A Statistical Analysis of the Impact of Gun Ownership on Mass Shootings in the USA Between 2013 and 2022.

Mass shootings (incidents with four or more people shot in a single event, not including the shooter) are becoming more frequent in the United States, posing a significant threat to public health and safety in the country. In the current study, we intended to analyze the impact of state-level prevalence of gun ownership on mass shootings-both the frequency and severity of these events. We applied the negative binomial generalized linear mixed model to investigate the association between gun ownership rate, as measured by a proxy (i.e., the proportion of suicides committed with firearms to total suicides), and population-adjusted rates of mass shooting incidents and fatalities at the state level from 2013 to 2022. Gun ownership was found to be significantly associated with the rate of mass shooting fatalities. Specifically, our model indicated that for every 1-SD increase-that is, for every 12.5% increase-in gun ownership, the rate of mass shooting fatalities increased by 34% (p value < 0.001). However, no significant association was found between gun ownership and rate of mass shooting incidents. These findings suggest that restricting gun ownership (and therefore reducing availability to guns) may not decrease the number of mass shooting events, but it may save lives when these events occur.

Outcomes following total ankle total talus replacement: A systematic review.

BACKGROUND: Prosthetic substitution of the talus presents a significant challenge to the foot and ankle surgeon. The shear and compressive forces on the talus and its tenuous blood supply lead to high rates of avascular necrosis and eventual talar collapse. The purpose of this systematic review is to evaluate whether total ankle total talus replacement (TATTR) leads to improved clinical and radiographic outcomes with appropriate safety metrics in patients with a history of avascular necrosis or significant trauma. METHODS: We searched the concepts of talus, prosthesis, and arthroplasty in MEDLINE (PubMed), Embase (Elsevier), CINAHL Complete (EBSCOhost), and Scopus (Elsevier) from the database's inception through March 9, 2023. Inclusion Criteria were 1) previous trauma to the talus, 2) post-traumatic arthritis to the tibiotalar joint, 3) avascular necrosis of talus, 4) multiple failed prior interventions, 5) degenerative osteoarthritis to the tibiotalar joint, and 6) inflammatory arthropathy to tibiotalar joint. Patients less than 18 years of age and manuscripts in non-English languages were excluded. RESULTS: Of the 7625 references, 16 studies met the inclusion criteria, yielding data from 136 patients (139 ankles). The studies varied in design, with case reports and retrospective case series being predominant. The overall weighted average modified Coleman Methodology Score (mCMS) was 70.4 out of 100, indicating moderate flaws in study design that may be subject to various forms of bias and possible confounders. Demographics showed a diverse range of etiologies, with alumina ceramic being the primary prosthesis material. Functional scores demonstrated improvements in dorsiflexion and plantarflexion, although patient-reported outcome measures (PROs) were inconsistently reported. Complications included fractures, heterotopic ossification, prolonged wound healing, and infections. Revision details were sparsely reported. CONCLUSION: TATTR is a promising treatment modality for improving short-term functional outcomes for patients with avascular necrosis or trauma-related issues. However, this systematic review underscores the need for standardized reporting, longer-term follow-ups, and further research to establish the procedure's efficacy and safety, particularly in comparison to other treatment modalities. LEVEL OF EVIDENCE: III, Systematic Review of Level IV Studies.

Outcomes following total talus replacement: A systematic review.

