Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology.

Introduction: A chemogenomic set of small molecules with annotated activities and implicated roles in Alzheimer's disease (AD) called the AD Informer Set was recently developed and made available to the AD research community: https://treatad.org/data-tools/ad-informer-set/. Methods: Small subsets of AD Informer Set compounds were selected for AD-relevant profiling. Nine compounds targeting proteins expressed by six AD-implicated genes prioritized for study by Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) teams were selected for G-protein coupled receptor (GPCR), amyloid beta (Aß) and tau, and pharmacokinetic (PK) studies. Four non-overlapping compounds were analyzed in microglial cytotoxicity and phagocytosis assays. Results: The nine compounds targeting CAPN2, EPHX2, MDK, MerTK/FLT3, or SYK proteins were profiled in 46 to 47 primary GPCR binding assays. Human induced pluripotent stem cell (iPSC)-derived neurons were treated with the same nine compounds and secretion of Aß peptides (Aß40 and Aß42) as well as levels of phosphophorylated tau (p-tau, Thr231) and total tau (t-tau) peptides measured at two concentrations and two timepoints. Finally, CD1 mice were dosed intravenously to determine preliminary PK and/or brain-specific penetrance values for these compounds. As a final cell-based study, a non-overlapping subset of four compounds was selected based on single-concentration screening for analysis of both cytotoxicity and phagocytosis in murine and human microglia cells. Discussion: We have demonstrated the utility of the AD Informer Set in the validation of novel AD hypotheses using biochemical, cellular (primary and immortalized), and in vivo studies. The selectivity for their primary targets versus essential GPCRs in the brain was established for our compounds. Statistical changes in tau, p-tau, Aß40, and/or Aß42 and blood-brain barrier penetrance were observed, solidifying the utility of specific compounds for AD. Single-concentration phagocytosis results were validated as predictive of dose-response findings. These studies established workflows, validated assays, and illuminated next steps for protein targets and compounds.

AD Informer Set: Chemical tools to facilitate Alzheimer's disease drug discovery.

Introduction: The portfolio of novel targets to treat Alzheimer's disease (AD) has been enriched by the Accelerating Medicines Partnership Program for Alzheimer's Disease (AMP AD) program. Methods: Publicly available resources, such as literature and databases, enabled a data-driven effort to identify existing small molecule modulators for many protein products expressed by the genes nominated by AMP AD and suitable positive control compounds to be included in the set. Compounds contained within the set were manually selected and annotated with associated published, predicted, and/or experimental data. Results: We built an annotated set of 171 small molecule modulators targeting 98 unique proteins that have been nominated by AMP AD consortium members as novel targets for the treatment of AD. The majority of compounds included in the set are inhibitors. These small molecules vary in their quality and should be considered chemical tools that can be used in efforts to validate therapeutic hypotheses, but which will require further optimization. A physical copy of the AD Informer Set can be requested on the Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) website. Discussion: Small molecules that enable target validation are important tools for the translation of novel hypotheses into viable therapeutic strategies for AD.

Reprogramming CBX8-PRC1 function with a positive allosteric modulator.

Canonical targeting of Polycomb repressive complex 1 (PRC1) to repress developmental genes is mediated by cell-type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7, and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small-molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing, and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity.

Mandibular metastasis of a prostatic carcinoma in a dog.

Skeletal metastasis is a common finding in dogs with prostatic carcinoma and most frequently involves the lumbar vertebrae and pelvis. In the present report, we describe the case of a prostatic carcinoma in a 6-year-old Labrador retriever, who developed apparent oral sensitivity and pain within a week of initial diagnosis. Computed tomography of the skull revealed a mixed osteoproductive and osteolytic mass of the condylar process of the left mandible, and cytologic evaluation of the mass was consistent with metastatic prostatic carcinoma. To our knowledge, this is the first published report of mandibular metastasis of a prostatic carcinoma in a dog.

