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.

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.

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.

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.

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.

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.

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 a novel series of pyridine and pyrimidine carboxamides as potent and selective covalent inhibitors of Btk.

Btk is an attractive target for the treatment of a range of Bcell malignancies as well as several autoimmune diseases such as murine lupus and rheumatoid arthritis. Several covalent irreversible inhibitors of Btk are currently in development including ibrutinib which was approved for treatment of B-cell malignancies. Herein, we describe our efforts using X-ray guided structure based design (SBD) to identify a novel chemical series of covalent Btk inhibitors. The resulting pyridine carboxamides were potent and selective inhibitors of Btk having excellent enzymatic and cellular inhibitory activity.

Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit.

Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR.

Optimization of the efflux ratio and permeability of covalent irreversible BTK inhibitors.

Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N-linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain. The hit molecules, however, displayed high P-gp mediated efflux ratio (ER) and poor A-B permeability in Caco-2 assay. By decreasing tPSA, installing steric hindrance and adjusting clogP, one top molecule 9 was discovered, which showed a 99% decrease in efflux ratio and a 90-fold increase in A-B permeability compared to hit molecule 1.

Ability of Bruton's Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency for Inhibition of Fc Receptor but not B-Cell Receptor Signaling.

Bruton's tyrosine kinase (Btk) is expressed in a variety of hematopoietic cells. Btk has been demonstrated to regulate signaling downstream of the B-cell receptor (BCR), Fc receptors (FcRs), and toll-like receptors. It has become an attractive drug target because its inhibition may provide significant efficacy by simultaneously blocking multiple disease mechanisms. Consequently, a large number of Btk inhibitors have been developed. These compounds have diverse binding modes, and both reversible and irreversible inhibitors have been developed. Reported herein, we have tested nine Btk inhibitors and characterized on a molecular level how their interactions with Btk define their ability to block different signaling pathways. By solving the crystal structures of Btk inhibitors bound to the enzyme, we discovered that the compounds can be classified by their ability to trigger sequestration of Btk residue Y551. In cells, we found that sequestration of Y551 renders it inaccessible for phosphorylation. The ability to sequester Y551 was an important determinant of potency against FcεR signaling as Y551 sequestering compounds were more potent for inhibiting basophils and mast cells. This result was true for the inhibition of FcγR signaling as well. In contrast, Y551 sequestration was less a factor in determining potency against BCR signaling. We also found that Btk activity is regulated differentially in basophils and B cells. These results elucidate important determinants for Btk inhibitor potency against different signaling pathways and provide insight for designing new compounds with a broader inhibitory profile that will likely result in greater efficacy.

Btk inhibition treats TLR7/IFN driven murine lupus.

Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors. In vitro studies using primary human macrophages revealed that Btk inhibition can block activation by immune complexes and TLR7 which contributes to tissue damage in SLE. Overall, our results provide translational insight into how Btk inhibition may provide benefit to a variety of SLE patients by affecting both BCR and FcR signaling.

Extraction of the envelope from impulse responses using pre-processed energy detection for early decay estimation.

The Schroeder's backward integration method and its applications have been widely studied in the literature; some papers analyze the performance of the method, some others suggest various enhancement techniques. In spite of these findings, there exist several cases where the energy decay curve extracted using the classical backward integration method and the parameters computed from it seem not always representative of the phenomenon under study. Among them, the cases where the early decay is dependent on strong, distinct reflections occurring just after the direct wave, as in most Italian opera houses. Other cases are measured impulse responses with a very low signal-to-noise ratio or missing the direct wave. In the literature, alternatives to the Schroeder's method have been proposed, ranging from Hilbert transform to non-linear processing techniques. In this work a method for the extraction of the envelope based on pre-processed energy detection for early decay estimation is proposed. It is shown that it returns an envelope well matching the first part of the decay even in non-linear cases, returning detailed information on the first part of the decay. The performance of the proposed method is presented and discussed for some exemplary impulse responses measured in historical opera houses. A preliminary study on the perceptive relevance of the method is finally presented.

Prevalence of ear disease in dogs undergoing multidetector thin-slice computed tomography of the head.

Previous reports describing the prevalence of ear diseases in dogs have primarily been based on dogs presenting with clinical signs of disease. The prevalence of subclinical ear disease remains unknown. The purpose of this cross-sectional retrospective study was to describe the prevalence of lesions consistent with middle and external ear disease in dogs presented for multidetector computed tomography (CT) of the head and/or cranial cervical spine at our hospital during the period of July 2011 and August 2013. For each included dog, data recorded were signalment, CT findings, diagnosis, and treatment. A total of 199 dogs met inclusion criteria. Nineteen dogs (9.5%) were referred for evaluation of suspected ear disease and 27 dogs (13.5%) had histories or physical examination findings consistent with otitis externa. A total of 163 dogs (81.9%) had CT lesions consistent with external ear disease (i.e. ear canal mineralization, external canal thickening, and/or narrowing of the external canal). Thirty-nine dogs (19.5%) had CT lesions consistent with middle ear disease (i.e. soft tissue attenuating/fluid material in the tympanic bullae, bulla wall thickening or lysis, and/or periosteal proliferation of the temporal bone). Findings from this study indicated that the prevalence of external and middle ear disease in dogs could be higher than that previously reported.

Looking good or doing better? Patterns of decoupling in the implementation of clinical directorates.