INTRODUCTION: The treatment of pathologic changes to the talus and surrounding joints presents a unique challenge to the foot and ankle surgeon. The purpose of this systematic review is to summarize the literature for unconstrained (no surrounding fusion or replacement) total talus replacement (TTR) and evaluate whether it leads to improved clinical and radiographic outcomes and appropriate safety metrics. METHODS: Concepts of talus and arthroplasty were searched in MEDLINE, Embase, CINAHL Complete, and Scopus from 2005 to 2021. Inclusion Criteria were 1) previous trauma to the talus, 2) post-traumatic or degenerative arthritis to the tibiotalar joint, 3) avascular necrosis of talus, 4) multiple failed prior interventions, and 5) inflammatory arthropathy to tibiotalar joint. Manuscripts in non-English languages or those with concomitant total ankle arthroplasty or revision arthroplasty were excluded. RESULTS: Twenty-two studies of 191 patients (196 ankles) were included. Nineteen studies utilized third generation implants, two studies used first generation (n = 9) and one study used second generation implants (n = 14) made largely of ceramic (n = 84), cobalt chrome (n = 49), or titanium (n = 24). Patient-reported outcome measures were favorable in all described categories (Table 4) with ten studies reporting an average postoperative change of + 2.92° of dorsiflexion and - 2.05° plantarflexion at final follow-up. The most common adverse outcome was adjacent joint arthritis with five studies reporting some degree of postoperative, degenerative changes in the surrounding joints (n = 52). CONCLUSION: TTR is an alternative to joint sacrificing procedures to maintain range of motion through the tibiotalar joint and allow for maintenance of normal foot and ankle biomechanics. Despite promising early- and mid-term outcomes, future, prospective, randomized research should be conducted to better assess survivorship and complication rates with direct comparison of TTR to existing forms of salvage options for advanced talar pathology. LEVEL OF EVIDENCE: III, Systematic Review of Level IV Studies.

Favorable Survival with Non-curative Treatments for Patients with Early-Stage Hepatocellular Carcinoma After Liver Transplant Denial.

BACKGROUND: Many patients are not candidates for liver transplant for non-tumor-related reasons including medical comorbidities and non-adherence. The prognosis of patients with hepatocellular carcinoma (HCC) who are not liver transplant candidates in the era of locoregional therapy (LRT) including y90 is not well defined. AIMS: This study seeks to evaluate outcomes and the natural history of early-stage HCC in patients who were denied liver transplant listing due to non-tumor reasons and instead were treated with LRT. METHODS: A retrospective evaluation was performed for all patients who completed liver transplant evaluation with their tumor within Milan criteria but were denied due to non-tumor reasons and were treated with LRT at a single tertiary referral center. RESULTS: The 61 patients included had a favorable overall survival, with a median survival 60.3 months (86.9% at 1 year and 52.7% at 5 years). Patients with Child-Pugh A cirrhosis (n = 34) had significantly longer overall survival compared to those with Child-Pugh B/C cirrhosis (median survival of 70.3 months versus 26.1 months, p = 0.005). Survival in patients with Child-Pugh A at 1, 3, and 5 years was 97%, 80%, and 73%, respectively, compared to 74%, 41%, and 31% in patients with Child-Pugh B/C. CONCLUSIONS: In a small single-center cohort, patients with HCC who were denied liver transplant due to non-tumor reasons and underwent LRT and had Child-Pugh A cirrhosis had survival approaching the national average for patients who undergo liver transplantation. Patients with Child-Pugh B/C cirrhosis had significantly worse outcomes than those with Child-Pugh A.

Three-Year Follow-Up of a Traumatic Critical-Sized Tibial Bone Defect Treated with a 3D Printed Titanium Cage: A Case Report.

CASE: We report a case involving a 21-year-old woman who sustained a Grade III open pilon fracture of the left ankle during a motor vehicle accident that resulted in a 12-cm critical-sized bone defect (CSD) that was successfully treated with a three-dimensional (3D) printed titanium alloy (Ti-6Al-4V) cage, a tibiotalocalcaneal intramedullary nail, and autogenous and allograft bone. The patient's reported outcome measures were comparable with those reported for non-CSD injuries at 3-year follow-up. The authors conclude that 3D printed titanium cages offers a unique approach to traumatic limb salvage for tibial CSD. CONCLUSIONS: 3D printing offers a novel solution to CSDs. To the best of our knowledge, this case report details the largest 3D printed cage, to date, used to treat tibial bone loss. This report describes a unique approach to traumatic limb salvage with favorable patient-reported outcomes and evidence of radiographic fusion at a 3-year follow up.