Precision medicine identifies a pathogenic variant of the ITGA2B gene responsible for Glanzmann's thrombasthenia in a cat.

BACKGROUND: A nonpedigreed male cat presented with epistaxis, severe bladder hemorrhage, and secondary urethral obstruction after cystocentesis. OBJECTIVES: To characterize the phenotype of a cat with bleeding diathesis and use a precision medicine approach to identify the molecular genetic defect by whole genome sequencing. METHODS: Adenosine diphosphate (ADP) and arachidonic acid (AA)-induced whole blood platelet aggregometry was performed in the affected cat and a healthy cat. Platelet activation, measured by P-selectin expression, and surface integrin subunit ß3 expression were evaluated by flow cytometry in the affected cat and healthy control. Total integrin subunit αIIb expression was assessed by western blot. Whole genome sequencing at 30× coverage was used to identify genetic variants that segregated in the affected cat compared to 194 cats from the 99 Lives Sequencing Consortium. RESULTS: Platelet aggregometry identified significant impairment in platelet aggregation in response to ADP and AA compared to the control cat. Targeted protein expression analyses by flow cytometry and immunoblot analysis determined that the surface expression and total expression of the integrin, αIIbß3, was absent. Whole genome sequencing identified a homozygous c.1986delC frameshift variant in the integrin subunit αIIb (ITGA2B) gene that was not detected in the control population. The p.Pro662fs (ITGA2B P662X) variant terminates translation of the protein at the extracellular domain of the integrin prematurely, which is predicted to affect expression of the ß3 unit. CONCLUSIONS AND CLINICAL IMPORTANCE: This novel ITGA2B variant and the associated phenotype closely resemble Glanzmann's thrombasthenia, which has never been reported in cats.

Ultrasonographic Evaluation of Uterine Stump Size in Ovariohysterectomized Dogs Receiving Estriol Compared to Control Dogs.

In ovariohysterectomized dogs, the uterine stump rarely causes clinical disease. However, changes could occur in this anatomic structure due to exposure to estrogen therapy. Ultrasonographic examination of the uterine stump has not been reported in dogs receiving estriol and normal dimensions for this area have not been reported for ovariohysterectomized dogs. Therefore, the aims of this study were to retrospectively evaluate records and ultrasound images from dogs receiving and not receiving (controls) estriol as well as defining a standard method to measure the uterine stump. Clinical features of dogs administered estriol were also reported. Fourteen dogs receiving estriol and 14 control dogs were included in the study. Seven dogs receiving estriol had changes associated with the external vulva, 5 were noted to be "hooded" and 3 were "prominent/swollen." Ultrasonographic transverse maximum uterine stump measurements were available for 4 dogs receiving estriol (median 0.81 cm, range 0.53-1.4). The maximum uterine height/aorta ratio was available for only 2 dogs receiving estriol (0.9 and 0.6). The median transverse maximum height of the uterine stump noted in the control group was 0.43 cm (range 0.28-0.52 cm); The maximal uterine height/aorta ratio was a median of 0.48 in the control group (range 0.32-1.1). Normal values for the uterine stump measurements can be standardized to the distal aorta for consistency. Vulvar enlargement was the most common physical examination change in our dogs receiving estriol. Routine screening, including ultrasonography is not usually indicated for dogs receiving estriol, but can be tailored to the individual patient.

Cadaveric evaluation of fluoroscopy-assisted placement of one-lung ventilation devices for video-assisted thoracoscopic surgery in dogs.

