Treating Benign Ovarian Lesions in the Pediatric Population: A Single Institution's Retrospective Investigation of Laparoscopy Versus Open Repair.

Background: Benign ovarian lesions in the pediatric population have variable risk of recurrence or development of metachronous lesions, leading to variations in operative approach. Our study compares outcomes with differing surgical approaches to better elucidate risk of recurrent or metachronous lesions, time to development of these lesions, and hospital length of stay to determine if one operative approach has superior outcomes. Methods: We retrospectively examined data from Indiana University Health facilities from 2002 to 2020. Patients ≤18 years old who underwent surgical management of a benign ovarian lesion were included. Patients were categorized as undergoing oophorectomy versus ovarian sparing surgery (OSS), with open and laparoscopic approaches. Significance was defined as P < .05. Results: We identified 127 patients who underwent an open (n = 65) versus laparoscopic (n = 55) surgical approach. Patients undergoing open surgery had a greater mean size of lesion (P = .05) and longer length of stay (P < .01). Complication rates (P = .1), rates of developing a metachronous or recurrent lesion postoperatively (P = .47), and time to formation of additional lesions were similar between groups (P = .25). The incidence of identifying an additional lesion after surgery was 14.2% (n = 18) in the mean time of 29.5 ± 31.6 months [SEM 7.5]. Risk of developing a metachronous lesion was similar regardless of the operative approach. Surgery for recurrent ovarian lesions was rare and occurred in only 1 case. Conclusions: Laparoscopic surgery was performed for smaller lesions and was associated with a shorter length of hospital stay. Laparoscopic and OSS was found to have no increased risk of developing metachronous lesions nor increased reoperative risk compared with traditional open and oophorectomy techniques.

Easing the Entry of Qualified International Medical Graduates to U.S. Medical Practice.

ABSTRACT: Almost one quarter of physicians and physicians-in-training in the United States are international medical graduates (IMGs), meaning they have graduated from a medical school not accredited in the United States. Some IMGs are U.S. citizens and others are foreign nationals. IMGs, many of whom have years of training and experience gained in their countries of origin, have long contributed to the U.S. health care system, especially by providing care to populations that have been historically underserved. Additionally, many IMGs contribute to the diversity of the health care workforce, which can enhance the health of the population. The diversity of the United States is increasing, and racial and ethnic concordance between a physician and a patient has been linked to improved health outcomes.IMGs must meet national- and state-level licensing and credentialing standards like any other U.S. physician. This assures the ongoing quality of the care provided by the medical workforce and protects the public. However, at the state level, variation in standards and standards that may be more challenging to meet than those for U.S. medical school graduates may hamper IMGs' contributions. IMGs who are not U.S. citizens also face visa and immigration barriers.In this article, the authors present insights gleaned from Minnesota's model IMG integration program as well as changes made in 2 states in response to the COVID-19 pandemic. Improving and streamlining processes for IMGs to be licensed and credentialed as well as the policies governing visas and immigration, where appropriate, can ensure that IMGs will be willing and able to continue to practice when and where they are needed. This, in turn, could increase the contribution of IMGs to addressing health care inequities, improving health care access through service in federally designated Health Professional Shortage Areas, and reducing the impact of potential physician shortages.

Maintaining Community During Disruption: Lessons From the Accelerating Change in Medical Education Consortium.