Metal Hypersensitivity Following Total Ankle Arthroplasty: Case Series and Literature Review.

Metal hypersensitivity following total ankle arthroplasty (TAA) is an underreported complication that can manifest as dermal, systematic, and orthopaedic-specific symptoms. It is critical to recognize that metal hypersensitivity is a diagnosis of exclusion; only after all other potential sources of failure, such as loosening or infection are ruled out, can this diagnosis be considered. Aside from imaging and common laboratory analysis, skin patch testing, leukocyte migration inhibition test (LMIT), and lymphocyte transformation test (LTT) are the testing options available for metal allergy. With regards to management of metal hypersensitivity, nonoperative modalities involving topical dermatological management are generally preferred. Severe cases of metal allergy may necessitate operative management consisting of explantation of the implant and either revision TAA with a custom hypoallergenic implant or conversion to an ankle fusion. We present 3 cases of presumed metal hypersensitivity following TAA. In all 3 cases, other forms of TAA failure were carefully ruled out. One patient underwent explantation and conversion to hypoallergenic implant, 1 patient underwent explantation and ankle arthrodesis with hypoallergenic hardware, and 1 patient elected for conservative care. In patients who underwent explantation and conversion to hypoallergenic hardware, no further symptoms associated with metal allergy were noted. Additional research is necessary to improve diagnostic accuracy of metal allergy and make treatment options more effective and accessible.Level of Evidence: Retrospective case series, IV.

The efficacy of platelet-rich plasma in osseous foot and ankle pathology: a review.

The purpose of this review is to develop evidence-based practices for the use of platelet-rich plasma (PRP) to treat osseous pathologies of the lower extremity. There is moderate high-quality evidence to support the efficacy of PRP as a surgical augment to microfracture in osteochondral lesions of the talus (OLT). The literature supports a conceivable positive impact on bony union and osseous healing. There is insufficient evidence to support PRP injections in the conservative management of OLT or symptomatic ankle osteoarthritis. PRP may serve as a viable treatment method in the surgical augmentation of microfracture surgery in OLT and has promise for increasing bony union following surgical operations. Further high-quality, comparative studies with longer clinical follow-up are required.

The purpose of this review is to develop evidence-based practices for the use of platelet-rich plasma (PRP) to treat bony pathologies of the lower extremity. There is moderate high-quality evidence to support the use of PRP in surgery to treat damage of both cartilage and bone in the foot. The literature supports a conceivable positive impact on bony healing after fracture. There is insufficient evidence to support PRP injections in the conservative management symptomatic ankle osteoarthritis. PRP may augment bone stimulation surgery in cases of cartilage and bone defects with promise for increasing bone to bone healing following surgical operations. Further high-quality, comparative studies with longer clinical follow-up are required.

Team Approach: Metal Hypersensitivity in Total Joint Arthroplasty.

¼: As total joint arthroplasty volume continues to grow nationwide, more uncommon complications such as metal implant hypersensitivity are reported with greater frequency in the literature. ¼: Metal hypersensitivity is a challenging diagnosis given the potentially vague symptomology. It should be considered a diagnosis of exclusion, necessitating careful consideration of other potential etiologies of a failing implant before arriving at the final diagnosis of metal hypersensitivity. ¼: Patients can experience substantial morbidity from implant rejection and in severe, refractory cases may even require revision arthroplasty and conversion to a hypoallergenic implant. ¼: Given the complex nature of the condition, successful treatment of metal hypersensitivity to orthopaedic implants is best achieved through the use of a multidisciplinary, team-based approach. Immunologists, radiologists, and infectious disease physicians as well as orthopaedic surgeons and mechanical engineers are all vital in appropriate diagnosis and treatment of the condition.

Nuclear damage in LMNA mutant iPSC-derived cardiomyocytes is associated with impaired lamin localization to the nuclear envelope.

