Tympanic membrane perforations cannot be reliably detected using computed tomography based on 15 cadaver dogs.

The integrity of the tympanic membrane is an important factor when deciding treatment and therapeutic recommendations for dogs with ear disease; however, otoscopic examination may be difficult to perform due to features of external ear canal disease or patient compliance. CT is useful for the evaluation of middle ear disease, including cases in which middle ear disease is detected incidentally. The tympanic membrane is detectable using CT, but anecdotally, apparent focal defects or discontinuities of the tympanic membrane are often seen in patients with and without ear disease. The purpose of this prospective, observer agreement study was to determine if perforations of the tympanic membrane are reliably detectable on CT. Fifteen cadaver dogs underwent CT and video otoscopy to verify the integrity of each tympanic membrane. Cadavers were randomly assigned to have the tympanic membranes left intact or to undergo a myringotomy on either the left, the right, or both sides. CT was performed immediately following the myringotomies. Four blinded evaluators evaluated the pre- and post-myringotomy scans for a total of 30 scans (60 tympanic membranes). Average accuracy was low (44%), and interobserver agreement for all four evaluators was fair. Although the tympanic membrane is visible on CT, perforations of the tympanic membrane are unlikely to be accurately detected or excluded. The appearance of an intact tympanic membrane or defect in the membrane on CT should not be used as criteria to guide clinical treatment recommendations based on this cadaver model.

Framing doctor-managers' resilience during Covid-19 pandemic: A descriptive analysis from the Italian NHS.

With the aim of providing evidence about doctor-managers' resilience during the Covid-19 pandemic, this study analyzes the characteristics of 114 doctor-managers operating within the Italian National Health Service (NHS). During the emergency, doctor-managers had to show adaptive capacities to deal with unexpected situations and develop new paradigms, procedures, and quick responses to patients' needs. This is in line with resilience, and in this perspective, it is crucial to investigate resilience determinants. The paper, therefore, provides an identikit of the resilient doctor-manager. The research was conducted between November and December 2020. Primary data were collected through an online questionnaire consisting of six sections. Participation was voluntary and anonymous. Data were analyzed using quantitative techniques and employing Stata 16. Confirmatory Factor Analysis was employed to test construct validity and scale reliability. Results show that increasing levels of individual resilience are related to increasing levels of managerial identity. Moreover, physicians' individual resilience has a positive association with commitment, knowledge diffusion, and Evidence-Based Medicine adoption. Finally, physicians' individual resilience has a negative association with their role in the university, their specialty, and their gender. The study suggests some practical implications for healtcare organizations. In general, career paths are decided primarily on competency assessment, while an important role should be devoted to behavioral characteristics. Furthermore, organizations should take care of the levels of individual commitment and encourage professional networking because both help doctor-managers cope with uncertainty. The originality of the study relies on a fresh look at all previous work. There are currently few contributions in the literature to explore and investigate resilience elements in doctor-managers during the pandemic era.

Discovery of Orally Available and Brain Penetrant AEP Inhibitors.

Alzheimer's Disease (AD) is the most widespread form of dementia, with one of the pathological hallmarks being the formation of neurofibrillary tangles (NFTs). These tangles consist of phosphorylated Tau fragments. Asparagine endopeptidase (AEP) is a key Tau cleaving enzyme that generates aggregation-prone Tau fragments. Inhibition of AEP to reduce the level of toxic Tau fragment formation could represent a promising therapeutic strategy. Here, we report the first orthosteric, selective, orally bioavailable, and brain penetrant inhibitors with an irreversible binding mode. We outline the development of the series starting from reversible molecules and demonstrate the link between inhibition of AEP and reduction of Tau N368 fragment both in vitro and in vivo.

Preclinical evidence for the effective use of TL-895, a highly selective and potent second-generation BTK inhibitor, for the treatment of B-cell malignancies.