ABSTRACT: When the COVID-19 pandemic emerged early in 2020, the American Medical Association's (AMA) Accelerating Change in Medical Education Consortium focused on maintaining its community of 37 medical schools and 11 graduate medical education projects along with the core substance of its work. The initial response was to cancel events and reduce the workload of consortium members, but it quickly became clear that the consortium needed additional strategies. The constituents needed resources, support, and community. The authors, along with the rest of the AMA team, learned to maximize the benefits and minimize the drawbacks of operating virtually. These insights supported the continuation, and even expansion, of the consortium's innovations despite extremely stressful circumstances. In this Scholarly Perspective, the authors outline the actions that they and the AMA team took in 2020 and 2021 at the beginning of the pandemic and as that crisis progressed and was further intensified by the significant distress reflected in the protests after the murder of George Floyd. The goal of these actions was to maintain the consortium's core substance, innovation, momentum, and sense of community. The authors describe lessons learned in 2020 and 2021 via a novel model developed to facilitate ongoing collaboration and respond rapidly to the needs of overwhelmed medical educators. This model is composed of 4 phases: assessing needs, mining experts, convening people, and generating products. This model for leveraging a community of practice can help educators optimize collaboration, whether educators are pursuing innovation in the training of physicians or other health care professionals and whether in times of extreme stress or stability, the model provides a pathway for maintaining community. The prepandemic way of working will not return. Virtual participation and collaboration will remain a part of work and daily life for the foreseeable future and beyond.

Supporting Medical Education Innovation: Evaluation of a Grants Initiative.

PROBLEM: Medical education must evolve to meet the changing needs of patients and communities. Innovation is a critical component of that evolution. As medical educators pursue innovative curricula, assessments, and evaluation techniques, the impact of innovations may be limited by minimal funding. The American Medical Association (AMA) Innovation Grant Program, launched in 2018, seeks to address the gap in funding and stimulate educational innovation and research in medical education. APPROACH: In 2018 and 2019, the Innovation Grant Program targeted innovation in content areas including health systems science, competency-based medical education, coaching, learning environment, and emerging technology. The authors reviewed the content of applications and final reports for the 27 projects completed during the first 2 years of the program. They also noted measures of success (completion of project, achievement of grant objectives, development of transferrable educational product, dissemination). OUTCOMES: In 2018, the AMA received 52 submissions and funded 13 proposals, dispersing $290,000 ($10,000 and $30,000 grants). In 2019, the AMA received 80 submissions and funded 15 proposals, dispersing $345,000. Among the 27 completed grants, 17 (63%) supported innovations related to health systems science. Fifteen (56%) were used to create educational products that could be shared, such as new assessment tools, curricula, and teaching modules. Five grant recipients (29%) published articles and 15 (56%) presented at national conferences. NEXT STEPS: The grant program advanced educational innovations, particularly in health systems science. The next steps will involve examining the long-term outcomes and impact of the completed projects on medical students, patients, and the health system; the professional development of the grantees; and the adoption and dissemination of the innovations.

Veteran Perspectives on Population-Based Suicide Risk Screening in VHA Primary Care: Mixed-Methods Study.

BACKGROUND: In late 2018, VHA implemented a multi-stage suicide risk screening and evaluation initiative, Suicide Risk Identification Strategy, or "Risk ID," in primary care settings. OBJECTIVE: The main objective of this study was to characterize VHA primary care patient perspectives regarding population-based suicide risk screening through the Risk ID program. DESIGN: Mixed methods; survey and qualitative interviews. PARTICIPANTS: Veterans screened for suicide risk using Risk ID in primary care (n = 868) participated in a survey of veteran attitudes about screening (45% response rate); thirty additionally participated in follow-up qualitative interviews. MAIN MEASURES: The quantitative survey consisted of three questions on attitudes about screening for suicidal thoughts in primary care. In qualitative interviews, veterans were asked about their experiences with the Risk ID processes and recommendations for improving Risk ID. KEY RESULTS: Over 90% of veterans reported that it is appropriate for primary care providers or nurses/medical assistants to ask veterans about thoughts of suicide during primary care visits. Approximately half of veterans indicated that veterans should be asked about suicidal thoughts at every visit. Qualitative findings revealed that while most veterans were generally supportive and appreciated VHA screening for suicidal thoughts, they also expressed concern for the potential for inadvertent harm. Participants expressed conflicting preferences for how screening should be handled and delivered. CONCLUSIONS: Findings suggest that most veterans support the integration of standardized suicide risk assessment into routine primary care visits. However, findings also suggest that population-based suicide risk assessment should further consider patient experiences and preferences. Specifically, additional guidance or training for staff conducting suicide risk screening may be warranted to ensure patients feel heard (e.g., eye contact, expressing empathy) and increase patient understanding of the purpose of the screening and potential outcomes. These patient-centered approaches may improve patient experience and facilitate disclosure of suicidal thoughts.

