Approaches to Measuring Beta Cell Reserve and Defining Partial Clinical Remission in Paediatric Type 1 Diabetes.

CONTEXT: Type 1 diabetes (T1D) results from the autoimmune T-cell mediated destruction of pancreatic beta cells leading to insufficient insulin secretion. At the time of diagnosis of T1D, there is residual beta cell function that declines over the subsequent months to years. Recent interventions have been approved to preserve beta cell function in evolving T1D. OBJECTIVE: The aim of this review is to summarise the approaches used to assess residual beta cell function in evolving T1D, and to highlight potential future directions. METHODS: Studies including subjects aged 0 to 18 years were included in this review. The following search terms were used; "(type 1 diabetes) and (partial remission)" and "(type 1 diabetes) and (honeymoon)". References of included studies were reviewed to determine if additional relevant studies were eligible. RESULTS: There are numerous approaches to quantifying beta cell reserve in evolving T1D. These include c-peptide measurement after a mixed meal or glucagon stimuli, fasting c-peptide, the urinary c-peptide/creatinine ratio, insulin dose-adjusted haemoglobin A1c, and other clinical models to estimate beta cell function. Other biomarkers may have a role, including the proinsulin/c-peptide ratio, cytokines, and microRNA. Studies using thresholds to determine if residual beta cell function is present often differ in values used to define remission. CONCLUSIONS: As interventions are approved to preserve beta cell function, it will become increasingly necessary to quantify residual beta cell function in research and clinical contexts. In this report, we have highlighted the strengths and limitations of the current approaches.

The lived experience of positive airway pressure therapy in patients with obstructive sleep apnea across the lifespan: a qualitative study.

STUDY OBJECTIVES: Although treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) therapy is effective, adherence is often poor. Understanding the patient perspective is needed to inform adherence-promoting interventions. This qualitative study assessed the experiences, preferences, facilitators, and barriers surrounding PAP therapy for the management of OSA in patients from adolescence to older adulthood. METHODS: Eligible participants ages 19 and older were identified from administrative health care claims; adolescent participants ages 12-18 and their parents/caregivers were identified via electronic health records of a tertiary sleep specialty clinic at a large children's hospital. Forty English-speaking patients and 10 parents of adolescents diagnosed with OSA and prescribed PAP therapy completed semistructured 60-minute telephone interviews conducted by a trained facilitator. Common themes and illustrative quotes were identified. RESULTS: Themes around OSA diagnosis, initiating OSA treatment, learning about OSA/PAP, decision to start PAP, PAP benefits and challenges, and reasons for nonadherence were identified. Participants suggested design and delivery changes to improve PAP devices. Issues unique to adolescents and their parents were discussed. CONCLUSIONS: The unique perspectives of patients regarding PAP therapy should be taken into consideration when developing interventions to increase PAP adherence and improve clinical care. Based on identified themes, opportunities for intervention may exist at all stages of care, from diagnosis to treatment initiation. Involving partners, parents, and other caregivers in PAP therapy may be beneficial for optimizing adherence. CITATION: Simon SL, Stephenson JJ, Haynes K, et al. The lived experience of positive airway pressure therapy in patients with obstructive sleep apnea across the lifespan: a qualitative study. J Clin Sleep Med. 2024;20(3):407-416.

Microbiome Transfer Partly Overrides Lack of IL-1RI Signaling to Alter Hepatic but not Adipose Tissue Phenotype and Lipid Handling following a High-Fat Diet Challenge.

SCOPE: IL-1RI-mediated inflammatory signaling alters metabolic tissue responses to dietary challenges (e.g., high-fat diet [HFD]). Recent work suggests that metabolic phenotype is transferrable between mice in a shared living environment (i.e., co-housing) due to gut microbiome exchange. The authors examine whether the metabolic phenotype of IL-1RI-/- mice fed HFD or low-fat diet (LFD) could be transferred to wild-type (WT) mice through gut microbiome exchange facilitated by co-housing. METHODS AND RESULTS: Male WT (C57BL/J6) and IL-1RI-/- mice are fed HFD (45% kcal) or LFD (10% kcal) for 24 weeks and housed i) by genotype (single-housed) or ii) with members of the other genotype in a shared microbial environment (co-housed). The IL-1RI-/-  gut microbiome is dominant to WT, meaning that co-housed WT mice adopted the IL-1RI-/- microbiota profile. This is concomitant with greater body weight, hepatic lipid accumulation, adipocyte hypertrophy, and hyperinsulinemia in co-housed WT mice, compared to single-housed counterparts. These effects are most evident following HFD. Primary features of microbiome differences are Lachnospiraceae and Ruminococcaceae (known producers of SCFA). CONCLUSION: Transfer of SCFA-producing microbiota from IL-1RI-/- mice highlights a new connection between diet, inflammatory signaling, and the gut microbiome, an association that is dependent on the nature of the dietary fat challenge.

Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline.

PURPOSE: To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes. METHODS: The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process. RESULTS: Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria. RECOMMENDATIONS: Patients with newly diagnosed BC and BRCA1/2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1/2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.

Role of health plan administrative claims data in participant recruitment for pragmatic clinical trials: An Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE) example.

AIM: The purpose of this study is to evaluate HealthCore/Anthem Research Network recruitment strategies, compare response and enrollment rates for different recruitment strategies, and describe demographic and clinical characteristics of responders and enrollees. METHODS: HealthCore/Anthem Research Network, a part of the Health Plan Research Network of the Patient-Centered Clinical Data Research Network, used administrative claims data to identify eligible health plan members for potential participation in the Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness study. We approached health plan members, identified with a validated Patient-Centered Clinical Data Research Network common data model computable phenotype, and their clinical providers during November 2017 to August 2018. Providers were offered the option to exclude their patients' participation in Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness prior to our direct patient (member) outreach. Member identification was in two phases: Phase 1: 1 January 2006 to 1 April 2017, and Phase 2: 1 January 2006 to 2 February 2018. Phase 1 consisted of two batches of mail and one phone call per patient. In Phase 2, which included two similar batches of patients, outreach was via either mail or brochure and one phone call. RESULTS: Phase 1 and Phase 2 included 133,373 and 51,777 members, respectively. We engaged 28,593 providers in Phase 1, and 5077 in Phase 2. In Phase 1, 264,158 mixed email/mail messages were delivered to 133,373 members, followed by 90,481 phone calls from November 2017 to February 2018. In Phase 2, after simple randomization to letter or brochure, 51,777 members were sent email/mail or mailed brochure in three waves from May 2018 to July 2018. In this 9-week period, 51,623 communications were sent to 25,914 members in the email/mail group, and 50,160 brochures to 25,863 in the brochure group. Following email/mail or mailed brochure outreach, 16,624 and 16,580 calls were made to the groups, respectively. Overall, 1549 health plan members visited the study portal by 1 September 2018; 355 electronically signed the Informed Consent Form and enrolled. Mailed brochures drove more portal visits in Phase 2, but a lower percentage of responders enrolled. Recruitment was better in Phase 2-2.3 enrollees per 1000 outreach members versus 1.8 in Phase 1. CONCLUSION: This study showed the ability of a health plan within Patient-Centered Clinical Data Research Network to identify potential study participants with administrative claims, and use different outreach methods to facilitate recruitment and enrollment for pragmatic clinical trials.

Improving medication adherence in adult kidney transplantation (IMAKT): A pilot randomised controlled trial.

Resources to support long-term medication adherence in kidney transplantation are limited. This study aimed to determine the efficacy of an intervention designed for kidney transplant recipients to enhance medication adherence. A single-blind, multi-site, 12-month pilot randomised controlled trial was conducted at all five public hospitals providing adult kidney transplantation in Victoria, Australia. Participants were recruited at 4 to 6 weeks post-transplantation. Thirty-five participants were randomly assigned to a 3-month intervention, involving a face-to-face meeting (a medication review and a consumer-centred video) and health coaching every two weeks. Thirty-six were randomised to receive usual care. All participants were followed for nine months post-intervention. There were no differences in adherence between groups measured by Medication Event Monitoring System (MEMS), however, it was underutilised by 42% of participants. Based on the self-reported Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS©) score, the percentage of adherent participants decreased significantly between baseline and 3 to 12 months in the control group (p-values < 0.001) whilst the percentage of adherent participants in the intervention group remained constant over time. No group differences were detected in other outcomes. Due to the complex medication regimen, developing and testing a medication adherence intervention is difficult in kidney transplantation.

Fatty Acids and NLRP3 Inflammasome-Mediated Inflammation in Metabolic Tissues.

