Building successful and sustainable academic health science partnerships: exploring perspectives of hospital leaders

Background: Clinical work-based internships form a key component of health professions education. Integral to these internships, academic health science partnerships (AHSPs) exist between universities and teaching hospitals. Our qualitative descriptive study explored the perspectives of hospital leadership on AHSPs: what they are composed of, and the facilitators and barriers to establishing and sustaining these partnerships.     Methods: Fifteen individuals in a variety of hospital leadership positions were purposively sampled to participate in face-to-face interviews, after which a thematic analysis was conducted.Results: Participants reported that healthcare and hospital infrastructure shapes and constrains the implementation of clinical education. The strength of the hospitals’ relationship with the medical profession facilitated the partnership, however other health professions’ partnerships were viewed less favourably. Participants emphasized the value of hospital leaders prioritizing education. Further, our findings highlighted that communication, collaboration, and involvement are considered as both facilitators and barriers to active engagement. Lastly, opportunities stemming from the partnership were identified as research, current best practice, improved patient care, and career development.Conclusion: Our study found that AHSPs involve the drive of the university and hospitals to gain valued capital, or opportunities. Reciprocal communication, collaboration, and involvement are modifiable components that are integral to optimizing AHSPs

Bromocriptine Improves Glucose Tolerance Independent of Circadian Timing, Prolactin, Or the Melanocortin-4 Receptor

Bromocriptine, a dopamine D2 receptor agonist originally used for the treatment of hyperprolactinemia, is largely successful in reducing hyperglycemia and improving glucose tolerance in type 2 diabetics. However, the mechanism behind bromocriptine’s effect on glucose intolerance is unclear. Here, we tested three hypotheses, that bromocriptine may exert its effects on glucose metabolism by 1) decreasing prolactin secretion, 2) indirectly increasing activity of key melanocortin receptors in the central nervous system, or 3) improving/restoring circadian rhythms. Using a diet-induced obese (DIO) mouse model, we established that a 2-wk treatment of bromocriptine is robustly effective at improving glucose tolerance. We then demonstrated that bromocriptine is effective at improving the glucose tolerance of both DIO prolactin-deficient and melanocortin-4 receptor (MC4R)-deficient mice, pointing to bromocriptine’s ability to affect glucose tolerance independently of prolactin or MC4R signaling. Finally, we tested bromocriptine’s dependence on the circadian system by testing its effectiveness in environmental (e.g., repeated shifts to the light-dark cycle) and genetic (e.g., the Clock mutant mouse) models of circadian disruption. In both models of circadian disruption, bromocriptine was effective at improving glucose tolerance, indicating that a functional or well-aligned endogenous clock is not necessary for bromocriptine’s effects on glucose metabolism. Taken together, these results do not support the role of prolactin, MC4R, or the circadian clock as integral to bromocriptine’s underlying mechanism. Instead, we find that bromocriptine is a robust diabetic treatment and resilient to genetically induced obesity, diabetes, and circadian disruption

Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Nature America for personal use, not for redistribution. The definitive version was published in Nature Neuroscience 12 (2009): 864-871, doi:10.1038/nn.2346.Selected vulnerability of neurons in Huntington’s disease (HD) suggests alterations in a cellular process particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal HD models (mouse and squid), but the molecular basis of this effect remains unknown. Here we show that polyQ-Htt inhibits FAT through a mechanism involving activation of axonal JNK. Accordingly, increased activation of JNK was observed in vivo in cellular and animal HD models. Additional experiments indicate that polyQ-Htt effects on FAT are mediated by the neuron-specific JNK3, and not ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in HD. Mass spectrometry identified a residue in the kinesin-1 motor domain phosphorylated by JNK3, and this modification reduces kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provides a molecular basis for polyQ-Htt-induced inhibition of FAT.This work was supported by 2007/2008 MBL summer fellowship to GM; an HDSA grant to GM; NIH grants MH066179 to GB; and ALSA, Muscular Dystrophy Association, and NIH (NS23868, NS23320, NS41170) grants to STB

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Decision-making about clinical trial options among older patients with metastatic cancer who have exhausted standard therapies