The LMNA gene encodes the nuclear envelope proteins Lamins A and C, which comprise a major part of the nuclear lamina, provide mechanical support to the nucleus, and participate in diverse intracellular signaling. LMNA mutations give rise to a collection of diseases called laminopathies, including dilated cardiomyopathy (LMNA-DCM) and muscular dystrophies. Although nuclear deformities are a hallmark of LMNA-DCM, the role of nuclear abnormalities in the pathogenesis of LMNA-DCM remains incompletely understood. Using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LMNA mutant patients and healthy controls, we show that LMNA mutant iPSC-CM nuclei have altered shape or increased size compared to healthy control iPSC-CM nuclei. The LMNA mutation exhibiting the most severe nuclear deformities, R249Q, additionally caused reduced nuclear stiffness and increased nuclear fragility. Importantly, for all cell lines, the degree of nuclear abnormalities corresponded to the degree of Lamin A/C and Lamin B1 mislocalization from the nuclear envelope. The mislocalization was likely due to altered assembly of Lamin A/C. Collectively, these results point to the importance of correct lamin assembly at the nuclear envelope in providing mechanical stability to the nucleus and suggest that defects in nuclear lamina organization may contribute to the nuclear and cellular dysfunction in LMNA-DCM.

Midterm Prospective Evaluation of Structural Allograft Transplantation for Osteochondral Lesions of the Talar Shoulder.

BACKGROUND: In cases of large osteochondral lesions of the talus (OLTs), fresh structural or bulk osteochondral allograft transplantation has yielded favorable outcomes in several retrospective and few prospective case series. The purpose of this study was to prospectively evaluate patients who received fresh structural allograft transplantation of the talar shoulder. METHODS: A prospective evaluation of patients who received a fresh structural allograft of an OLT was performed. Preoperative imaging included magnetic resonance imaging (MRI) and/or computed tomography (CT) with plain radiographs. The following patient-reported outcomes questionnaires were administered preoperatively and yearly after surgery: 36-Item Short-Form Health Survey (SF-36), visual analog scale (VAS) for pain, and the Short Musculoskeletal Functional Assessment (SMFA). Preoperative and postoperative imaging were evaluated for allograft assimilation, evidence of arthritic changes, or functional range of motion abnormalities. RESULTS: Thirty-one patients with a mean age of 41.4 years (±14.1, range 18-69) underwent structural fresh osteochondral allograft transplantation to the talar shoulder and were included in this study. The mean follow-up was 56.2 months (±36.1, range 24-142). The majority of patients were female (n=17, 54.8%), reported some history of prior ankle trauma (n=21, 67.7%), and underwent prior ankle surgery (n=23, 74.2%). The mean lesion size on CT scan was 1879 mm3 (n = 27) compared to the mean lesion size of 3877 mm3 (n = 21) on MRI. There was a significant improvement in the mean preoperative VAS score (P < .0001), SF-36 score (P < .0005), SMFA bother index (P < .0015), and the SMFA function index (P < .0001) at final follow-up. A total of 15 (48.4%) patients underwent an additional surgery following their osteochondral allograft transplant, most commonly arthroscopic debridement or removal of hardware, performed at an average of 25.2 (±13.0) from their index procedure. There was one failure that required a total ankle replacement. The overall graft survival rate was 96.8%. CONCLUSION: Fresh, structural allograft transplantation resulted in significant improvement in patient-reported postoperative pain and function in patients suffering from OLTs. The graft survival rate was 96.8% at a mean of 56.2 months follow-up, with half of patients requiring a second procedure. LEVEL OF EVIDENCE: Level IV, prospective case series.

Clinical Outcomes and Complications of Simultaneous or Sequential Bilateral Total Ankle Arthroplasty: A Single-Center Comparative Cohort Study.

