Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication.

INTRODUCTION: The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell-cell communication of non-malignant liver cells. MATERIALS AND METHODS: To investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum. RESULTS: The loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors. CONCLUSION: YAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell-cell communication originating from NPCs.

Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma.

BACKGROUND: Activation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma (iCCA); however, the expression pattern and the functional impact of its paralogue WW domain-containing transcription regulator 1 (WWTR1; synonym: TAZ) are not well described in different CCA subtypes. METHODS: Immunohistochemical analysis of YAP and TAZ in iCCA and extrahepatic CCA (eCCA) cohorts was performed. YAP/TAZ shuttling and their functional impact on CCA cell lines were investigated. Target genes expression after combined YAP/TAZ inhibition was analyzed. RESULTS: Immunohistochemical analysis of iCCA and eCCA revealed YAP or TAZ positivity in up to 49.2%; however, oncogene co-expression was less frequent (up to 23%). In contrast, both proteins were jointly detectable in most CCA cell lines and showed nuclear/cytoplasmic shuttling in a cell density-dependent manner. Next to the pro-proliferative function of YAP/TAZ, both transcriptional co-activators cooperated in the regulation of a gene signature that indicated the presence of chromosomal instability (CIN). A correlation between YAP and the CIN marker phospho-H2A histone family member X (pH2AX) was particularly observed in tissues from iCCA and distal CCA (dCCA). The presence of the CIN genes in about 25% of iCCA was statistically associated with worse prognosis. CONCLUSIONS: YAP and TAZ activation is not uncoupled from cell density in CCA cells and both factors cooperatively contribute to proliferation and expression of CIN-associated genes. The corresponding group of CCA patients is characterized by CIN and may benefit from YAP/TAZ-directed therapies.

Subnational mobility and consumption-based environmental accounting of US corn in animal protein and ethanol supply chains.

Corn production, and its associated inputs, is a relatively large source of greenhouse gas emissions and uses significant amounts of water and land, thus contributing to climate change, fossil fuel depletion, local air pollutants, and local water scarcity. As large consumers of this corn, corporations in the ethanol and animal protein industries are increasingly assessing and reporting sustainability impacts across their supply chains to identify, prioritize, and communicate sustainability risks and opportunities material to their operations. In doing so, many have discovered that the direct impacts of their owned operations are dwarfed by those upstream in the supply chain, requiring transparency and knowledge about environmental impacts along the supply chains. Life cycle assessments (LCAs) have been used to identify hotspots of environmental impacts at national levels, yet these provide little subnational information necessary for guiding firms' specific supply networks. In this paper, our Food System Supply-Chain Sustainability (FoodS3) model connects spatial, firm-specific demand of corn purchasers with upstream corn production in the United States through a cost minimization transport model. This provides a means to link county-level corn production in the United States to firm-specific demand locations associated with downstream processing facilities. Our model substantially improves current LCA assessment efforts that are confined to broad national or state level impacts. In drilling down to subnational levels of environmental impacts that occur over heterogeneous areas and aggregating these landscape impacts by specific supply networks, targeted opportunities for improvements to the sustainability performance of supply chains are identified.

Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness.

The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the basolateral cell polarity complex protein scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison with HCC cells stably expressing wild-type Scrib (ScribWT ), mutated Scrib with enforced cytoplasmic enrichment (ScribP305L ) induced AKT signaling through the destabilization of phosphatase and tensin homolog (PTEN) and PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1). Cytoplasmic ScribP305L stimulated a gene signature and a phenotype characteristic for epithelial to mesenchymal transition (EMT) and HCC cell invasiveness. ScribP305L -dependent invasion was mediated by the activator protein 1 (AP-1) constituents ATF2 and JunB through induction of paracrine-acting secreted protein acidic and cysteine-rich (SPARC). Coexpression of ScribP305L and the oncogene c-MYC through hydrodynamic gene delivery in mouse livers promoted tumor formation and increased abundance of pAKT, pATF2, and SPARC in comparison with controls. Finally, cytoplasmic Scrib localization correlated with AKT and ATF2 phosphorylation in human HCC tissues, and the ScribP305L -dependent gene signature was enriched in cancer patients with poor prognosis. CONCLUSION: Perturbation of hepatocellular polarity due to overexpression and cytoplasmic enrichment of Scrib supports tumor initiation and HCC cell dissemination through specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patients with higher risk for the development of metastasis. (Hepatology 2018;67:1842-1856).

