem-structuring framework used to assess the causes, consequences and responses to change in a holistic way. Despite DPSIR being used for a long time, there is still confusion over the definition of its terms and so to be appropriate for current marine management, we contend that this confusion needs to be addressed. Our viewpoint advocates that DPSIR should be extended to DAPSI(W)R(M) (pronounced dap-see-worm) in which Drivers of basic human needs require Activities which lead to Pressures. The Pressures are the mechanisms of State change on the natural system which then leads to Impacts (on human Welfare). Those then require Responses (as Measures). Furthermore, because of the complexity of any managed sea area in terms of multiple Activities, there is the need for a linked-DAPSI(W)R(M) framework, and then the connectivity between marine ecosystems and ecosystems in the catchment and further at sea, requires an interlinked, nested-DAPSI(W)R(M) framework to reflect the continuum between adjacent ecosystems. Finally, the unifying framework for integrated marine management is completed by encompassing ecosystem structure and functioning, ecosystem services and societal benefits. Hence, DAPSI(W)R(M) links the socio-ecological system of the effects of changes to the natural system on the human uses and benefits of the marine system. However, to deliver these sustainably in the light of human activities requires a Risk Assessment and Risk Management framework; the ISO-compliant Bow-Tie method is used here as an example. Finally, to secure ecosystem health and economic benefits such as Blue Growth, successful, adaptive and sustainable marine management Responses (as Measures) are delivered using the 10-tenets, a set of facets covering all management disciplines and approaches.

Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer.

BACKGROUND: Methylnaltrexone (MNTX), a peripherally acting µ-opioid receptor (MOR) antagonist, is FDA-approved for treatment of opioid-induced constipation (OIC). Preclinical data suggest that MOR activation can play a role in cancer progression and can be a target for anticancer therapy. PATIENTS AND METHODS: Pooled data from advanced end-stage cancer patients with OIC, despite laxatives, treated in two randomized (phase III and IV), placebo-controlled trials with MNTX were analyzed for overall survival (OS) in an unplanned post hoc analysis. MNTX or placebo was given subcutaneously during the double-blinded phase, which was followed by the open-label phase, allowing MNTX treatment irrespective of initial randomization. RESULTS: In two randomized, controlled trials, 229 cancer patients were randomized to MNTX (117, 51%) or placebo (112, 49%). Distribution of patients' characteristics and major tumor types did not significantly differ between arms. Treatment with MNTX compared with placebo [76 days, 95% confidence interval (CI) 43-109 versus 56 days, 95% CI 43-69; P = 0.033] and response (laxation) to treatment compared with no response (118 days, 95% CI 59-177 versus 55 days, 95% CI 40-70; P < 0.001) had a longer median OS, despite 56 (50%) of 112 patients ultimately crossing over from placebo to MNTX. Multivariable analysis demonstrated that response to therapy [hazard ratio (HR) 0.47, 95% CI 0.29-0.76; P = 0.002) and albumin ≥3.5 (HR 0.46, 95% CI 0.30-0.69; P < 0.001) were independent prognostic factors for increased OS. Of interest, there was no difference in OS between MNTX and placebo in 134 patients with advanced illness other than cancer treated in these randomized studies (P = 0.88). CONCLUSION: This unplanned post hoc analysis of two randomized trials demonstrates that treatment with MNTX and, even more so, response to MNTX are associated with increased OS, which supports the preclinical hypothesis that MOR can play a role in cancer progression. Targeting MOR with MNTX warrants further investigation in cancer therapy. CLINICAL TRIALS NUMBER: NCT00401362, NCT00672477.

Factors at scene and in transfer related to the development of hypothermia in major burns.

There is a paucity of evidence regarding incidence and causes of hypothermia in patients with major burns and its impact on outcomes. This paper identifies contributing factors to hypothermia and its relationship with the severity of physiological scoring systems on admission to a tertiary centre. Patients with burns >20% TBSA admitted between March 2010 and July 2013 comprised this retrospective survey. Data relating to causative factors at time of burn, during transfer, physiological outcome scores (BOBI, SOFA, RTS and APACHE II), length of hospital stay and mortality were collected. SPSS statistical software was used for analysis. The study included 31 patients (medians: age 32 years, burn size 30% TBSA). 13% (n=4) of patients died during hospital admission. 42% (n=13) of patients had a temperature <36.0C on arrival. Temperature on arrival at the burns centre was related to the severity of all physiological scores (p=<0.001). There was no difference between groups in terms of mortality in hospital (p=0.151) or length of hospital stay (p=0.547). Our results show that hypothermia is related to burn severity and patient physiological status. They do not show a relationship between hypothermia and external factors at the time of the burn. This paper prompts further investigation into the prevention of hypothermia in patients with major burns.