BACKGROUND: The interest toward hospital restructuring has risen significantly in recent years. In spite of its potential benefits, often organizational restructuring in health care produces unexpected consequences. Extant research suggests that institutional theory provides a powerful theoretical lens through which hospital restructuring can be described and explained. According to this perspective, the effectiveness of change is strongly related to the extent to which innovative arrangements, tools, or practices are adopted and implemented within hospitals. Whenever these new arrangements require a substantial modification of internal processes and practices, resistance to implementation emerges and organizational change is likely to become neutralized. PURPOSE: This study analyzes how hospital organizations engage in decoupling by adopting but not implementing a new organizational model named clinical directorate. METHODOLOGY: We collected primary data on the diffusion of the clinical directorate model, which was mandated by law in the Italian National Health Service to improve hospital services. We surveyed the adoption and implementation of the clinical directorate model by monitoring the presence of clinical governance tools (measures for the quality improvement of hospital services) within single directorates. In particular, we compared hospitals that adopted the model before (early adopters) or after (later adopters) the mandate was introduced. FINDINGS: Hospitals were engaged in decoupling by adopting the new arrangement but not implementing internal practices and tools for quality improvement. The introduction of the law significantly affected the decoupling, with late-adopter hospitals being less likely to implement the adopted model. PRACTICE IMPLICATIONS: The present research shows that changes in quality improvement processes may vary in relation to policy makers' interventions aimed at boosting the adoption of new hospital arrangements. Hospital administrators need to be aware and identify the institutional changes that might be driven by law to be able to react consistently with expectations of policymakers.

Invited review--Off-site PET imaging programs: challenges and opportunities.

Veterinarians are gaining interest in and access to Position Emission Tomography (PET and PET/CT) imaging for both clinical and research applications. This manuscript provides an overview of how veterinarians may approach the use of off-site PET and PET/CT scanners already in use for human medical imaging in order to gain access to this technology without direct investment in costly equipment and infrastructure. An overview of general procedures, animal transport, and radiation safety considerations is offered along with references to key regulatory statutes that may apply to the operation of PET imaging facilities in individual states.

Maintaining health service during COVID-19: A study on regional health services.

The pandemic has inevitably led to disruptions in the provision of health services for all those patients not affected by COVID-19. At the same time, we have observed differences among health services in their ability to maintain their activities in the face of shocks: while some health services were largely able to ensure core functions, other suffered delays in prevention, acute care, and rehabilitation. In this paper, we explore the effect of regional health policies in terms of governance, workforce, and health service delivery on the ability to maintain oncological services during the COVID-19 pandemic to assess the resilience of the system. The study is based on secondary data collected on the 21 Italian regional health services during the first wave of the pandemic. We discuss the theoretical and practical implications of providing health services with specific characteristics pertaining to governance, workforce, and health service delivery to support the resilience of regional health policies during a crisis or shock.

The emergence and organizational choices of patient advocacy associations: Evidence from the Italian context.

BACKGROUND: Within many advanced healthcare systems, patient advocacy associations are gaining a more relevant role in healthcare policy decisions. These associations provide help, representation, and voice to patients and citizens. However, although their role is important, a paucity of research exists analyzing their foundation dynamics, including their organizational decision, from a managerial perspective. To fill this knowledge gap, we formulated two research questions to investigate the motivations underlying the foundation of patient advocacy associations and the institutional pressures influencing the changes that have occurred in these associations throughout their evolution. METHODS: Using a semi-structured questionnaire developed as part of a larger research project, we collected data about 31 patient advocacy associations operating within the Italian National Health Service. We employed qualitative analysis to examine the associations' birth and evolution as well as the motivations and influences driving change within the sampled organizations. RESULTS: Questionnaire responses provided information about the patient advocacy associations' histories and highlighted their close links with the Italian National Health Service. Our results indicated the motivations for the associations' establishment could be grouped into five categories: support at the system level, patient protection and support, actions to increase awareness, actions for improving patients' health and quality of life, and dissemination of knowledge. We also identified the frequency and nature of the changes within the associations and explored the institutional pressures that influenced these organizational changes. CONCLUSIONS: The results can be interpreted considering the organizational theories that focus on organizations' establishment decisions and how external pressures impact organizations' dynamics and evolution.

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.

Magnetic resonance imaging of the canine abdomen: effect of pulse sequence on diagnostic quality.

Motion artifact is an important limiting factor for abdominal magnetic resonance imaging (MRI) in veterinary patients. The purpose of this study was to determine the effects of pulse sequence on abdominal MRI diagnostic quality in dogs. Ten normal dogs were each scanned using 16 MRI pulse sequences. Sequences included breath-holding sequences, respiratory navigation sequences, and traditional spin-echo sequences. Four observers independently scored diagnostic quality for each sequence based on the appearance of specific organs, overall diagnostic quality, and degree of artifactual interference. Signal-to-noise ratio and contrast-to-noise ratio were also calculated for each sequence. The sequence with the highest overall mean diagnostic quality score was the dorsal T2 turbo spin echo (TSE) with fat saturation and breath-holding. The sequence with the lowest mean diagnostic quality score was the dorsal T2 fast spin echo. The sequence with the highest signal-to-noise ratio for all evaluated organs was the sagittal T1 spin echo. Signal-to-noise and contrast-to-noise ratios did not correlate with subjective assessment of overall diagnostic quality for the majority of the sequences evaluated (P < 0.05). The three sequences considered to have the highest diagnostic quality for the cranial abdomen were the dorsal T2 TSE with fat saturation and breath-hold, transverse T1 turbo fast low-angle shot gradient echo with breath-hold, and dorsal T2 half-Fourier acquisition single shot TSE with respiratory navigation. These sequences had short acquisition times, yielded studies of similar diagnostic quality, provided complementary information, and are therefore recommended for routine canine abdominal MRI protocols.