OBJECTIVE: To evaluate the feasibility of fluoroscopy-assisted placement of one-lung ventilation (OLV) devices in dogs. STUDY DESIGN: Experimental study. SAMPLE POPULATION: Canine cadavers (n = 8) weighing between 20.2 and 37.4 kg. METHODS: Thoracoscopic access with a two-port approach was established to evaluate bilateral lung ventilation patterns. Advancement of a left-sided Robertshaw double-lumen endobronchial tube (DLT) and the EZ-blocker (EZ) were evaluated under direct fluoroscopic guidance. Each dog also underwent bronchoscopy-assisted placement of an Arndt endobronchial blocker (EBB). Time to initial placement, success of creating complete OLV (after initial placement attempt and after up to two repositionings), and ease of placement score were recorded. Device position was evaluated bronchoscopically after each fluoroscopy-assisted placement attempt. RESULTS: Time to initial placement was significantly shorter for EZ than for DLT and EBB. The rate of successful placement after up to two repositioning attempts was 87.5%, 87.5%, and 100.0% on the right and 87.5%, 100.0%, 100.0% on the left for DLT, EZ, and EBB, respectively, and was not different between devices. Ease of placement scores were significantly higher for DLT compared with EZ and EBB on both the left and the right sides. CONCLUSION: Fluoroscopy-assisted placement of DLT and EZ appears feasible in canine cadavers. EZ-blocker placement was efficient and technically easier than DLT, but positioning must be adapted for dogs. Bronchoscopy-assisted placement of EBB remains highly successful. CLINICAL SIGNIFICANCE: Fluoroscopy-assisted placement of EZ and DLT is a useful alternative to bronchoscopy-assisted placement of these OLV devices.

Use of video capsule endoscopy to identify gastrointestinal lesions in dogs with microcytosis or gastrointestinal hemorrhage.

BACKGROUND: Video capsule endoscopy (VCE) is a noninvasive imaging modality that can identify mucosal lesions not detected with traditional endoscopy or abdominal sonography. In people, VCE is used in diagnostic and management protocols of various gastrointestinal (GI) disorders, particularly in GI bleeding of obscure origin or unexplained iron deficiency anemia (IDA). OBJECTIVE: To evaluate the utility of VCE in the identification of mucosal lesions in dogs with evidence of GI hemorrhage. ANIMALS: Sixteen client-owned dogs that underwent VCE. METHODS: Retrospective case-control study. Medical records were reviewed to include dogs with microcytosis, low normal mean corpuscular volume, or clinical GI bleeding that received VCE. RESULTS: Median age of dogs was 8.7 years (range, 8 months to 15 years) with a median weight of 21.7 kg (range, 6.9-62.5 kg). Abdominal ultrasound (16), abdominal radiography (4), and abdominal CT (1) did not identify a cause for GI blood loss. Gastric mucosal lesions were identified by VCE in 15 of 16 dogs and small intestinal lesions in 12 of 14 dogs, with 2 capsules remaining in the stomach. Endoscopy was performed in 2 dogs before VCE; 1 dog had additional small intestinal lesions identified through the use of VCE. CONCLUSIONS AND CLINICAL IMPORTANCE: Video capsule endoscopy is a minimally invasive diagnostic tool that can identify GI lesions in dogs presenting with microcytosis with or without GI hemorrhage when ultrasonography is inconclusive; however, the majority of lesions identified would have been apparent with conventional endoscopy.

Factors associated with postobstructive diuresis following decompressive surgery with placement of ureteral stents or subcutaneous ureteral bypass systems for treatment of ureteral obstruction in cats: 37 cases (2010-2014).

OBJECTIVE: To describe postobstructive diuresis (POD) in cats undergoing surgical placement of ureteral stents or subcutaneous ureteral bypass systems for treatment of ureteral obstruction in cats and to identify factors associated with duration and maximum severity of POD. DESIGN: Retrospective case series. ANIMALS: 37 client-owned cats with ureteral obstruction treated between August 2010 and December 2014. PROCEDURES: Medical records were reviewed, and data extracted included signalment, history, results from physical examinations and clinical laboratory analyses, treatment, urine output, and outcome. Data were evaluated to identify factors associated with POD duration and maximum severity, alone or in combination. RESULTS: Serum concentrations of creatinine, potassium, phosphorus, and BUN before surgery positively correlated with duration and maximum severity of POD. Absolute changes in serum concentrations of creatinine, potassium, and BUN from before surgery to after surgery positively correlated with POD duration. Cats with anuria before surgery had longer POD than did other cats; however, there was no difference in POD duration or maximum severity with unilateral versus bilateral ureteral obstruction. Thirty-four of 37 (92%) cats survived to hospital discharge, which was not associated with whether ureteral obstruction was unilateral or bilateral. Azotemia resolved in 17 of the 34 (50%) cats that survived to hospital discharge. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the present study indicated that several factors were associated with POD duration and maximum severity, alone or in combination, and that with intensive management of fluid and electrolyte derangements, regardless of the extent of the original azotemia, a high percentage of cats survived to hospital discharge.

