Opioid-stimulant trends in overdose toxicology by race, ethnicity, & gender: An analysis in Delaware, 2013-2019.

Recent upticks of stimulant presence in overdose deaths suggest the opioid epidemic is morphing, which raises questions about what drugs are involved and who is impacted. We investigate annual and growth rate trends in combined opioid-stimulant overdose toxicology between 2013 and 2019 for White, Black, and Hispanic male and female decedents in Delaware. During these years, toxicology shifted to illegal drugs for all with fentanyl leading the increase and opioid-cocaine combinations rising substantially. While combined opioid-cocaine toxicology grew among Black and Hispanic Delawareans, White males continue to report the highest rates overall. These findings depart from historical patterns and may challenge existing opioid epidemic policies.

Elderly men with renal dysfunction are most at risk for poor outcome after neck of femur fractures.

BACKGROUND: both acute and chronic renal dysfunction (ARD and CRD) have been reported to influence outcomes after neck of femur fractures. We have examined the relationship between the length of stay, mortality and renal dysfunction using biomarkers. These included pre-operative (admission) serum concentrations of urea, creatinine and albumin, and estimated glomerular filtration rates (eGFR) derived from four- and six-variable Modification of Diet in Renal Disease (MDRD) study equations. METHODS: complete outcomes data for 566 patients and the patterns of variations in the biomarkers were analysed using generalised linear models. Cox-proportional hazard analyses investigated the association between kidney function (as assessed by the above-mentioned biochemical data) and post-operative length of stay and mortality. All patients were stratified for CRD according to their eGFR. RESULTS: serum urea and creatinine were significantly, positively correlated with age. After adjusting for age and sex, risk of mortality was positively related to six-variable eGFR and creatinine, and marginally so for urea. One-year mortality risk thus worsened with stages of CRD (1-4), increasing age and male gender. Risk of discharge from trauma ward, the length of stay in trauma ward and the overall length of stay were not related to urea and creatinine, but were negatively related to both four- and six-variable eGFR. CONCLUSIONS: the study has identified elderly renal-impaired males as the subgroup of patients most at risk for poor survival. This subgroup may require a more targeted approach to the management of their fluid and electrolyte homoeostasis to help improve their outcomes.

Understanding Escalation Through Intimate Partner Homicide Narratives.

The study aims to expand our understanding of escalation from intimate partner violence to intimate partner homicide (IPH) by exploring the known circumstances leading up to a lethal event. The study draws on qualitative data from law enforcement reports and coroner/medical examiner reports within the National Violent Death Reporting System to identify themes preceding and surrounding IPH incidents. Findings support the utility of risk assessments in identifying escalation while illustrating the complex ways that violence between current or former intimate partners can escalate to lethality, particularly the role of separation and the use of firearms.

An Examination of Seasonal Trends in Delaware Drug Overdoses, 2016-2020.

Objective: To examine whether overdose deaths and related metrics-overdose calls for service to police and non-fatal overdose emergency department visits-in Delaware follow within-year (i.e., seasonal) patterns during the most recent years of the opioid epidemic (2016-2020). Methods: We begin by providing descriptive statistics on yearly trends in overdose metrics, followed by Analysis of Variance (ANOVA) to analyze whether seasonal variations have a significant impact on the patterns of Delaware's overdose metrics while controlling for annual variations. Results: We find yearly variations across the three overdose-related metrics, with overdose deaths reporting the only consistent increases per year. Within-year, or seasonal, variations show the spring months have the most consistent increases in overdose deaths and overdose calls for service across years we studied. Finally, we report significant differences for all overdose metrics across years and seasons. Conclusions: As in prior studies, we find significant variation in overdose-related metrics by season in Delaware. Policy Implications: These findings lend support to existing interventions in slowing yearly growth in overdose deaths. However, allocation of resources and interventions to specific times of the year-when overdoses are highest-may further reduce risks and harms.

Comparison of opioid receptor distributions in the rat central nervous system.