Primary Care and Mental Health Staff Perspectives on Universal Suicide Risk Screening and Care Coordination.

Little is known about staff or patient perspectives on suicide risk screening programs. The objectives of this study were to characterize Veterans Health Administration (VHA) primary care and mental health staff perspectives regarding the VHA Suicide Risk Identification Strategy screening and assessment program and to describe coordination of suicide prevention-related care following positive screening results. Qualitative interviews were conducted with 40 primary care and mental health staff at 12 VHA facilities. An inductive-deductive hybrid approach was used to conduct a thematic analysis. Several key themes were identified. Primary care and mental health staff participants accepted having a structured process for screening for suicidal ideation and conducting risk assessments, but both groups noted limitations and challenges with initial assessment and care coordination following screening. Mental health staff reported more concerns than primary care staff about negative impacts of the screening and assessment process on treatment. Both groups felt that better training was needed for primary care staff to effectively discuss and evaluate suicide risk. The results suggested that additional modifications of the screening and assessment process are needed for patients already known to have elevated risk of suicide or chronic suicidal ideation.

Beyond Training the Next Generation of Physicians: The Unmeasured Value Added by Residents to Teaching Hospitals and Communities.

Following medical school, most newly graduated physicians enter residency training. This period of graduate medical education (GME) is critical to creating a physician workforce with the specialized skills needed to care for the population. Completing GME training is also a requirement for obtaining medical licensure in all 50 states. Yet, crucial federal and state funding for GME is capped, creating a bottleneck in training an adequate physician workforce to meet future patient care needs. Thus, additional GME funding is needed to train more physicians. When considering this additional GME funding, it is imperative to take into account not only the future physician workforce but also the value added by residents to teaching hospitals and communities during their training. Residents positively affect patient care and health care delivery, providing intrinsic and often unmeasured value to patients, the hospital, the local community, the research enterprise, and undergraduate medical education. This added value is often overlooked in decisions regarding GME funding allocation. In this article, the authors underscore the value provided by residents to their training institutions and communities, with a focus on current and recent events, including the global COVID-19 pandemic and teaching hospital closures.

The Interaction of Obesity and Reproductive Function in Adolescents.

Obesity is increasing worldwide, including in pediatrics. Adequate nutrition is required for initiation of menses, and there is a clear secular trend toward earlier pubertal onset and menarche in females in countries around the globe. Similar findings of earlier pubertal start are suggested in males. However, as individuals and populations have crossed into over-nutritional states including overweight and obesity, the effect of excess weight on disrupting reproductive function has become apparent. Hypothalamic hypogonadism and polycystic ovary syndrome are two conditions where reproductive function appears to directly relate to excess weight. Clinical findings in individuals with certain polygenic and monogenic obesity syndromes, which also have reproductive disruptions, have helped elucidate neurologic pathways that are common to both. Clinical endocrinopathies such as hypothyroidism or panhypopituitarism also aide in the understanding of the role of the endocrine system in weight gain. Understanding the intersection of obesity and reproductive function may lead to future therapies which can treat both conditions.

Fertility Counseling Practices for Patients with Turner Syndrome in Pediatric Endocrine Clinics: Results of a Pediatric Endocrine Society Survey.