BACKGROUND: The risk-benefit profiles of simultaneous total ankle arthroplasty (TAA) compared with sequential TAA continue to be debated. There are limited case series reporting outcomes after bilateral TAA, with no previous comparison of simultaneous TAA with sequential TAA. Patients with bilateral pathology represent a unique population with an overall more debilitating condition. Thus, we aimed to compare bilateral simultaneous and sequential TAAs, including perioperative complications and patient-reported outcome measures. METHODS: We performed a comparative cohort study of patients who underwent primary bilateral TAA, performed in a simultaneous or sequential fashion, from 2007 to 2019 at a single academic center. Data on patient demographic characteristics, comorbidities, perioperative complications, reoperations, and implant failures were collected. Patient-reported outcome measures included preoperative and postoperative visual analog scale (VAS) scores for pain, Short Form-36 Health Survey (SF-36) scores, and Short Musculoskeletal Function Assessment (SMFA) scores. RESULTS: A total of 50 patients (100 ankles) were included, with 25 patients (50 ankles) each in the bilateral simultaneous and sequential cohorts. The mean follow-up was 52.2 ± 27.3 months (range, 24 to 109 months). The mean time between sequential TAAs was 17.5 ± 20.1 months (range, 3 to 74 months). The mean patient age was 64.3 ± 10.6 years (range, 21 to 76 years), and 32 (64.0%) were men. The majority of patients (28 patients [56.0%]) had primary osteoarthritis. Both cohorts had equivalent preoperative patient-reported outcome measures and experienced improvements in all measures, which were maintained at the final follow-up with no significant between-group differences (all p > 0.05). There were no differences between the simultaneous TAA group and the sequential TAA group in perioperative complication rates (22.0% compared with 24.0%; p = 0.7788), reoperations (12.0% compared with 10.0%; p = 0.7354), 5-year reoperation-free survival (88.0% compared with 90.0%; p = 0.4612), or failure-free survival (100%). One patient in the simultaneous TAA cohort required metal component revision at 8 years postoperatively. CONCLUSIONS: The patient-reported outcome measures, complications, and prosthesis survival of patients who underwent bilateral simultaneous TAA were comparable with those of patients who underwent bilateral sequential TAA. We advocate that simultaneous bilateral TAA is a safe and effective method for the treatment of bilateral end-stage ankle osteoarthritis. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Outcomes of Surgical Reconstruction Using Custom 3D-Printed Porous Titanium Implants for Critical-Sized Bone Defects of the Foot and Ankle.

BACKGROUND: Treating critically sized defects (CSDs) of bone remains a significant challenge in foot and ankle surgery. Custom 3D-printed implants are being offered to a small but growing subset of patients as a salvage procedure in lieu of traditional alternates such as structural allografts after the patient has failed prior procedures. The long-term outcomes of 3D-printed implants are still unknown and understudied because of the limited number of cases and short follow-up durations. The purpose of this study was to evaluate the outcomes of patients who received custom 3D-printed implants to treat CSDs of the foot and ankle in an attempt to aid surgeons in selecting appropriate surgical candidates. METHODS: This was a retrospective study to assess surgical outcomes of patients who underwent implantation of a custom 3D-printed implant made with medical-grade titanium alloy powder (Ti-6Al-4V) to treat CSDs of the foot and ankle between June 1, 2014, and September 30, 2019. All patients had failed previous nonoperative or operative management before proceeding with treatment with a custom 3D-printed implant. Univariate and multivariate odds ratios (ORs) of a secondary surgery and implant removal were calculated for perioperative variables. RESULTS: There were 39 cases of patients who received a custom 3D-printed implant with at least 1 year of follow-up. The mean follow-up time was 27.0 (12-74) months. Thirteen of 39 cases (33.3%) required a secondary surgery and 10 of 39 (25.6%) required removal of the implant because of septic nonunion (6/10) or aseptic nonunion (4/10). The mean time to secondary surgery was 10 months (1-22). Multivariate logistic regression revealed that patients with neuropathy were more likely to require a secondary surgery with an OR of 5.76 (P = .03). CONCLUSION: This study demonstrated that 74% of patients who received a custom 3D-printed implant for CSDs did not require as subsequent surgery (minimum of 1-year follow-up). Neuropathy was significantly associated with the need for a secondary surgery. This is the largest series to date demonstrating the efficacy of 3D-printed custom titanium implants. As the number of cases using patient-specific 3D-printed titanium implant increases, larger cohorts of patients should be studied to identify other high-risk groups and possible interventions to improve surgical outcomes. LEVEL OF EVIDENCE: Level IV, case series.