The opioid receptors, mu, delta and kappa, conduct the major pharmacological effects of opioid drugs, and exhibit intriguing functional relationships and interactions in the CNS. Previously established hypotheses regarding the mechanisms underlying these phenomena specify theoretical patterns of relative cellular localisation for the different receptor types. In this study, we have used double-label immunohistochemistry to compare the cellular distributions of delta and kappa receptors with those of mu receptors in the rat CNS. Regions of established significance in opioid addiction were examined. Extensive mu/delta co-localisation was observed in neuron-like cells in several regions. mu and kappa receptors were also often co-localised in neuron-like cell bodies in several regions. However, intense kappa immunoreactivity (ir) also appeared in a separate, morphologically distinct population of cells that did not express mu receptors. These small, ovoid cells were often closely apposed against the larger, mu-ir cell bodies. Such cellular appositions were seen in several regions, but were particularly common in the medial thalamus, the periaqueductal grey and brainstem regions. These findings support proposals that functional similarities, synergy and cooperativity between mu and delta receptors arise from widespread co-expression by cells and intracellular molecular interactions. Although co-expression of mu and kappa receptors was also detected, the appearance of a separate population of kappa-expressing cells supports proposals that the contrasting and functionally antagonistic properties of mu and kappa receptors are due to expression in physiologically distinct cell types. Greater understanding of opioid receptor interaction mechanisms may provide possibilities for therapeutic intervention in opioid addiction and other conditions.

Effects of oxytocin on serotonin 1B agonist-induced autism-like behavior in mice.

Social impairments in autism remain poorly understood and without approved pharmacotherapies. Novel animals models are needed to elucidate mechanisms and evaluate novel treatments for the social deficits in autism. Recently, serotonin 1B receptor (5-HT1B) agonist challenge in mice was shown to induce autism-like behaviors including perseveration, reduced prepulse inhibition, and delayed alternation deficits. However, the effects of 5-HT1B agonists on autism-related social behaviors in mice remain unknown. Here, we examine the effects of 5-HT1B agonist challenge on sociability and preference for social novelty in mice. We also examine the effects of 5-HT1B agonist treatment on average rearing duration, a putative rodent measure of non-selective attention. Non-selective attention is an associated feature of autism that is also not well understood. We show that 5-HT1B receptor activation reduces sociability, preference for social novelty, and rearing in mice. In addition, we examine the ability of oxytocin, an off-label treatment for the social impairments in autism, to reverse 5-HT1B agonist-induced social and attention deficits in mice. We show that oxytocin restores social novelty preference in mice treated with a 5-HT1B agonist. We also show that oxytocin attenuates 5-HT1B agonist-induced sociability and rearing deficits in mice. Our results suggest that 5-HT1B agonist challenge provides a useful pharmacological mouse model for aspects of autism, and implicate 5-HT1B in autism social and attention deficits. Moreover, our findings suggest that oxytocin may treat the social deficits in autism through a mechanism involving 5-HT1B.

Characterisation of opioid receptors involved in modulating circular and longitudinal muscle contraction in the rat ileum.

1. The aim of the present investigation was to characterise the opioid receptor subtypes present in the rat ileum using a method that detects drug action on the enteric nerves innervating the circular and longitudinal muscles. 2. Neurogenic contractions were reversibly inhibited by morphine (circular muscle pEC50, 6.43+/-0.17, Emax 81.7+/-5.0%; longitudinal muscle pEC50, 6.65+/-0.27, Emax 59.7+/-7.8%), the mu-opioid receptor-selective agonist, DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin acetate) (circular pEC50, 7.85+/-0.04, Emax 97.8+/-3.6%; longitudinal pEC50, 7.35+/-0.09, Emax 56.0+/-6.1%), the delta-selective agonist DADLE ([D-Ala2,D-Leu5]enkephalin acetate) (circular pEC50, 7.41+/-0.17, Emax, 93.3+/-8.4%; longitudinal pEC50, 6.31+/-0.07, Emax 66.5+/-5.2%) and the kappa-selective agonist U 50488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide methanesulphonate) (circular pEC50, 5.91+/-0.41, Emax, 83.5+/-26.8%; longitudinal pEC50, 5.60+/-0.08, Emax 74.3+/-7.2%). Agonist potencies were generally within expected ranges for activity at the subtype for which they are selective, except for U 50488H, which was less potent than expected. 3. The mu and delta receptor-selective antagonists, CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) and naltrindole, caused progressive, parallel rightward shifts in the DAMGO and DADLE curves, respectively. Analysis indicated conformity to theoretical simple competitive antagonist behaviour. U 50488H effects were insensitive to the kappa-selective antagonist, n-BNI. A high concentration (1 microM) of naltrexone caused apparent potentiation of U 50488H effects. 4. CTAP pK(B) estimates were consistent with previously reported values for mu receptor antagonism (circular 7.84+/-0.17, longitudinal 7.64+/-0.35). However, the naltrindole pK(B) estimates indicated lower antagonist potency than expected (circular 8.22+/-0.23, longitudinal 8.53+/-0.35). 5. It is concluded that mu and possibly atypical delta receptors (but not kappa receptors) mediate inhibition of contraction in this model. Nonopioid actions of U 50488H are probably responsible for the inhibitory effects seen with this compound.