INTRODUCTION: Turner syndrome (TS) is associated with a high risk of primary ovarian insufficiency. Current guidelines recommend early fertility counseling for affected youth and their families. This study assessed clinical providers' (MD, NP, or PA) fertility counseling practices for girls with TS. METHODS: TS providers were invited to complete a survey via the Pediatric Endocrine Society listserv. Descriptive statistics summarized variables of interest. Correlations were used to identify associations between barriers/practice characteristics and fertility preservation (FP) referral. Thematic analysis was used to examine qualitative responses. RESULTS: 119 providers completed the survey. Seventy percent reported discussing fertility implications of TS routinely in pediatric care. Fifty-six percent reported often or always referring patients with spontaneous menarche to FP specialists, whereas only 19% reported often or always referring their patients without spontaneous menarche (p < 0.001). Barriers associated with FP referral frequency included unfamiliarity with FP options, belief that FP is not a possible goal for their patients, and absence of a local reproductive endocrinologist. Qualitatively, four referral barrier themes were identified: (1) questionable utility of referral, (2) lack of perceived interest among patients/families, (3) provider barriers (e.g., lack of knowledge), (4) logistical/structural barriers to accessing fertility-related care. DISCUSSION/CONCLUSION: Pediatric endocrinology providers report inconsistently discussing fertility implications of TS. The frequency of referral to an FP specialist and factors/barriers affecting the decision to refer remain variable. Future research should focus on expanding provider education, addressing barriers to high-quality fertility counseling and referral for patients with TS, and investigating FP outcomes in TS.

Development and Preliminary Evaluation of an Education Program for Primary Care Teams on Discussing Firearms Storage Safety with Veterans.

BACKGROUND: Reducing access to lethal means is one of the few empirically supported approaches for lowering suicide rates, and safe firearms storage practices have been associated with reduced risk of death by suicide. Although there is substantial opportunity for primary care to assist in addressing lethal means with veterans, approaches to intervention and educating staff are not well documented. We sought to 1) describe development of an education program for primary care teams to help them discuss firearms storage safety (FSS) with veterans during primary care visits; and 2) conduct a preliminary evaluation of the pilot education program. METHODS: We used an iterative process involving veterans and primary care staff stakeholders to develop program content, format, and supplemental materials. A grounded theory approach was used to analyze data from focus groups and individual interviews. Following piloting of the program with 71 staff members in two primary care clinics, we analyzed pre- and post-training participant surveys of program satisfaction and attitudes comfort related to firearms safety discussions. RESULTS: During the development phase, 68 veterans and 107 staff members participated in four veteran focus groups and four primary care focus groups, respectively, and/or individual interviews. The program that was developed, "'Just in Case': Discussing means safety with veterans at elevated risk for suicide," addresses knowledge and skills learning objectives, and includes video demonstrations and skills practice. Survey data obtained just prior to the pilot training sessions showed low self-reported rates of discussing firearms safety with veterans who may be at elevated risk for suicide. Immediate post-training data showed generally high satisfaction with the program and significant improvements in participant self-reported ratings of the importance of, and comfort with FSS. CONCLUSIONS: This interactive knowledge and skill-based means safety curriculum shows promise as a means for educating primary care staff to deliver messaging about firearms safety to veterans. Additional research is needed to refine and evaluate impacts of this or similar training programs on clinician and veteran behaviors over time.

Veterans Health Administration staff experiences with suicidal ideation screening and risk assessment in the context of COVID-19.

Universal screening for suicidal ideation in primary care and mental health settings has become a key prevention tool in many healthcare systems, including the Veterans Healthcare Administration (VHA). In response to the coronavirus pandemic, healthcare providers faced a number of challenges, including how to quickly adapt screening practices. The objective of this analyses was to learn staff perspectives on how the pandemic impacted suicide risk screening in primary care and mental health settings. Forty semi-structured interviews were conducted with primary care and mental health staff between April-September 2020 across 12 VHA facilities. A multi-disciplinary team employed a qualitative thematic analysis using a hybrid inductive/deductive approach. Staff reported multiple concerns for patients during the crisis, especially regarding vulnerable populations at risk for social isolation. Lack of clear protocols at some sites on how to serve patients screening positive for suicidal ideation created confusion for staff and led some sites to temporarily stop screening. Sites had varying degrees of adaptability to virtual based care, with the biggest challenge being completion of warm hand-offs to mental health specialists. Unanticipated opportunities that emerged during this time included increased ability of patients and staff to conduct virtual care, which is expected to continue benefit post-pandemic.