Safety and efficacy of venoplasty in MS: A randomized, double-blind, sham-controlled phase II trial.

OBJECTIVE: To determine the safety and efficacy of balloon vs sham venoplasty of narrowing of the extracranial jugular and azygos veins in multiple sclerosis (MS). METHODS: Patients with relapsing or progressive MS were screened using clinical and ultrasound criteria. After confirmation of >50% narrowing by venography, participants were randomized 1:1 to receive balloon or sham venoplasty of all stenoses and were followed for 48 weeks. Participants and research staff were blinded to intervention allocation. The primary safety outcome was the number of adverse events (AEs) during 48 weeks. The primary efficacy outcome was the change from baseline to week 48 in the patient-reported outcome MS Quality of Life-54 (MSQOL-54) questionnaire. Standardized clinical and MRI outcomes were also evaluated. RESULTS: One hundred four participants were randomized (55 sham; 49 venoplasty) and 103 completed 48 weeks of follow-up. Twenty-three sham and 21 venoplasty participants reported at least 1 AE; one sham (2%) and 5 (10%) venoplasty participants had a serious AE. The mean improvement in MSQOL-54 physical score was +1.3 (sham) and +1.4 (venoplasty) (p = 0.95); MSQOL-54 mental score was +1.2 (sham) and -0.8 (venoplasty) (p = 0.55). CONCLUSIONS: Our data do not support the continued use of venoplasty of extracranial jugular and/or azygous venous narrowing to improve patient-reported outcomes, chronic MS symptoms, or the disease course of MS. CLINICALTRIALSGOV IDENTIFIER: NCT01864941. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with MS, balloon venoplasty of extracranial jugular and azygous veins is not beneficial in improving patient-reported, standardized clinical, or MRI outcomes.

Hypertensive Crisis From the Aquamantys Bipolar Sealing System.

Hypertension is a common occurrence during general anesthesia. Apart from pathological causes of hypertension, it is rarely extreme enough to be classified as a hypertensive crisis (systolic blood pressure >180 mm Hg or diastolic blood pressure >120 mm Hg). There is literature concerning the unintentional electrocauterization of the adrenal gland leading to hypertensive crisis, but to date, no reports have been made of adrenal stimulation from the use of an Aquamantys for hemostasis. Here, we report such a case when a hypertensive crisis (systolic blood pressure >300 mm Hg) occurred while using an Aquamantys during a liver transplant after unintentional stimulation of the adrenal glands.

Multiple gastric erosions diagnosed by means of capsule endoscopy in a dog.

CASE DESCRIPTION A 6-year-old spayed female Golden Retriever was evaluated for a 2-week history of progressive hyporexia, signs of abdominal pain, and weight loss. CLINICAL FINDINGS Physical examination findings included mild signs of pain on palpation of the cranial part of the abdomen and a body condition score of 4 (scale, 1 to 9). A CBC revealed mild microcytosis and hypochromasia; results of serum biochemical analysis were within the respective reference ranges, and abdominal ultrasonography revealed no abnormalities. Capsule endoscopy was performed, and numerous gastric erosions and hemorrhages were detected, with rare dilated lacteals in the proximal aspect of the small intestine. TREATMENT AND OUTCOME Treatment was initiated with omeprazole and sucralfate for 6 weeks, and the dog was transitioned to a novel protein diet. Capsule endoscopy was repeated at the end of the initial treatment course and revealed overall improvement, with a few small erosions remaining; medical treatment was continued for an additional 2 weeks. At last follow-up 9 months after treatment ended, the dog was clinically normal. CLINICAL RELEVANCE Capsule endoscopy was useful for initial detection and subsequent reevaluation of gastrointestinal lesions in this patient without a need for sedation or anesthesia. Information obtained in the follow-up evaluation was valuable in identifying a need to extend the duration of medical treatment.