The risk of cardiorespiratory deaths persists beyond 30 days after proximal femoral fracture surgery.

INTRODUCTION: 30-day mortality is routinely used to assess proximal femoral fracture care, though patients might remain at risk for poor outcome for longer. This work has examined the survivorship out to one year of a consecutive series of patients admitted for proximal femoral fracture to a single institution. We wished to quantify the temporal impact of fracture upon mortality, and also the influence of patient age, gender, surgical delay and length of stay on mortality from both cardiorespiratory and non-cardiorespiratory causes. PATIENTS AND METHODS: Data were analysed for 561 consecutive patients with 565 fragility type proximal femoral fractures treated surgically at our trauma unit. Dates and causes of death were obtained from death certificates and also linked to data from the Office of National Statistics. Mortality rates and causes were collated for two time periods: day 0-30, and day 31-365. RESULTS: Cumulative incidence analysis showed that mortality due to cardiorespiratory causes (pneumonia, myocardial infarction, cardiac failure) rose steeply to around 100 days after surgery and then flattened reaching approximately 12% by 1 year. Mortality from non-cardiorespiratory causes (kidney failure, stroke, sepsis etc.) was more progressive, but with a rate half of that of cardiorespiratory causes. Progressive modelling of mortality risks revealed that cardiorespiratory deaths were associated with advancing age and male gender (p<0.001 for both), but the effect of age declined after 100 days. Non-cardiorespiratory deaths were not time-dependent. CONCLUSION: We believe this analysis extends our understanding of the temporal impact of proximal femoral fracture and its surgical management upon outcome beyond the previously accepted standard (30 days) and supports the use of a new, more relevant timescale for this high risk group of patients. It also highlights the need for planning and continuing physiotherapy, respiratory exercises and other chest-protective measures from 31 to 100 days.

C-5 propyne-modified oligonucleotides penetrate the epidermis in psoriatic and not normal human skin after topical application.

We have previously shown that antisense oligonucleotides effectively reduced insulin-like growth factor I receptor expression in human psoriatic skin grafted on to nude mice when injected intradermally. We therefore investigated the penetration of C-5 propyne modified antisense oligonucleotides into human normal and psoriatic skin after topical administration. Oligonucleotide (37.5 microg; 250 microM) was applied in aqueous solution or 5% methylcellulose gel for 24 h, prior to live confocal microscopy and fluorescence microscopy of fixed sections. We found that oligonucleotide could penetrate through the stratum corneum of psoriatic but not normal human skin over large regions of the epidermis. The oligonucleotide was localized to the nucleus of large parakeratotic cells in the psoriatic skin as well as smaller basal and suprabasal keratinocytes. In normal human skin, oligonucleotide was confined to the stratum corneum, with little or no oligonucleotide apparent in the viable epidermis. Electrophoresis of oligonucleotide recovered from treated psoriatic and normal skin revealed that the oligonucleotide remained intact over the 24 h period. In summary, we found that C-5 propyne modified antisense oligonucleotides could reach the target cells (in this case basal keratinocytes) after topical administration to psoriatic but not normal skin.

Catastrophic osteomyelitis following percutaneous wire fixation of a distal radial fracture: a cautionary tale of poor patient selection followed by surgical mishap.