Tibiopedal Motion Following Tendo-Achilles Lengthening or Gastrocnemius Recession in Total Ankle Replacement: A Comparative Cohort Study.

BACKGROUND: End-stage ankle arthritis is a debilitating condition often necessitating total ankle replacement (TAR). Tendo-Achilles lengthening (TAL) and gastrocnemius recession (GR) are commonly performed with TAR to improve ankle dorsiflexion (DF). No studies to date have radiographically analyzed tibiopedal motion to guide surgical management. The purpose of this study is to determine the effect of a TAL or GR during TAR on radiographic tibiopedal range of motion (ROM). METHODS: A retrospective review of a prospectively maintained database was conducted followed by a propensity score-matched analysis of 110 patients who underwent TAL (n = 26), GR (n = 29), or no lengthening procedure (n = 55) with TAR. Minimum of 1-year ROM radiographic follow-up was required. Exclusion criteria included (1) calcaneal osteotomies, (2) simultaneous or previous hindfoot or midfoot arthrodesis, (3) prior ankle arthrodesis, or (4) revision TAR. Demographic data were extracted from the TAR database. Radiographic assessment included tibiopedal dorsiflexion (DF) and plantarflexion (PF). RESULTS: DF improved by 2.8 degrees (P = .0286) and by 6.0 degrees (P < .0001) in the TAL and GR cohorts, respectively, with no difference in the control group (+0.7 degrees, P = .3764). PF was decreased by 4.5 degrees (P = .0152) and by 7.2 degrees (P = .0002) in the TAL and GR cohorts, respectively, with no difference in the control group (-0.2 degrees, P = .8546). Minimal differences were observed for total arc of motion for all 3 groups (control 0.5 degrees, GR -1.2 degrees, TAL -1.7 degrees), all of which were nonsignificant (all P > .05). There was no between-group difference in the change in overall arc of motion between the groups (P = .3599). GR resulted in a greater increase in DF (6.0 vs 2.8 degrees; P = .1074), with a reciprocal greater decrease in PF (7.2 vs 4.5 degrees; P = .2416) compared with the TAL cohort. CONCLUSION: Both TAL and GR increased postoperative DF; however, this was accompanied by a reciprocal loss in PF. Minimal differences were observed for total arc of motion. Patients should be counseled that concomitant procedures performed to increase DF will do so at the expense of PF. LEVEL OF EVIDENCE: Level III, retrospective review of prospectively collected data.

Efficacy of Platelet-Rich Plasma in Soft Tissue Foot and Ankle Pathology.

➢: The preparation methodology for platelet-rich plasma (PRP) may have important clinical implications with varying effectiveness with leukocyte, platelet, and growth factor concentrations. ➢: There is high-quality evidence to support the superiority of PRP over corticosteroids in the case of chronic plantar fasciitis. ➢: There is moderate-quality to high-quality evidence for PRP's ability to increase tendon thickness with no capacity to decrease pain, increase function, or augment percutaneous tenotomy in Achilles tendinopathy. ➢: There is insufficient evidence to support PRP injections in the definitive treatment of Achilles tendon rupture. However, PRP may contribute to postoperative recovery after tendon rupture repair, but this requires further research. ➢: The biochemical theory supporting the clinical use of PRP must be reinforced with high-level evidence research. Based on the current literature, PRP may serve as a viable treatment method in chronic plantar fasciitis. Further high-quality, comparative studies with longer clinical follow-up are required to support recommendations for use of PRP in the treatment of Achilles tendon pathology.