Survey of Pharmacy Preceptors' Expectations and Experiences with Students on Rotations in an Inaugural Combined BScPhm/PharmD Class.

BACKGROUND: In September 2011, the Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, began offering a combined BScPhm/PharmD program to third-year students and postbaccalaureate graduates. Learning consisted of in-class teaching and Advanced Pharmacy Practice Experience (APPE) rotations. OBJECTIVE: To explore preceptors' expectations and perceptions of student performance in the APPE rotations of the new combined degree program. METHODS: A survey was distributed via email to 132 pharmacists from the Toronto Academic Health Science Network who had acted as preceptors for the combined degree program in academic year 2011/2012. The 17 questions were designed to gather information on preceptors' demographic characteristics and their expectations and evaluations of the combined-program students. Responses were analyzed qualitatively for common themes and quantitatively using sums and means. Survey responses were compared to identify alignment and discrepancies between preceptors' expectations and evaluations of students. RESULTS: The survey response rate was 48% (63/132). Most respondents (46 [73%]) were from a teaching hospital, and the same proportion (46 [73%]) reported being preceptors for a direct patient care rotation. Forty-four (70%) of the respondents expected students to be at the level of traditional PharmD students, hospital residents, or advanced-level Structured Practical Experience Program students, and 35 (80%) of these 44 respondents reported that their students met or exceeded expectations. According to survey responses, 31% of respondents (18/58) ranked students at the corresponding level of performance on the faculty's assessment form, while 62% (36/58) ranked students at a higher level (5 respondents did not complete the question). Only one-third of respondents felt that they personally had received adequate training before taking on preceptor duties for combined-program students. CONCLUSIONS: Preceptors' perceptions of the rotation and their expectations of students varied widely and were influenced by prior teaching and learning experiences. There was a disconnect between preceptor-specific expectations and preceptors' final evaluations of students. Training to standardize the expected level of performance and additional training for preceptors would further enhance the APPE rotations of the combined degree program.