TL-895 (formerly known as M7583) is a potent, highly selective, adenosine triphosphate (ATP)-competitive, second-generation, irreversible inhibitor of Bruton's tyrosine kinase (BTK). We characterized its biochemical and cellular effects in in vitro and in vivo models. TL-895 was evaluated preclinically for potency against BTK using IC50 concentration-response curves; selectivity using a 270-kinase panel; BTK phosphorylation in Ramos Burkitt's lymphoma cells by ProteinSimple Wes analysis of one study; anti-proliferative effects in primary chronic lymphocytic leukemia (CLL) blasts; cell viability effects in diffuse large B-cell lymphoma (DLBCL) and mantle-cell lymphoma (MCL) cell lines; effects on antibody-dependent cell-mediated cytotoxicity (ADCC) from Daudi cells and chromium-51 release from human tumor cell lines; and efficacy in vivo using four MCL xenograft model and 21 DLBCL patient-derived xenograft (PDX) models (subtypes: 9 ABC, 11 GCB, 1 Unclassified). TL-895 was active against recombinant BTK (average IC50 1.5 nM) and inhibited only three additional kinases with IC50 within tenfold of BTK activity. TL-895 inhibited BTK auto-phosphorylation at the Y223 phosphorylation site (IC50 1-10 nM). TL-895 inhibited the proliferation of primary CLL blasts in vitro and inhibited growth in a subset of activated DLBCL and MCL cell lines. TL-895 inhibited the ADCC mechanism of therapeutic antibodies only at supra-clinical exposure levels. TL-895 significantly inhibited tumor growth in the Mino MCL xenograft model and in 5/21 DLBCL PDX models relative to vehicle controls. These findings demonstrate the potency of TL-895 for BTK and its efficacy in models of B-cell lymphoma despite its refined selectivity.

Epiploic foramen entrapment in a dog.

OBJECTIVE: To report small intestinal herniation through the epiploic foramen in a dog. ANIMALS: Nine-year-old male castrated Shih Tzu. STUDY DESIGN: Case report. METHODS: The dog presented with an 8-year history of vomiting and regurgitation and acute onset of melena, lethargy, anorexia, anemia, and suspected gastrointestinal mass or obstruction on prereferral imaging. Abnormalities on abdominal radiographs included a large, midcaudal soft tissue structure and cranial displacement and segmental dilation of the small intestine. On abdominal ultrasound, severe gastric dilation, jejunal tortuosity and stacking, and peritoneal effusion were observed. Epiploic herniation of the small intestine and segmental jejunal devitalization was diagnosed on exploratory laparotomy, and the dog underwent hernia reduction, jejunal resection and anastomosis, and nasogastric tube placement. RESULTS: Severe gastric distention and atony persisted 24 h after surgery, despite medical management. The dog was taken to surgery for decompressive gastrotomy and placement of gastrostomy and nasojejunostomy tubes for postoperative decompression and feeding, respectively. Three days after the original surgery, the dog developed a septic abdomen from anastomotic dehiscence and underwent jejunal resection and anastomosis and peritoneal drain placement. Gastric dysmotility gradually resolved with the administration of motility stimulants, removal of gastric residual volume, and nutritional support via nasojejunostomy tube feedings. Three months after discharge, the dog was clinically normal. CONCLUSION: Epiploic foramen entrapment should be considered a type of herniation in dogs. Clinical suspicion should be raised in dogs with unresolving regurgitation and vomiting, visceral displacement, and stacking and distension of small intestine.

Exploration of the mediating role of physicians' managerial attitude in the relationship between their self-efficacy and workplace performance.

PURPOSE: Self-efficacy, or a person's belief in his/her ability to perform specific tasks, has been correlated with workplace performance and role adjustments. Despite its relevance, and numerous studies of it in the management literature, evidence regarding its function in professionals employed in hybrid roles, such as doctor-managers, is lacking. The aim of this study was to fill this gap by exploring the mediating effect of physicians' managerial attitude on the relationship between their self-efficacy and workplace performance. DESIGN/METHODOLOGY/APPROACH: Primary and secondary data from 126 doctor-managers were obtained from the Italian National Health Service. A structural equation modeling approach was used for analysis. FINDINGS: This study's results provide for the first time empirical evidence about a surprisingly little-analyzed topic: how physicians' managerial attitude mediates the relationship between their self-efficacy and workplace performance. The study offers important evidence both for scholars and organizations. PRACTICAL IMPLICATIONS: This study's results provide valuable input for the human resources management of hybrid roles in professional-based organizations, suggesting a systematic provision of feedback about doctor-managers' performance, the adoption of a competence approach for their recruitment, and a new design of doctor-managers' career paths. ORIGINALITY/VALUE: The authors provide new evidence about the importance of managerial traits for accountable healthcare organizations, documenting that behavioral traits of physicians enrolled into managerial roles matter for healthcare organizations success.