ObjectivesOlder adults under-enroll in early phase cancer clinical trials. There are limited data on their trial experiences, which hampers our ability to understand potential reasons and responses to under-enrollment. We aimed to explore older adults' experiences and deliberations with phase 1 trials.Materials and methodsWe analyzed 101 in-depth interviews with 39 adults (average 2.6 interviews per participant) about their experiences with phase 1 trials. All respondents were ≥ 65 years and had advanced cancer. Interviews lasted 60-90 min and were audio-recorded, transcribed, and analyzed to identify respondents' understanding of clinical research, perceptions of early phase trials, and experiences with enrollment.ResultsClinical trial participation was an interactive process that unfolded over time. Older adults relied on ongoing guidance and discussion with their oncologist to navigate the process. Respondents were generally interested in life-prolonging therapies, including enrollment in early phase clinical trials, but did not necessarily state this explicitly to their oncologist. While respondents did not mention age as a limitation to trials participation, participants age > 70 were less enthusiastic about participation and more often discussed their quality of life and weighed benefits of trial participation in the context of their remaining months of life.ConclusionEarly phase clinical trial enrollment is complex, and older adults rely on their oncologist to navigate this process. Acknowledging this complexity through shared decision-making may ensure that older adults have appropriate opportunities to enroll in early phase clinical trials and guard against inappropriate under-enrollment

Caloric Restriction Prevents Obesity- and Intermittent Hypoxia-Induced Cardiac Remodeling in Leptin-Deficient ob/ob Mice

Background: Intermittent hypoxia (IH), a key characteristic of obstructive sleep apnea, is independently associated with cardiometabolic impairment. While endogenous leptin levels may provide cardioprotective effects against hypoxia, leptin resistance is common among obese individuals presenting with obstructive sleep apnea. Methods: Here, we assessed left ventricle (LV) function using M-mode echocardiography in lean wild-type, calorically-restricted ob/ob, and obese ob/ob mice before and after 6 days of IH to determine how obesity and intermittent hypoxia interact to affect cardiac function independent of leptin signaling. Results: Calorically-restricting ob/ob mice for 4 weeks prior to IH exposure prevented weight gain (−2.1 ± 1.4 g) compared to free-fed ob/ob mice (8.7 ± 1.1 g). Free-fed ob/ob mice exhibited increased LV mass (0.713 ± 0.008 g) relative to wild-type mice (0.685 ± 0.004 g) and increased posterior wall thickness (0.089 ± 0.006 cm) relative to calorically-restricted ob/ob mice (0.072 ± 0.004 cm). Following 6 days of IH, free-fed ob/ob mice exhibited increases in cardiac output (44.81 ± 2.97 pre-IH vs. 57.14 ± 3.09 ml/min post-IH), LV diameter (0.400 ± 0.007 pre-IH vs. 0.428 ± 0.009 cm post-IH) and end diastolic volume (0.160 ± 0.007 pre-IH vs. 0.195 ± 0.012 ml post-IH) that were not detected in wild-type or calorically-restricted ob/ob mice. Conclusion: Caloric restriction can prevent obesity-induced LV hypertrophy and protect against acute IH-induced cardiac remodeling independent of leptin signaling. These findings may have clinical implications for obstructive sleep apnea

Caloric Restriction Prevents Obesity- and Intermittent Hypoxia-Induced Cardiac Remodeling in Leptin-Deficient \u3cem\u3eob/ob\u3c/em\u3e Mice

Background: Intermittent hypoxia (IH), a key characteristic of obstructive sleep apnea, is independently associated with cardiometabolic impairment. While endogenous leptin levels may provide cardioprotective effects against hypoxia, leptin resistance is common among obese individuals presenting with obstructive sleep apnea. Methods: Here, we assessed left ventricle (LV) function using M-mode echocardiography in lean wild-type, calorically-restricted ob/ob, and obese ob/ob mice before and after 6 days of IH to determine how obesity and intermittent hypoxia interact to affect cardiac function independent of leptin signaling. Results: Calorically-restricting ob/ob mice for 4 weeks prior to IH exposure prevented weight gain (−2.1 ± 1.4 g) compared to free-fed ob/ob mice (8.7 ± 1.1 g). Free-fed ob/ob mice exhibited increased LV mass (0.713 ± 0.008 g) relative to wild-type mice (0.685 ± 0.004 g) and increased posterior wall thickness (0.089 ± 0.006 cm) relative to calorically-restricted ob/ob mice (0.072 ± 0.004 cm). Following 6 days of IH, free-fed ob/ob mice exhibited increases in cardiac output (44.81 ± 2.97 pre-IH vs. 57.14 ± 3.09 ml/min post-IH), LV diameter (0.400 ± 0.007 pre-IH vs. 0.428 ± 0.009 cm post-IH) and end diastolic volume (0.160 ± 0.007 pre-IH vs. 0.195 ± 0.012 ml post-IH) that were not detected in wild-type or calorically-restricted ob/ob mice. Conclusion: Caloric restriction can prevent obesity-induced LV hypertrophy and protect against acute IH-induced cardiac remodeling independent of leptin signaling. These findings may have clinical implications for obstructive sleep apnea