Triple Challenge: How Medical Students May Solve 3 Long-Standing Problems Bedeviling Health Systems and Medical Education.

Medical education and the health system must address challenges that, despite significant effort, seem unsolvable. Health systems science (HSS)-the fundamental understanding of how care is delivered, how health professionals work together to deliver that care, and how the health system can improve patient care and health care delivery-is increasingly being recognized as a potential source of solutions to these challenges. In this article, the authors review the 43 abstracts submitted to the American Medical Association Accelerating Change in Medical Education 2018 Health Systems Science Student Impact Competition that aligned with the goals of HSS. Their qualitative review identified 3 long-standing problems in medicine and medical education that were frequently addressed by the submissions: improving care for those with mental illness (5 submissions), improving diversity in medicine (4 submissions), and improving teamwork and interprofessional education (4 submissions). The authors extracted lessons learned from these abstracts. Many of the projects detailed in this article continue to make an impact at multiple levels. While not all projects were scientifically rigorous enough to be published on their own and the quality of the data presented in the abstracts varied widely, many provide innovative ideas for potentially solving long-standing problems that may have been overlooked or not considered sufficiently. These projects and their subsequent analysis demonstrate that not only do medical students make significant impacts on the health system, patients, and other health professionals when equipped with HSS skills, working in health care teams, and advised by mentors, but they also may be able to address some of medicine's and medical education's long-standing challenges. The fresh perspective and high energy of medical students are valuable and should be nurtured and encouraged.

Veterans Are Agreeable to Discussions About Firearms Safety in Primary Care.

BACKGROUND: Discussing safe storage of firearms, including access, during times of crisis with veterans in primary care settings may enhance suicide prevention efforts. However, veteran attitudes toward such discussions are not well understood. The goal of this study is to understand the perspectives of veterans on discussing firearms storage safety with staff during primary care visits. METHODS: Individual semistructured interviews with veterans were conducted by telephone, qualitatively coded, and analyzed for themes. The sample was composed of veterans (n = 27) who had positive depression or post-traumatic stress disorder screens and who received care from Veterans Health Administration primary care team members trained to discuss firearms storage safety with patients. RESULTS: Citing the urgent need to prevent veteran suicide, most veterans felt discussing firearms safety was acceptable and needed, even if discussions felt uncomfortable or they had concerns. Veterans identified the need for providers to be transparent in their purposes for asking about firearms and to respect veterans' unique relationships with firearms. DISCUSSION: Conducting firearms safety discussions in a primary care setting with veterans who are at elevated risk for suicide is acceptable to veterans when a respectful, veteran-centered, and transparent approach is used.

The Accelerating Change in Medical Education Consortium: Key Drivers of Transformative Change.

The American Medical Association's (AMA's) Accelerating Change in Medical Education (ACE) initiative, launched in 2013 to foster advancements in undergraduate medical education, has led to the development and scaling of innovations influencing the full continuum of medical training. Initial grants of $1 million were awarded to 11 U.S. medical schools, with 21 schools joining the consortium in 2016 at a lower funding level. Almost one-fifth of all U.S. MD- and DO-granting medical schools are represented in the 32-member consortium. In the first 5 years, the consortium medical schools have delivered innovative educational experiences to approximately 19,000 medical students, who will provide a potential 33 million patient care visits annually. The core initiative objectives focus on competency-based approaches to medical education and individualized pathways for students, training in health systems science, and enhancing the learning environment. At the close of the initial 5-year grant period, AMA leadership sought to catalogue outputs and understand how the structure of the consortium may have influenced its outcomes. Themes from qualitative analysis of stakeholder interviews as well as other sources of evidence aligned with the 4 elements of the transformational leadership model (inspirational motivation, intellectual stimulation, individualized consideration, and idealized influence) and can be used to inform future innovation interventions. For example, the ACE initiative has been successful in stimulating change at the consortium schools and propagating those innovations broadly, with outputs involving medical students, faculty, medical schools, affiliated health systems, and the broader educational landscape. In summary, the ACE initiative has fostered a far-reaching community of innovation that will continue to drive change across the continuum of medical education.