Worldwide obesity rates have reached epidemic proportions and significantly contribute to the growing prevalence of metabolic diseases. Chronic low-grade inflammation, a hallmark of obesity, involves immune cell infiltration into expanding adipose tissue. In turn, obesity-associated inflammation can lead to complications in other metabolic tissues (e.g., liver, skeletal muscle, pancreas) through lipotoxicity and inflammatory signaling networks. Importantly, although numerous signaling pathways are known to integrate metabolic and inflammatory processes, the nucleotide-binding and oligomerization domain-like receptor, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome is now noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome can be influenced by various metabolites, including fatty acids. Specifically, although saturated fatty acids may promote NLRP3 inflammasome activation, monounsaturated fatty acids and polyunsaturated fatty acids have recently been shown to impede NLRP3 activity. Therefore, the NLRP3 inflammasome and associated metabolic inflammation have key roles in the relationships among fatty acids, metabolites, and metabolic disease. This review focuses on the ability of fatty acids to influence inflammation and the NLRP3 inflammasome across numerous metabolic tissues in the body. In addition, we explore some perspectives for the future, wherein recent work in the immunology field clearly demonstrates that metabolic reprogramming defines immune cell functionality. Although there is a paucity of information about how diet and fatty acids modulate this process, it is possible that this will open up a new avenue of research relating to nutrient-sensitive metabolic inflammation.

Metabolic Inflammation-Differential Modulation by Dietary Constituents.

Obesity arises from a sustained positive energy balance which triggers a pro-inflammatory response, a key contributor to metabolic diseases such as T2D. Recent studies, focused on the emerging area of metabolic-inflammation, highlight that specific metabolites can modulate the functional nature and inflammatory phenotype of immune cells. In obesity, expanding adipose tissue attracts immune cells, creating an inflammatory environment within this fatty acid storage organ. Resident immune cells undergo both a pro-inflammatory and metabolic switch in their function. Inflammatory mediators, such as TNF-α and IL-1ß, are induced by saturated fatty acids and disrupt insulin signaling. Conversely, monounsaturated and polyunsaturated fatty acids do not interrupt metabolism and inflammation to the same extent. AMPK links inflammation, metabolism and T2D, with roles to play in all and is influenced negatively by obesity. Lipid spillover results in hepatic lipotoxicity and steatosis. Also in skeletal muscle, excessive FFA can impede insulin's action and promote inflammation. Ectopic fat can also affect pancreatic ß-cell function, thereby contributing to insulin resistance. Therapeutics, lifestyle changes, supplements and dietary manipulation are all possible avenues to combat metabolic inflammation and the subsequent insulin resistant state which will be explored in the current review.

Examining the preparation and ongoing support of adults to take their medications as prescribed in kidney transplantation.

RATIONALE, AIMS AND OBJECTIVES: The shortage of kidney donors and benefits of kidney transplantation make graft success imperative. Medication adherence is critical to prevent the risk of graft rejection. This paper examines how adults are prepared and supported by renal transplant co-ordinators and pharmacists to take their medications as prescribed in kidney transplantation. METHODS: Renal transplant co-ordinators and pharmacists of all five hospitals offering adult kidney transplantation in Victoria, Australia, were interviewed between November 2013 and February 2014. All data underwent qualitative descriptive analysis. RESULTS: Nine renal transplant co-ordinators and six pharmacists were interviewed. Although there was no standardized approach to education or other evidence-based strategies to facilitate medication adherence, there were similarities between sites. These similarities included printed information, pre-transplant education sessions, the use of medication lists and medication administration aids, intensive education in hospital and ensuring an adequate supply of medications post-discharge. CONCLUSIONS: Renal transplant co-ordinators and pharmacists recognized the importance of early patient education concerning immunosuppressant medication. However, each site had developed their own way of preparing a patient for kidney transplantation and follow-up in the acute hospital setting based on experience and practice. Other non-educational strategies involving behavioural and emotional aspects were less common. Differences in usual care reinforce the necessity for evidence-based health care for best patient outcomes.

The role of CCAAT enhancer-binding protein homologous protein in human immunodeficiency virus protease-inhibitor-induced hepatic lipotoxicity in mice.