Il n'existe que peu de données sur l'incidence et les causes de survenue d'une hypothermie chez les brûlés, ni de son incidence sur le devenir. Cette étude répertorie les facteurs contribuant à l'hypothermie à l'admission dans un centre de référence et sa relation avec les scores de gravité initiaux. Cette étude rétrospective a concerné les patients brûlés sur plus de 20% de SCT admis entre mars 2010 et juillet 2013. Les données concernant les causes d'hypothermie au moment de la brûlure et pendant le transfert, les scores de gravité (BOBI, SOFA, RTS et APACHE II), la durée de séjour et la mortalité ont été relevées. Trente et un dossiers ont été étudiés (âge médian 32 ans, surface brûlée 30%). Quatre (13%) d'ente eux décédés. Treize (42%) avait une température <36°C à l'admission et il existait une corrélation entre la température et les scores de gravité (p<0.001). Il n'y avait pas de différence en termes de mortalité ni de durée de séjour. Cette étude montre que l'hypothermie est corrélée à la gravité de la brûlure et à la gravité générale des patients. On ne retrouve pas de relation entre les facteurs environnementaux au moment de la brûlure et l'hypothermie. Des données supplémentaires sont nécessaires pour la prévention de l'hypothermie liée à la brûlure.

Inhibition of the phosphoinositide 3-kinase pathway for the treatment of patients with metastatic metaplastic breast cancer.

BACKGROUND: Mesenchymal/metaplastic breast cancers (MpBCs) are often triple-negative (TNBC), and chemo-refractory, and can harbor phosphoinositide 3-kinase (PI3kinase) alterations; thus, therapy with mTor inhibitors may demonstrate activity. PATIENTS AND METHODS: Patients with mesenchymal/MpBC treated with temsirolimus-based regimens were evaluated. Mutational analyses [polymerase chain reaction (PCR)-based DNA sequencing method, mass spectrometric detection (Sequenom MassARRAY), or next-generation sequencing] as well as loss of phosphatase and tensin homolog (PTEN) (immunohistochemistry) were performed (archived tissue when available). RESULTS: Twenty-three patients (one of whom was on two separate trials) were treated using temsirolimus-containing regimens: temsirolimus alone (n = 1 patient) or combined with the following: liposomal doxorubicin and bevacizumab (DAT, n = 18); liposomal doxorubicin (DT, n = 1); paclitaxel and bevacizumab (TAT, n = 2); paclitaxel (TT, n = 1); carboplatin and bevacizumab (CAT, n = 1). Response rate [complete response (CR) + partial response (PR)] was 25% across all regimens; 32% in the anthracycline-based regimens [DAT and DT (CR = 2, PR = 4; N = 19)]. An additional two patients achieved stable disease (SD) ≥6 months [total SD ≥6 months/CR/PR = 8 (33%)]. Molecular aberrations in the PI3K pathway were common: PIK3CA mutation = 6/15 (40%), PTEN mutation = 3/11 (27%), and PTEN loss = 2/11 (18%). A point mutation in the NF2 gene (K159fs*16; NF2 alterations can activate mTor) was found in one patient who attained CR (3+ years). Of the eight patients who achieved SD ≥6 months/CR/PR, all 4 patients with available tissue had a molecular aberration that activate the PIK3CA/Akt/mTOR axis: PIK3CA mutation = 2; PTEN loss = 1; NF2 aberration = 1. CONCLUSIONS: DAT has activity in MpBCs including complete CRs. Molecular aberrations that can activate the PI3 K/Akt/mTOR axis are common in MpBC.

A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer.

BACKGROUND: Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. RESULTS: Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. CONCLUSIONS: The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00789633.