Adaptive weighting of taste and odor cues during flavor choice.

Colloquially referred to as "taste," flavor is in reality a thoroughly multisensory experience. Yet, a mechanistic understanding of the multisensory computations underlying flavor perception and food choice is lacking. Here, we used a multisensory flavor choice task in rats to test specific predictions of the statistically optimal integration framework, which has previously yielded much insight into cue integration in other multisensory systems. Our results confirm three key predictions of this framework in the unique context of flavor choice behavior, providing novel mechanistic insight into multisensory flavor processing.NEW & NOTEWORTHY The authors demonstrate that rats make choices about which flavor solution (i.e., taste-odor mixture) to consume by weighting the individual taste and odor components according to the reliability of the information they provide about which solution is the preferred one. A similar weighting operation underlies multisensory cue combination in other domains and offers novel insight into the computations underlying multisensory flavor perception and food choice behavior.

Ensuring the Availability of Clinical Clerkships at U.S. Hospitals: A Tale of 2 States.

U.S. medical schools are facing growing competition for limited clinical training resources, notably slots for the core clerkships that students most often complete in the third year of their undergraduate medical education. In particular, medical schools in the Caribbean (often referred to as offshore medical schools) are buying clerkship slots at U.S. hospitals for their students, most of whom will be U.S. citizen international medical graduates. For hospitals, especially those that are financially stressed, these payments are an attractive source of revenue. Yet, this practice has put pressure on U.S. medical schools to provide similar remuneration for clerkship slots for their students or to find new clinical training sites.In this Perspective, the authors outline the scope of the challenge facing U.S. medical schools and the U.S. medical education system. They outline legislative strategies implemented in 2 states (New York and Texas) to address this issue and propose the passage of similar legislation in other states to ensure that students at U.S. medical schools can access the clerkships they need to obtain the requisite clinical experience before entering residency. Such legislation would preserve the availability of clerkships for U.S. medical students and the educational quality of these clinical training experiences and, therefore, preserve the quantity and quality of the future physician workforce in the United States.

Multisensory interactions underlying flavor consumption in rats: the role of experience and unisensory component liking.

The mechanisms by which taste and odor are combined in determining food choice behavior are poorly understood. Previous work in human subjects has yielded mixed results, potentially due to differences in task context across studies, and a lack of control over flavor experience. Here, we used rats as a model system to systematically investigate the role of experience and unisensory component liking in the multisensory interactions underlying consumption behavior. We demonstrate that taste-smell mixture consumption is best explained by a linear average of component liking. The observed pattern of results was not dependent on prior experience with specific taste-smell combinations, and unique for multisensory as opposed to unisensory mixture consumption. The results are discussed with respect to existing models of flavor integration, and a maximum-likelihood integration model previously described for multisensory judgments in other systems.

The American Medical Association Medical Education Innovation Challenge: Incorporating the Student Voice Into Medical Education Transformation.

PROBLEM: Medical education needs to evolve to continue producing physicians who are able to meet the needs of diverse patient populations. Students can be a unique source of ideas about medical education transformation. APPROACH: In the fall of 2015, the authors created the American Medical Association Medical Education Innovation Challenge, an incentive-based competition for teams of two to four students. The challenge called for teams to "turn medical education on its head" by proposing a change to some aspect of medical education that would better prepare students to meet the health care needs of the future. OUTCOMES: Teams submitted 154 proposals. Themes from the winning teams and those that received an honorable mention included innovative uses of technology, creating physical spaces to pursue solutions to health care problems, wellness education, and longitudinal learning experiences around health equity and advocacy. The authors invited all teams to submit an abstract of their proposal to be published in an abstract book. The four winning teams and the 24 teams that received an honorable mention and submitted an abstract were surveyed to assess the impact of the challenge. Fifteen teams (54%) responded. Ten of those teams (67%) were implementing their idea or a related innovation to some degree. NEXT STEPS: The American Medical Association continues to run a wide variety of innovation challenges (e.g., Healthier Nation Innovation Challenge, Health Care Interoperability & Innovation Challenge) that draw in diverse stakeholders to solve problems in medical education and the health care system more broadly.