Discovery of Covalent Bruton's Tyrosine Kinase Inhibitors with Decreased CYP2C8 Inhibitory Activity.

Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage. Evidence has shown that inhibition of BTK has clinical benefit for the treatment of a wide array of autoimmune and inflammatory diseases. Previously we reported the discovery of a novel nicotinamide selectivity pocket (SP) series of potent and selective covalent irreversible BTK inhibitors. The top molecule 1 of that series strongly inhibited CYP2C8 (IC50 =100 nM), which was attributed to the bridged linker group. However, our effort on the linker replacement turned out to be fruitless. With the study of the X-ray crystal structure of compound 1, we envisioned the opportunity of removal of this liability via transposition of the linker moiety in 1 from C6 to C5 position of the pyridine core. With this strategy, our optimization led to the discovery of a novel series, in which the top molecule 18 A displayed reduced CYP inhibitory activity and good potency. To further explore this new series, different warheads besides acrylamide, for example cyanamide, were also tested. However, this effort didn't lead to the discovery of molecules with better potency than 18 A. The loss of potency in those molecules could be related to the reduced reactivity of the warhead or reversible binding mode. Further profiling of 18 A disclosed that it had a strong hERG (human Ether-a-go-go Related Gene) inhibition, which could be related to the phenoxyphenyl group.

Discovery of potent and selective reversible Bruton's tyrosine kinase inhibitors.

Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose the discovery of a novel imidazo[4,5-b]pyridine series of potent, selective reversible BTK inhibitors through a rational design approach. From a starting hit molecule 1, medicinal chemistry optimization led to the development of a lead compound 30, which exhibited 58 nM BTK inhibitory potency in human whole blood and high kinome selectivity. Additionally, the compound demonstrated favorable pharmacokinetics (PK), and showed potent dose-dependent efficacy in a rat CIA model.

Vitamin A failed to ameliorate clinical signs in dogs with pituitary-dependent hypercortisolaemia.

BACKGROUND: In dogs with pituitary-dependent hypercortisolaemia, retinoic acid was shown to lower cortisol, reduce pituitary tumour size and decrease clinical signs when administered for six months. Oral vitamin A (retinol) has been used to treat various canine dermatoses in which retinoic acid has been efficacious. OBJECTIVES: To determine if orally administered vitamin A lowers cortisol and reduces clinical signs in dogs with pituitary-dependent hypercortisolaemia over a five month period. METHODS AND MATERIALS: Five dogs were enrolled in this study. Diagnosis of hypercortisolaemia was based on the presence of at least three clinical signs and one abnormal screening test. Diagnosis of pituitary-dependent disease was based on low dose dexamethasone suppression (LDDS) test results and symmetrical adrenal glands on ultrasound. Adrenocorticotropic hormone (ACTH) stimulation testing and adrenal ultrasound were performed at each visit. Plasma was collected at each visit and stored at -80°C for batch analysis of endogenous ACTH at conclusion of the study. RESULTS: Four dogs completed the study. A fifth dog died from complications of hypercortisolaemia before the third month. One dog showed improvement in clinical signs, yet there was no significant decrease in adrenal gland size or cortisol concentrations. Endogenous ACTH concentrations at the fifth month were decreased from baseline in two dogs and increased from baseline in one dog. The treatment had no adverse effects. CONCLUSIONS AND CLINICAL IMPORTANCE: Results from this study failed to show an improvement in clinical signs or cortisol concentration after five months of oral daily vitamin A in dogs with hypercortisolaemia.

The microfoundations of physicians' managerial attitude.

BACKGROUND: Accountable care has profoundly changed the organizational models adopted by health care organizations and, consequently, the skill set required for doctor-managers who have become middle managers and must deal with the operational management of their units. The aim of this study was to identify the psychological microfoundations (i.e., traits) of physicians' managerial attitude. Specifically, we analysed the roles played by narcissism, specialization choices and identification with the organization. METHODS: We collected primary data on a population of ward unit heads in the Italian National Health Service. A logistic regression model predicting the levels of managerial attitude was employed. RESULTS: The results indicate that high levels of narcissism and identification with the organization are related to higher managerial attitude (instead of clinical attitude). Additionally, we found that physicians with a technique-oriented specialization present a higher probability of manifesting managerial attitude (in comparison to clinical attitude). CONCLUSIONS: Hospital managers can benefit from the use of these findings by developing a strategic approach to human resource management that allows them to identify, train and select the right mix of technical knowledge and managerial skills for middle-management roles.