Biodegradation of renewable polyurethane foams in marine environments occurs through depolymerization by marine microorganisms.

Accumulation of plastics in the Earth's oceans is causing widespread disruption to marine ecosystems. To help mitigate the environmental burden caused by non-degradable plastics, we have previously developed a commercially relevant polyurethane (PU) foam derived from renewable biological materials that can be depolymerized into its constituent monomers and consumed by microorganisms in soil or compost. Here we demonstrate that these same PU foams can be biodegraded by marine microorganisms in the ocean and by isolated marine microorganisms in an ex situ seawater environment. Using Fourier-transform infrared (FTIR) spectroscopy, we tracked molecular changes imparted by microbial breakdown of the PU polymers; and utilized scanning electron microscopy (SEM) to demonstrate the loss of physical structure associated with colonization of microorganisms on the PU foams. We subsequently enriched, isolated, and identified individual microorganisms, from six marine sites around San Diego, CA, that are capable of depolymerizing, metabolizing, and accumulating biomass using these PU foams as a sole carbon source. Analysis using SEM, FTIR, and gas chromatography-mass spectrometry (GCMS) confirmed that these microorganisms depolymerized the PU into its constitutive diols, diacids, and other PU fragments. SEM and FTIR results from isolated organismal biodegradation experiments exactly matched those from ex situ and ocean biodegradation samples, suggesting that these PU foam would undergo biodegradation in a natural ocean environment by enzymatic depolymerization of the PU foams and eventual uptake of the degradation products into biomass by marine microorganisms, should these foams unintentionally end up in the marine environment, as many plastics do.

Relevance of pharmacogenomics for developing countries in Europe.

Pharmacogenomics holds promise of personalized treatment for patients suffering from many common diseases, particularly those with multiple treatment modalities. Owing to recent advances in the deciphering of the human genome sequence, high throughput genotyping technology has led to the reduction of the overall costs of genetic testing and allowed the inclusion of genotype-related dosing recommendations into drug package inserts, hence enabling the integration of pharmacogenomics into clinical practice. Although pharmacogenomics gradually assumes an important part in routine clinical practice in developed countries, many countries, particularly from the developing world, still do not have access either to the knowledge or the resources to individualize drug therapy. The PharmacoGenetics for Every Nation Initiative (PGENI) aims to fill this gap, by making pharmacogenomics globally applicable, not only by defining population-specific pharmacogenomic marker frequency profiles but also by formulating country-specific recommendations for drug efficacy and safety. This article aims to highlight the PGENI activities in Europe in an effort to make pharmacogenomics readily applicable in the European healthcare systems, particularly those in developing countries.

Multicenter Placebo-Controlled Randomized Study of Ethyl Pyruvate in Horses Following Surgical Treatment for ≥ 360° Large Colon Volvulus.