CONTEXTE: En septembre 2011, la Faculté de pharmacie Leslie Dan de l'Université de Toronto à Toronto, en Ontario, a commencé à offrir un programme de double diplôme, B. Sc. Phm.­Pharm. D., aux étudiants de troisième année et aux diplômés titulaires d'un baccalauréat. Le programme reposait d'une part sur un enseignement en classe et d'autre part sur des stages offrant une expérience pratique avancée de la pharmacie (Advanced Pharmacy Practice Experience [APPE]). OBJECTIF: Étudier les attentes des précepteurs envers la performance des étudiants participant aux stages APPE du nouveau programme de double diplôme ainsi que la perception qu'ils en ont. MÉTHODES: Un sondage a été envoyé par courriel à 132 pharmaciens œuvrant dans le Toronto Academic Health Science Network et ayant agi à titre de précepteurs dans le programme de double diplôme durant l'année universitaire 2011­2012. Les 17 questions du sondage ont été conçues dans le but de recueillir des informations sur les caractéristiques démographiques des précepteurs ainsi que sur leurs attentes envers les étudiants et les évaluations qu'ils ont faites de ceux-ci dans le cadre du programme double. Les réponses ont été analysées qualitativement pour établir des thèmes communs ainsi que quantitativement à l'aide de sommes et de moyennes. Les réponses au sondage ont été comparées afin de relever des concordances et des divergences entre les attentes des précepteurs envers les étudiants et les évaluations qu'ils ont faites d'eux. RÉSULTATS: Le taux de réponse au sondage était de 48 % (63/132). La majorité des répondants (46 [73 %]) travaillaient dans un hôpital universitaire et un même nombre de répondants (46 [73 %]) ont indiqué agir à titre de précepteurs pour un stage de soins directs aux patients. Quarante-quatre (70 %) des répondants s'attendaient à ce que les étudiants soient à la hauteur des étudiants du programme de Pharm. D. traditionnel, des résidents hospitaliers ou des étudiants de haut niveau dans le programme structuré d'expérience pratique (Structured Practical Experience Program) et 35 (80 %) de ces 44 répondants ont déclaré que leurs étudiants avaient satisfait aux attentes ou les avaient dépassées. Selon le sondage, 31 % des répondants (18/58) ont classé les étudiants au niveau de performance correspondant sur le formulaire d'évaluation de la faculté, tandis que 62 % (36/58) ont classé les étudiants à un niveau supérieur (cinq répondants ont négligé cette question). Seul le tiers des répondants estimaient avoir reçu une formation suffisante avant d'endosser le rôle de précepteur auprès des étudiants du programme de double diplôme. CONCLUSIONS: Les perceptions des précepteurs envers le stage de même que leurs attentes envers les étudiants variaient grandement et étaient influencées par des expériences d'enseignement et d'apprentissage passées. Il y avait un écart entre les attentes des précepteurs et leurs évaluations finales des étudiants. Un enseignement visant à normaliser le niveau de performance attendu ainsi qu'une formation supplémentaire pour les précepteurs amélioreraient davantage les stages APPE du programme de double diplôme.

Reporting Guidelines for Clinical Pharmacokinetic Studies: The ClinPK Statement.

BACKGROUND AND OBJECTIVE: Transparent reporting of all research is essential for assessing the validity of any study. Reporting guidelines are available and endorsed for many types of research but are lacking for clinical pharmacokinetic studies. Such tools promote the consistent reporting of a minimal set of information for end users, and facilitate knowledge translation of research. The objective of this study was to create a guideline to assist in the transparent and complete reporting of clinical pharmacokinetic studies. METHODS: Preliminary content to be considered was identified from a systematic search of the literature and regulatory documents. Stakeholders were identified to participate in a modified Delphi exercise and a virtual meeting to generate consensus for items considered essential in the reporting of clinical pharmacokinetic studies. The proposed checklist was pilot tested on 100 recently published clinical pharmacokinetic studies. Overall and itemized compliance with the proposed guidance was determined for each study. RESULTS: Sixty-eight stakeholders from nine countries consented to participate. Four rounds of a modified Delphi survey and a series of small virtual meetings were required to generate consensus for a 24-item checklist considered to be essential to the reporting of clinical pharmacokinetic studies. When applied to the 100 most recently published clinical pharmacokinetic studies, 45 were determined to be compliant with at least 80 % of the checklist items. Explanatory text was prepared using examples of compliant reporting from these and other relevant studies. CONCLUSIONS: The reader's ability to judge the validity of pharmacokinetic research can be greatly compromised by the incomplete reporting of study information. Using consensus methods, we have developed a tool to guide transparent and accurate reporting of clinical pharmacokinetic studies. Endorsement and implementation of these guidelines by researchers, clinicians and journals would promote more consistent reporting of these studies and allow for better assessment of utility for clinical applications.

The effect of initial purity on the stability of solutions in storage.