The Timing of Intermittent Hypoxia Differentially Affects Macronutrient Intake and Energy Substrate Utilization in Mice

Sleep apnea is a common sleep disorder characterized by periodic breathing cessation and intermittent hypoxia (IH). Although previous studies have demonstrated that IH alone can influence metabolic outcomes such as body weight, it remains unclear how the timing of IH can specifically affect these outcomes. Here, we examine how pairing 10-h periods of IH to either the animals’ resting phase (e.g., IH during the day) or active phase (e.g., IH during the night) differentially affects body weight, macronutrient selection, energy expenditure, respiratory exchange rate, and glucose tolerance. We find that in contrast to mice exposed to IH during the night, mice exposed to IH during the day preferentially decrease their carbohydrate intake and switch to fat metabolism. Moreover, when the IH stimulus was removed, mice that had been exposed to day IH continued to eat a minimal amount of carbohydrates and consumed a higher percentage of kilocalorie from fat for at least 5 days. These data demonstrate that food choice and substrate utilization are secondary to the timing of IH but not IH itself. Taken together, these data have key clinical implications for individuals with sleep apnea and particularly those who are also experiencing circadian disruption such as night-shift workers

Comparative efficacy and safety of bortezomib, thalidomide, and dexamethasone (VTd) without and with daratumumab (D‐VTd) in CASSIOPEIA versus VTd in PETHEMA/GEM in transplant‐eligible patients with newly diagnosed multiple myeloma, using propensity score matching

Abstract Background Traditional bortezomib, thalidomide, and dexamethasone (VTd) regimens for patients with newly diagnosed multiple myeloma (NDMM) include doses of thalidomide up to 200 mg/day (VTd‐label). Clinical practice has evolved to use a lower dose (100 mg/day) to reduce toxicity (VTd‐mod), which was evaluated in the phase III CASSIOPEIA study, without or with daratumumab (D‐VTd; an anti‐CD38 monoclonal antibody). We used propensity score matching to compare efficacy and safety for VTd‐mod and D‐VTd with VTd‐label. Methods Patient‐level data for VTd‐mod and D‐VTd from CASSIOPEIA (NCT02541383) and data for VTd‐label from the PETHEMA/GEM study (NCT00461747) were analyzed. Propensity scores were estimated using logistic regression, and nearest‐neighbor matching procedure was used. Outcomes included overall survival (OS), progression‐free survival (PFS), time to progression (TTP), postinduction and posttransplant responses, as well as rate of treatment discontinuation and grade 3/4 peripheral neuropathy. Results VTd‐mod was noninferior to VTd‐label for OS, PFS, TTP, postinduction very good partial response or better (≥VGPR) and overall response rate (ORR). VTd‐mod was significantly better for posttransplant ≥VGPR and ORR versus VTd‐label. VTd‐mod safety was not superior to VTd‐label despite the lower thalidomide dose. D‐VTd was significantly better than VTd‐label for OS, PFS, TTP, postinduction and posttransplant ≥VGPR and ORR, and was noninferior to VTd‐label for safety outcomes. Conclusions In transplant‐eligible patients with NDMM, D‐VTd had superior efficacy compared with VTd‐label. Despite a lower dose of thalidomide, VTd‐mod was noninferior to VTd‐label for safety and was significantly better for posttransplant ≥VGPR/ORR. These data further support the first‐line use of daratumumab plus VTd