Individual and job-related determinants of bias in performance appraisal: The case of middle management in health care organizations.

BACKGROUND: Accountable care has changed organizational models adopted by health care organizations profoundly and, consequently, the skill set required for doctor-managers who have become middle managers and must deal with the operational management of their units. Doctor-managers must carry out clinical tasks as well as tasks related to budgeting, goal setting, and performance evaluation. The performance evaluation bias, defined as the misalignment between a ward unit's objective performance (as assessed by technical bodies or agencies) and self-assessed performance by the head of the unit, may have serious consequences for individuals and organizations. PURPOSE: The aim of this study was to identify determinants of performance appraisal bias based on the mismatch between self-reported and official performance data. Specifically, we analyzed the role played by managerial behavior, training, engagement, and perceived organizational support at the individual level, as well as the particular unit's task diversity, complexity, and predictability. METHODOLOGY: We collected primary and secondary data referable to a population of ward unit heads in the Italian National Health Service. A linear regression model predicting performance appraisal bias was employed. FINDINGS: High levels of engagement and perceived organizational support were associated with reduced performance appraisal bias, whereas high levels of predictability and task diversity were associated with increased degree of error. Doctor-managers attending training programs in health care management and ward unit task complexity did not affect bias significantly. PRACTICE IMPLICATIONS: Policy makers and hospital managers should provide heads of units with tools that enable them to conduct ongoing monitoring and accurate appraisal of performance. Doctor-manager performance appraisal bias may be diminished by a perception of having support of the organization and direct superiors. Training programs can be revised to incorporate performance appraisal, and good performance may be incentivized with rewards.

Discovery of BAY-298 and BAY-899: Tetrahydro-1,6-naphthyridine-Based, Potent, and Selective Antagonists of the Luteinizing Hormone Receptor Which Reduce Sex Hormone Levels in Vivo.

The human luteinizing hormone receptor (hLH-R) is a member of the glycoprotein hormone family of G-protein-coupled receptors (GPCRs), activated by luteinizing hormone (hLH) and essentially involved in the regulation of sex hormone production. Thus, hLH-R represents a valid target for the treatment of sex hormone-dependent cancers and diseases (polycystic ovary syndrome, uterine fibroids, endometriosis) as well as contraception. Screening of the Bayer compound library led to the discovery of tetrahydrothienopyridine derivatives as novel, small-molecule (SMOL) hLH-R inhibitors and to the development of BAY-298, the first nanomolar hLH-R antagonist reducing sex hormone levels in vivo. Further optimization of physicochemical, pharmacokinetic, and safety parameters led to the identification of BAY-899 with an improved in vitro profile and proven efficacy in vivo. BAY-298 and BAY-899 serve as valuable tool compounds to study hLH-R signaling in vitro and to interfere with the production of sex hormones in vivo.

Discovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological Diseases.

Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

Novel CT Features of an Abdominal Gossypiboma in a Female Dog.

CASE DESCRIPTION: An eight-year-old Golden Retriever was presented with hypercalcemia and a complex abdominal mass. CLINICAL FINDINGS: A well-defined, heterogeneously contrast-enhancing, cavitary, soft tissue attenuating, non-organ associated abdominal mass was identified caudal to the right kidney. This mass was confluent with the distal tip of the right limb of the pancreas. A connected large, rim enhancing, cystic subcutaneous mass was also present in the right lumbar subcutaneous tissues, and there were multiple fistulous tracts through the hypaxial musculature. TREATMENT AND OUTCOME: The dog underwent a surgical exploratory laparotomy and a gossypiboma was removed from the intra-abdominal mass; the cystic extra-abdominal mass was drained percutaneously. Surgical recovery was uneventful and a follow-up CT after 3 months was consistent with resolving granulomatous inflammation and fibrosis. CLINICAL RELEVANCE: The presence of multiple peripherally enhancing tracts extending from the abdominal mass through the hypaxial musculature is a CT feature which has not yet been described in the veterinary literature. Additionally, incorporation of the pancreas into the abdominal mass has also not yet been described in the veterinary literature.

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models.