We present a case of distal radius fracture. Several sequential unfortunate events resulted in a poor outcome. The patient was poorly selected because the degree of early dementia was not fully appreciated, due to intermittent periods of lucidity. Having elected to treat this distal radius fracture with Kirschner wires, a wire snapped during the procedure and was deemed safe to leave within the medullary cavity. Subsequently, the patient was left in a cast for 4 weeks without regular pin site inspection. When the cast was removed a gross osteomyelitis had developed. This series of events, led to unnecessary morbidity and extended the immobilisation time with reduced wrist function. This case highlights the importance of careful patient selection, surgical tactics and continuity of care.

Does the timing of presentation of neck of femur fractures affect the outcome of surgical intervention.

OBJECTIVES: There is growing emphasis on minimizing surgical delay for neck of femur fractures. Surgery within 36 h of diagnosis by the emergency department (ED) is classed as a key performance indicator. We aimed to determine the influence of the effect of time of presentation to the ED on surgical delay and 90-day mortality. The influence of age (<85 vs. ≥85 years) on these outcomes was also examined. METHODS: A retrospective study was carried out. Data on 663 patients admitted over 30 months to a single unit were analysed for times of presentation to ED, radiographs in ED, admission to trauma ward and surgery. The delays to admission and surgery were calculated. The patients were divided into four 'time classes' depending on their time of presentation in the ED (i.e. 00:00-06:00, 06:00-12:00, 12:00-18:00 and 18:00-00:00) and into two 'age cohorts' (i.e. <85 and ≥85 years). RESULTS: The four 'time classes' included 58, 157, 259 and 189 patients, respectively. Patients who presented between 00:00 and 06:00 had a significantly reduced surgical interval and delay (P<0.001). There were no significant differences in the outcome measures, that is 36-h operation and 90-day mortality rates between the four classes. Overall, 386 patients were aged below 85 years and 277 were aged at least 85 years. Admission and surgical delays were similar between the two age cohorts, as were the 36-h operation rates. The 90-day mortality rates were 5.7 and 17.7%, respectively (P<0.0001). CONCLUSION: This study showed that the time of presentation to the ED could influence surgical delay. However, there was no direct relationship between surgical delay and 90-day mortality.

Factors influencing length of stay and mortality after first and second hip fractures: an event modeling analysis.

OBJECTIVE: The aim of this study was to investigate factors influencing length of stay and mortality in first and second hip fractures. DESIGN: This was a retrospective study with data analysis. SETTING: The study was conducted at a level 1 trauma center. PATIENTS: Six hundred and seventy-two patients treated for hip fractures (OTA 31-A, 31-B, 32-A1.1) over 30 months were split into 2 groups. 1FG: Six hundred and ten patients (90.8%) suffered a fracture for the first time. 2FG: Sixty-two patients (9.2%) had previously sustained contralateral fractures. INTERVENTION: Dynamic hip screws or cephalomedullary nails (31-A fractures); cephalomedullary nails (32-A1.1); dynamic hip screws or cannulated screws (undisplaced 31-B fractures); and hemiarthroplasty (displaced 31-B fractures) were used. MAIN OUTCOME MEASURES: Postoperative lengths of stay on trauma ward (LOS-T) on the rehabilitation unit (LOS-R) and in hospital (LOS-H) were calculated. Dates of death were recorded. Event analysis and structural equation modeling were used to assess the impact of second fractures, fracture types, age, gender, and ASA grades on these. RESULTS: : The 2 groups were comparable in gender distribution, ASA grades, fracture types, LOS, and mortality at 120 days. 2FG patients were older than 1FG (mean 83.3 vs 80.2 years) with a higher proportion being discharged to institutional care (35.5% vs 18.5%). Event modeling analysis showed that LOS-T was dependent on ASA grade, whereas mortality was dependent on ASA grade, age, and gender. Second fractures were not related to the risks of increased LOS-T, LOS-R, and mortality. CONCLUSIONS: Second fractures per se do not increase the risk of longer postoperative stay or higher mortality. Any observed effect on these outcomes in second fractures represents the influence of increasing age. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Sclerostin monoclonal antibodies on bone metabolism and fracture healing.