Many modern compound-screening technologies are highly miniaturized, resulting in longer-lasting solution stocks in compound management laboratories. As the ages of some stocks stretch into years, it becomes increasingly important to ensure that the DMSO solutions remain of high quality. It can be a burden to check the quality of a large library of compound solutions continuously, and so a study was devised to link the effects of initial compound purity and physicochemical properties of the compounds with the current purity of DMSO solutions. Approximately 5000 compounds with initial purity of at least 80% were examined. Storage conditions were held or observed to be relatively constant and so were eliminated as potential predictors. This allowed the evaluation of the effects of other factors on the stability of solutions, such as initial purity, number of freeze-thaw cycles, age of the solution, and multiple calculated physicochemical parameters. Of all the factors investigated, initial purity was the only one that had a clear effect on stability. None of the other parameters investigated (physicochemical properties, number of freeze-thaw cycles, age of solutions) had a statistically significant effect on stability.

Assessment of shock index in healthy dogs and dogs in hemorrhagic shock.

OBJECTIVE: To compare the shock index (SI) in a population of healthy dogs to a population of dogs with confirmed hemorrhagic shock. DESIGN: Retrospective analysis of data collected prospectively from 2 previous studies. SETTING: University teaching hospital. ANIMALS: Seventy-eight healthy control dogs enrolled in a study to establish a reference interval for a tissue oxygen monitor; 38 dogs with confirmed hemorrhagic shock enrolled in a study to evaluate the tissue oxygen monitor in hemorrhagic shock. The heart rate and systolic blood pressure obtained during the respective studies were used to calculate the SI. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Shock index was significantly higher in the hemorrhage group (median 1.37, range 0.78-4.35) than the control group (median 0.91, range 0.57-1.53); 92% of the dogs in hemorrhagic shock had an SI of >0.91. Compared with controls, dogs in hemorrhagic shock had significantly lower body temperatures (median 38.3°C, range 35.6-39.9°C versus median 38.7°C, range 37.5-39.9°C), higher heart rates (median 150/min, range 120-220/min versus median 110/min range 80-150/min), lower systolic blood pressures (mean 112 mm Hg, SD ±35.8 mm Hg versus mean 125 mm Hg, SD ±21.5 mm Hg), higher lactate concentrations (median 0.51 mmol/L, range 0.078-1.41 mmol/L versus median 0.11 mmol/L, range 0.033-0.33 mmol/L), and lower hemoglobin concentrations (median 81 g/L, range 56-183 g/L versus median 162.5 g/L, range 133-198 g/L). CONCLUSIONS: Shock index is a simple and easy calculation that can be used as an additional triage tool and should prompt further investigation for hemorrhage if the values are >0.9.

Shorter androgen receptor CAG repeat lengths associated with cryptorchidism risk among Hispanic white boys.

CONTEXT: Cryptorchidism is the most frequent congenital malformation among males, the major established risk factor for testicular germ cell tumors, and a presumed infertility risk factor. Androgens are essential for testicular descent, and functional genetic polymorphisms in the androgen receptor gene (AR) are postulated to influence cryptorchidism risk. OBJECTIVE: The aim of the study was to investigate whether the CAG repeat length polymorphism in exon 1 of the AR is associated with cryptorchidism risk. DESIGN AND SETTING: We conducted a family-based genotype-risk association study employing the transmission disequilibrium test for genotypic variants transmitted on the X-chromosome at a university-affiliated regional children's hospital. PARTICIPANTS: We studied 127 Hispanic boys with persistent cryptorchidism and comorbidities described in detail and their biological mothers. INTERVENTION: Genotypes defined by number of CAG repeats were measured for each member of participating son-mother pairs. MAIN OUTCOME MEASURE: Associations between CAG tract length genotype and cryptorchidism risk were estimated using matched-pairs logistic regression. RESULTS: Cryptorchidism risk was significantly associated with shorter CAG repeats [CAG≤19 vs. CAG≥20, odds ratio (OR)=0.44; 95% confidence interval (CI), 0.23-0.88]. This association was restricted to cryptorchidism with accompanying comorbidities, which was primarily hernia [CAG≤19 vs. CAG≥20, OR=0.35 (95% CI, 0.16-0.78)], and was strongest for bilateral cryptorchidism [CAG≤19 vs. CAG≥20, OR=0.09 (95% CI, 0.010-0.78)]. CONCLUSIONS: Androgen receptor genotypes encoding moderate functional variation may influence cryptorchidism risk, particularly among boys with bilateral nondescent or congenital hernia, and may explain in part the elevated risk of testicular seminoma experienced by ex-cryptorchid boys. Mechanistic research is warranted to examine both classical and nonclassical mechanisms through which androgens may influence risk of cryptorchidism and related conditions.