Identifying therapies that mitigate ischemic colonic injury and improve mucosal healing and intestinal viability are crucial to improving survival in horses with ≥360° large colon volvulus (LCV). Ethyl pyruvate is the ethyl ester of pyruvate with diverse pharmacologic effects that limit ischemic injury and hasten intestinal mucosal repair in preclinical rodents, sheep and swine models. The objective of this study was to determine the effects of ethyl pyruvate on systemic indices of colon viability, expression of inflammatory genes in whole blood, morbidity and survival after surgical correction of LCV compared to controls. Horses received either 150 mg/kg ethyl pyruvate in 1 liter lactated Ringer's solution (LRS) or 1 liter LRS intravenously (IV) every 6 h for 24 h following surgical recovery for correction of LCV. Colic duration, perioperative heart rate (HR), packed cell volume (PCV), total solids (TS), blood L-lactate concentration, surgical time, intraoperative episodes of hypoxemia and hypotension, expression of inflammatory cytokine genes, fecal consistency and survival to hospital discharge were compared between ethyl pyruvate treated horses and controls. Twenty-two horses, 12 receiving ethyl pyruvate and 10 controls, were enrolled in the study. Ethyl pyruvate was safely administered to horses following surgical correction of LCV. No significant effects of ethyl pyruvate on post-operative variables, including survival, were found. Seven of 12 ethyl pyruvate treated horses and 5/10 controls survived to hospital discharge. Higher HR, PCV and blood L-lactate concentration at the time of hospital admission, P = 0.005, 0.01, 0.04, respectively, 24 h after surgery, P = 0.001, 0.03, 0.02, respectively, were associated with death. Heart rate, P = 0.005, 48 h after surgery was associated with death. Ethyl pyruvate was safely administered to horses following correction of LCV with no apparent adverse events but was not associated with improved post-operative outcomes including survival. A larger, randomized control trial is needed to fully evaluate the effectiveness of ethyl pyruvate. A major limitation of this investigation is the small sample size, making the study underpowered and creating a high possibility of type II error.

Multiple adrenocortical steroid response to administration of exogenous adrenocorticotropic hormone to hospitalized foals.

BACKGROUND: The hypothalamic-pituitary-adrenal axis regulates the response to sepsis-associated stress. Relative adrenal insufficiency or adrenocorticotropic hormone (ACTH):cortisol imbalance, defined as a poor cortisol response to administration of ACTH, is common and associated with death in hospitalized foals. However, information on other adrenal steroid response to ACTH stimulation in sick foals is minimal. OBJECTIVE: To investigate the response of multiple adrenocortical steroids to administration of ACTH in foals. ANIMALS: Hospitalized (n = 34) and healthy (n = 13) foals. METHODS: In this prospective study, hospitalized foals were categorized into 2 groups using cluster analysis based on adrenal steroids response to ACTH stimulation: Cluster 1 (n = 11) and Cluster 2 (n = 23). After baseline blood sample collection, foals received 10 µg of ACTH with additional samples collected at 30 and 90 minutes after ACTH. Steroid and ACTH concentrations were determined by immunoassays. The area under the curve (AUC) and Delta0-30 were calculated for each hormone. RESULTS: The AUC for cortisol, aldosterone, androstenedione, pregnenolone, 17α-OH-progesterone, and progesterone were higher in critically ill (Cluster 1) compared to healthy foals (P < .01). Delta0-30 for cortisol and 17α-OH-progesterone was lower in Cluster 1 (24%, 26.7%) and Cluster 2 (16%, 11.2%) compared to healthy foals (125%, 71%), respectively (P < .05). Foals that died had increased AUC for endogenous ACTH (269 versus 76.4 pg/mL/h, P < .05) accompanied by a low AUC for cortisol (5.5 versus 15.5 µg/dL/h, P < .05), suggesting adrenocortical dysfunction. CONCLUSION AND CLINICAL IMPORTANCE: The 17α-OH-progesterone response to administration of ACTH was a good predictor of disease severity and death in hospitalized foals.

Transudative pleural effusion of malignant etiology: Rare but real.

A 62-year-old female presented to the emergency room with one-month history of epigastric abdominal pain, nausea and vomiting. She endorsed progressive dyspnea over two weeks. CT of the abdomen demonstrated bilateral pleural effusions and pancreatic inflammation, so the working diagnosis was pancreatitis. A diagnostic thoracentesis was performed and the pleural fluid analysis was classified as transudate by Light's criteria. Given the atypical features in history and concern for malignancy, fluid was sent for cytological examination and immunohistochemistry which suggested a mucinous malignancy. EGD revealed poorly differentiated signet ring cell adenocarcinoma of stomach. Patient underwent placement of indwelling pleural catheters for symptomatic improvement and was discharged to hospice. The decision whether to routinely send transudative effusions for cytological evaluation remains controversial. This case demonstrates the importance of using clinical judgement to guide that decision.