Because of its role in mediating both B cell and Fc receptor signaling, Bruton's tyrosine kinase (BTK) is a promising target for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Evobrutinib is a novel, highly selective, irreversible BTK inhibitor that potently inhibits BCR- and Fc receptor-mediated signaling and, thus, subsequent activation and function of human B cells and innate immune cells such as monocytes and basophils. We evaluated evobrutinib in preclinical models of RA and SLE and characterized the relationship between BTK occupancy and inhibition of disease activity. In mouse models of RA and SLE, orally administered evobrutinib displayed robust efficacy, as demonstrated by reduction of disease severity and histological damage. In the SLE model, evobrutinib inhibited B cell activation, reduced autoantibody production and plasma cell numbers, and normalized B and T cell subsets. In the RA model, efficacy was achieved despite failure to reduce autoantibodies. Pharmacokinetic/pharmacodynamic modeling showed that mean BTK occupancy in blood cells of 80% was linked to near-complete disease inhibition in both RA and SLE mouse models. In addition, evobrutinib inhibited mast cell activation in a passive cutaneous anaphylaxis model. Thus, evobrutinib achieves efficacy by acting both on B cells and innate immune cells. Taken together, our data show that evobrutinib is a promising molecule for the chronic treatment of B cell-driven autoimmune disorders.

HRM practices and organizational change: Evidence from Italian clinical directorates.

PURPOSE: The healthcare sector has been facing major reforms, among which the introduction of the Clinical Directorate (CD) model for hospitals. The purpose of this work is to explore the degree of implementation of innovative Human Resource Management (HRM) practices within CDs, in order to understand whether, after more than 15 years from their introduction, they have been able to transform their managerial approach concretely, in line with the CD model's objectives. The tools have been attributed to three main HR initiatives: training, control, and evaluation ones. DESIGN AND METHODS: During on-site visits in 33 Italian hospitals, data were collected by conducting semi-structured interviews with their CEOs and Clinical Directors. Data concerned both the mere adoption of HRM tools within CDs, as well as their effective degree of implementation. The answers to the questions were translated into a system of percentage scores, so as to detect mean percentages of implementation in each CD. Findings: The general degree of implementation of HRM practices is still somewhat distant from a theoretically excellent and full implementation, especially if we consider the important lag of time since the reforms affected the sector. Nevertheless, results open the way to important considerations about the effectiveness of the CD model. Original value: The original methodology and scoring system suggested in this work produce a concise evaluation of the development of an effective HRM system within CDs. Our framework of analysis allows interesting benchmarking activities among different CDs of an organization and, ultimately, among different organizations. Moreover, the methodology presented may constitute a valid source of information in order to carry out future research on the items able to affect the implementation of such tools.

Relative skeletal distribution of proliferating marrow in the adult dog determined using 3'-deoxy-3'-[18 F]fluorothymidine.

3'-deoxy-3'-[18 F]fluorothymidine (18 FLT) is a radiopharmaceutical tracer used with positron emission tomography (PET), often in combination with computed tomography (CT), to image DNA synthesis, and thus, cellular proliferation. Characteristic accumulation of the tracer within haematopoietic bone marrow provides a noninvasive means to assess marrow activity and distribution throughout the living animal. The present study utilizes three-dimensional analysis of 18 FLT-PET/CT scans to quantify the relative skeletal distribution of active marrow by anatomic site in the dog. Scans were performed on six healthy, adult (3-6 years of age), mixed-breed dogs using a commercially available PET/CT scanner consisting of a 64-slice helical CT scanner combined with an integrated four ring, high-resolution LSO PET scanner. Regions of interest encompassing 11 separate skeletal regions (skull, cervical vertebral column, thoracic vertebral column, lumbar vertebral column, sacrum, ribs, sternum, scapulae, proximal humeri, ossa coxarum, and proximal femora) were manually drawn based on CT images and thresholded by standardized uptake value to delineate bone marrow activity. Activity within each skeletal region was then divided by the total skeletal activity to derive the per cent of overall marrow activity within an individual site. The majority of proliferative marrow was located within the vertebral column. Of the sites traditionally accessed clinically for marrow sampling, the proximal humerus contained the largest percentage, followed by the ossa coxarum, proximal femur, and sternum, respectively. This information may be used to guide selection of traditional marrow sampling sites as well as inform efforts to spare important sites of haematopoiesis in radiation therapy planning.