Early comparison of nephrectomy options in children (open, transperitoneal laparoscopic, laparo-endoscopic single site (LESS), and robotic surgery).

OBJECTIVE: To compare the perioperative parameters of paediatric patients who underwent nephrectomy via laparo-endoscopic single site (LESS) surgery (also known as single incision laparoscopic surgery or SILS) with those who underwent nephrectomy via conventional laparoscopy (LAP), robotic-assisted laparoscopy (RALN), and open surgery (OPEN). PATIENTS AND METHODS: The medical records of 69 paediatric patients at a single institution who underwent nephrectomies for non-functioning kidneys in 72 renal units (39 OPEN, 11 LAP, 11 RALN and 11 LESS) were reviewed for patient demographics and perioperative clinical parameters. RESULTS: The minimally invasive modalities in children, including LESS nephrectomy, were associated with shorter lengths of hospital stay (P < 0.001) and decreased postoperative pain medication usage (P < 0.001) than with open surgery. Similar surgical times were noted with LESS and the other minimally invasive modalities (LAP and RALN) (P= 0.056). However, the minimally invasive modalities (LESS, LAP and RALN) were associated with slightly longer surgical times when compared with open surgery (P < 0.001), which may, in part, be secondary to learning curve factors. No differences were noted among the minimally invasive modalities for postoperative pain medication usage (P= 0.354) and length of hospital stay (P= 0.86). CONCLUSIONS: The minimally invasive modalities for nephrectomy in children, including LESS nephrectomy, are associated with shorter lengths of hospital stay and decreased postoperative pain medication use when compared with open surgery. LESS nephrectomy in children is associated with similar surgical times, lengths of hospital stay and postoperative pain medication use as the other minimally invasive modalities (LAP and RALN). Slightly longer surgical times are noted with the minimally invasive modalities, including LESS nephrectomy, when compared with open surgery, which may, in part, be secondary to learning curve factors.

Human capital gains associated with robotic assisted laparoscopic pyeloplasty in children compared to open pyeloplasty.

PURPOSE: Robotic assisted laparoscopic pyeloplasty is an emerging, minimally invasive alternative to open pyeloplasty in children for ureteropelvic junction obstruction. The procedure is associated with smaller incisions and shorter hospital stays. To our knowledge previous outcome analyses have not included human capital calculations, especially regarding loss of parental workdays. We compared perioperative factors in patients who underwent robotic assisted laparoscopic and open pyeloplasty at a single institution, especially in regard to human capital changes, in an institutional cost analysis. MATERIALS AND METHODS: A total of 44 patients 2 years old or older from a single institution underwent robotic assisted (37) or open (7) pyeloplasty from 2008 to 2010. We retrospectively reviewed the charts to collect demographic and perioperative data. The human capital approach was used to calculate parental productivity losses. RESULTS: Patients who underwent robotic assisted laparoscopic pyeloplasty had a significantly shorter average hospital length of stay (1.6 vs 2.8 days, p <0.05). This correlated with an average savings of lost parental wages of $90.01 and hospitalization expenses of $612.80 per patient when excluding amortized robot costs. However, cost savings were not achieved by varying length of stay when amortized costs were included. CONCLUSIONS: Robotic assisted laparoscopic pyeloplasty in children is associated with human capital gains, eg decreased lost parental wages, and lower hospitalization expenses. Future comparative outcome analyses in children should include financial factors such as human capital loss, which can be especially important for families with young children.