INTRODUCTION: The biological enhancement of fracture healing may prevent complications such as non-union and revision surgery. Sclerostin is produced by osteocytes and binds to the LRP5/6 receptor. This inhibits the Wnt signalling pathway and thereby reduces bone formation. AREAS COVERED: Targeted deletion of the sclerostin gene has been found to enhance bone formation and fracture healing in rodent models. A number of in vivo studies have investigated the effect of sclerostin antibody on bone density with promising results. It also has an ability to promote fracture healing, screw fixation and metaphyseal bone healing in vivo. Early clinical studies have also demonstrated that it can increase bone mineral density, whilst being safe and well tolerated by patients. EXPERT OPINION: The data support the further investigation of this agent for the promotion of fracture healing. We aim to review the current literature and present an update on the use of this agent to promote bone formation and healing.

The outcome of displaced intra-articular calcaneal fractures that involve the calcaneocuboid joint.

INTRODUCTION: The outcome of displaced intra-articular fractures of the calcaneus is affected by many factors such as fracture type and age. The restoration and maintenance of the posterior facet is a priority and has a strong correlation with improved outcome. The fracture occasionally extends anteriorly to the calcaneocuboid joint (CCJ). Currently there is little literature discussing pain, functional or radiographic information about calcaneal fractures, which involve the CCJ or those that do not. The aim of this study was to compare pain and functional outcome measurements in a cohort of calcaneal fractures treated operatively and non-operatively to determine whether CCJ involvement was important. PATIENTS AND METHODS: A prospective database of calcaneal fractures managed by a single surgeon was reviewed. CT images allowed us to assess the degree of CCJ involvement before and after surgery. Final outcome was determined by pain (validated visual analogue score) and functional outcomes (SF-36) taken 2 years after injury with further CT imaging used to determine the presence of arthritic change at the CCJ. 59 patients with 64 intra-articular calcaneal fractures were identified who also had 35 fractures that extended to the CCJ. Pre-operative CT imaging identified 3 levels of CCJ involvement: Undisplaced fracture line (n=27); fractures that involved <50% of the CCJ (n=4) and fractures that involved >50% of the CCJ with joint subluxation (n=4). RESULTS: Pain and functional scores were comparable between fractures that involved the CCJ and those that did not. All fractures that involved >50% of the CCJ demonstrated arthritic change 2-years after injury. DISCUSSION: Displaced intra-articular fractures of the calcaneus will often have a fracture line extending into the CCJ. This is commonly undisplaced and does not appear to predict continued pain, dysfunction on radiographic appearance using generalised outcome measurements.

Cerebral emboli and cognitive function after intramedullary fracture fixation.

INTRODUCTION: Cerebral emboli have been detected during intramedullary orthopaedic procedures. The quantity of emboli produced and their clinical effects are currently not known. This study aimed to quantify the intra-operative cerebral embolic load using transcranial Doppler ultrasound during the intramedullary stabilisation of femoral and tibial diaphyseal fractures. Clinical cognitive function was also assessed after surgery and any relationship to the cerebral embolic load determined. PATIENTS AND METHODS: Prospective cohort study of 20 patients with femoral or tibial diaphyseal fractures treated with reamed intramedullary nailing. The intra-operative cerebral embolic load was measured using transcranial Doppler ultrasound of the middle meningeal artery. Cognitive function was assessed 3 days after surgery using a range of validated neuropsychological tests. The cognitive results were compared to predicted scores matched for age and intelligence quotient as is the standard method of cognitive assessment after trauma. RESULTS: Four patients had detectable cerebral emboli with counts of only 2, 3, 3, and 9 respectively. A significantly poorer than predicted cognitive score occurred in immediate and delayed memory recall tests. However there was no significant difference in any cognitive function score between those patients who had detectable cerebral emboli and those who did not. DISCUSSION: Small numbers of cerebral emboli were detected during intramedullary stabilisation of lower limb long bone fractures but with no apparent cognitive effect. This poor correlation is similar to recent studies performed on arthroplasty patients and also conforms to the extensive cardiac surgery literature which would indicate that such low levels of systemic embolisation are unlikely to consistently produce cerebral clinical effects.