UNLABELLED: Human immunodeficiency virus (HIV) protease inhibitors (HIV PIs) are the core components of highly active antiretroviral therapy, which has been successfully used in the treatment of HIV-1 infection in the past two decades. However, benefits of HIV PIs are compromised by clinically important adverse effects, such as dyslipidemia, insulin resistance, and cardiovascular complications. We have previously shown that activation of endoplasmic reticulum (ER) stress plays a critical role in HIV PI-induced dys-regulation of hepatic lipid metabolism. HIV PI-induced hepatic lipotoxicity is closely linked to the up-regulation of CCAAT enhancer binding protein homologous protein (CHOP) in hepatocytes. To further investigate whether CHOP is responsible for HIV PI-induced hepatic lipotoxicity, C57BL/6J wild-type (WT) or CHOP knockout (CHOP(-/-) ) mice or the corresponding primary mouse hepatocytes were used in this study. Both in vitro and in vivo studies indicated that HIV PIs (ritonavir and lopinavir) significantly increased hepatic lipid accumulation in WT mice. In contrast, CHOP(-/-) mice showed a significant reduction in hepatic triglyceride accumulation and liver injury, as evidenced by hematoxylin and eosin and Oil Red O staining. Real-time reverse-transcriptase polymerase chain reaction and immunoblotting data showed that in the absence of CHOP, HIV PI-induced expression of stress-related proteins and lipogenic genes were dramatically reduced. Furthermore, tumor necrosis factor alpha and interleukin-6 levels in serum and liver were significantly lower in HIV PI-treated CHOP(-/-) mice, compared to HIV PI-treated WT mice. CONCLUSION: Taken together, these data suggest that CHOP is an important molecular link of ER stress, inflammation, and hepatic lipotoxicity, and that increased expression of CHOP represents a critical factor underlying events leading to hepatic injury. (HEPATOLOGY 2013).

Self-assembly of hybrid organic-inorganic polyoxovanadates: functionalised mixed-valent clusters and molecular cages.

Herein we report the intra- and inter-molecular assembly of a {V(5)O(9)} subunit. This mixed-valent structural motif can be stabilised as [V(5)O(9)(L(1-3))(4)](5-/9-) (1-3) by a range of organoarsonate ligands (L(1)-L(3)) whose secondary functionalities influence its packing arrangement within the crystal structures. Variation of the reaction conditions results in the dodecanuclear cage structure [V(12)O(14)(OH)(4)(L(1))(10)](4-) (4) where two modified convex building units are linked via two dimeric {O(4)V(IV)(OH)(2)V(IV)O(4)} moieties. Bi-functional phosphonate ligands, L(4)-L(6) allow the intramolecular connectivity of the {V(5)O(9)} subunit to give hybrid capsules [V(10)O(18)(L(4-6))(4)](10-) (5-7). The dimensions of the electrophilic cavities of the capsular entities are determined by the incorporated ligand type. Mass spectrometry experiments confirm the stability of the complexes in solution. We investigate and model the temperature-dependent magnetic properties of representative complexes 1, 4, 6 and 7 and provide preliminary cell-viability studies of three different cancer cell lines with respect to Na(8)H(2)[6]·36H(2)O and Na(8)H(2)[7]·2DMF·29H(2)O.

Coronary artery bypass graft surgery and cognitive performance.

BACKGROUND: Some studies have indicated a decline in patients' cognitive performance after coronary artery bypass graft surgery. OBJECTIVE: To evaluate cognitive performance before and after coronary artery bypass graft surgery. METHODS: Patients' cognitive performance before and after coronary artery bypass graft surgery was evaluated in a prospective observational multicenter study in 5 academic medical centers. A total of 242 men and 123 women were evaluated before surgery; 333 men and 216 women, 5 to 11 months after surgery (197 men and 99 women were evaluated both before and after surgery). Verbal ability, attention/concentration, logical/verbal and visual memory, and facial recognition were measured. Data on demographic, medical, and psychosocial characteristics also were collected. RESULTS: After surgery, patients' overall performance improved (P < .001) for attention/concentration, verbal fluency, and logical/verbal memory. Patients with more education (high school or greater) performed better on each test (P < .001) than did patients with less education. No strong effects of sex or age on cognitive performance were observed before or after surgery, and no important differences in sex, age, or education were associated with changes in scores from before to after surgery. CONCLUSION: On average, cognitive performance improved rather than declined after coronary artery bypass graft surgery. The improvements were consistent across sex, age, and education.