Barriers to Medical Students' Electronic Health Record Access Can Impede Their Preparedness for Practice.

Medical students need hands-on experience documenting clinical encounters as well as entering orders to prepare for residency and become competent physicians. In the era of paper medical records, students consistently acquired experience writing notes and entering orders as part of their clinical experience. Over the past decade, however, patient records have transitioned from paper to electronic form. This change has had the unintended consequence of limiting medical students' access to patient records. This restriction has meant that many students leave medical school without the appropriate medical record skills for transitioning to residency.In this article, the authors explore medical students' current access to electronic health records (EHRs) as well as policy proposals from medical societies, innovative models implemented at some U.S. medical schools, and other possible solutions to ensure that students have sufficient experiential learning opportunities with EHRs in clinical settings. They also contend that competence in the use of EHRs is necessary for students to become physicians who can harness the full potential of these tools rather than physicians for whom EHRs hinder excellent patient care. Finally, the authors argue that meaningful experiences using EHRs should be consistently incorporated into medical school curricula and that EHR-related skills should be rigorously assessed with other clinical skills.

Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ release.

OBJECTIVE: Caffeine reduces toxic Ca2+ signals in pancreatic acinar cells via inhibition of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated signalling, but effects of other xanthines have not been evaluated, nor effects of xanthines on experimental acute pancreatitis (AP). We have determined effects of caffeine and its xanthine metabolites on pancreatic acinar IP3R-mediated Ca2+ signalling and experimental AP. DESIGN: Isolated pancreatic acinar cells were exposed to secretagogues, uncaged IP3 or toxins that induce AP and effects of xanthines, non-xanthine phosphodiesterase (PDE) inhibitors and cyclic adenosine monophosphate and cyclic guanosine monophosphate (cAMP/cGMP) determined. The intracellular cytosolic calcium concentration ([Ca2+]C), mitochondrial depolarisation and necrosis were assessed by confocal microscopy. Effects of xanthines were evaluated in caerulein-induced AP (CER-AP), taurolithocholic acid 3-sulfate-induced AP (TLCS-AP) or palmitoleic acid plus ethanol-induced AP (fatty acid ethyl ester AP (FAEE-AP)). Serum xanthines were measured by liquid chromatography-mass spectrometry. RESULTS: Caffeine, dimethylxanthines and non-xanthine PDE inhibitors blocked IP3-mediated Ca2+ oscillations, while monomethylxanthines had little effect. Caffeine and dimethylxanthines inhibited uncaged IP3-induced Ca2+ rises, toxin-induced Ca2+ release, mitochondrial depolarisation and necrotic cell death pathway activation; cAMP/cGMP did not inhibit toxin-induced Ca2+ rises. Caffeine significantly ameliorated CER-AP with most effect at 25 mg/kg (seven injections hourly); paraxanthine or theophylline did not. Caffeine at 25 mg/kg significantly ameliorated TLCS-AP and FAEE-AP. Mean total serum levels of dimethylxanthines and trimethylxanthines peaked at >2 mM with 25 mg/kg caffeine but at <100 µM with 25 mg/kg paraxanthine or theophylline. CONCLUSIONS: Caffeine and its dimethylxanthine metabolites reduced pathological IP3R-mediated pancreatic acinar Ca2+ signals but only caffeine ameliorated experimental AP. Caffeine is a suitable starting point for medicinal chemistry.