Reducing anticipated non-suicidal self-injury by improving body esteem in individuals with weight suppression: A proof of concept study.

OBJECTIVE: Research suggests that weight suppression (WS) is linked to non-suicidal self-injury (NSSI) and that drive for thinness and depression may explain this association. We conducted a proof-of-concept study using a randomized control trial design to determine if improving body esteem and reducing depressive symptoms reduced NSSI in individuals with WS. METHOD: Weight suppressed participants (N = 60) who engaged in NSSI were recruited from the community and randomly assigned to an on-line intervention or control condition. The on-line intervention was adapted from a cognitive-dissonance intervention originally designed to reduce thin-ideal internalization in females to an intervention to reduce internalization of unhealthy body ideals in both genders. Participants' weight/shape concerns, depressive symptoms, and NSSI were assessed at pre- and post-intervention, or at baseline and 2-week follow-up for controls. RESULTS: Compared to controls, participants in the treatment condition reported greater decreases in likelihood of future NSSI [Cohen's d (95% CI) = -0.38 (-0.90-0.15)], weight/shape concerns [-1.19 (-1.75 to -0.62)], depressive symptoms [-1.00 (-1.56 to -0.45)], and significant improvements in appearance [1.27 (0.70-1.84)] and weight esteem [1.38 (0.80-1.96)]. DISCUSSION: Future work could test this intervention in a larger trial with an active alternative treatment condition.

Exercise dependence: Associations with capability for suicide and past suicidal behavior.

OBJECTIVE: Exercise dependence has been linked to capability for suicide and suicidal behavior; however, less understood are which facets of exercise dependence confer risk for suicidal behavior and the potential mechanisms of this association. This study examined relationships between exercise dependence, capability for suicide, and past suicidal behavior. METHODS: A sample of 540 individuals recruited via MTurk completed online measures of their exercise dependence, capability for suicide, and history of suicidal behavior. RESULTS: Suicide attempters reported higher levels of continuance in exercise despite physical or psychological consequences, lack of control over exercise, and reductions in other activities due to exercise than nonattempters. Capability for suicide accounted for the relationship between continuance in exercise despite adverse consequences and lifetime number of suicide attempts. CONCLUSIONS: When exercise becomes pathological in the form of exercise dependence, steps should be taken to reduce such engagement due to its observed association with suicidal behavior.

Vaginal versus Robotic Hysterectomy for Commonly Cited Relative Contraindications to Vaginal Hysterectomy.

STUDY OBJECTIVE: To compare outcomes of vaginal hysterectomy (VH) and robotic-assisted hysterectomy (RH) among women with conditions perceived as contraindications to VH (uterine size ≥ 12 weeks' gestation, no vaginal parity, prior cesarean delivery, and obesity). DESIGN: Retrospective chart review (Canadian Task Force classification II-2). SETTING: Tertiary US medical center. PATIENTS: Women with VH or RH. Women with conditions perceived as contraindications affecting surgical choice were excluded. INTERVENTIONS: VH or RH for benign uterine disease at our institution during 2009 through 2013. MEASUREMENTS AND MAIN RESULTS: Among women with the perceived contraindications, a logistic regression model was fit to compare each binary outcome between VH and RH. Models were weighted using inverse probability of treatment weights derived from propensity scores to adjust for covariate imbalance between procedures. The cohort had 692 VHs and 472 RHs. Among 160 women with uterine size ≥ 12 weeks' gestation, RH patients were less likely to have uterine debulking (adjusted odds ratio [aOR], .37; 95% confidence interval [CI], .15-.95]) than VH patients and more likely to have accordion grade ≥ 2 postoperative complications (aOR, 7.20; 95% CI, 1.46-35.42) and readmission (aOR, 15.55; 95% CI. .85-285.20). Among 272 women with prior cesarean section, RH patients were more likely to have grade ≥ 2 postoperative complications (aOR, 2.85; 95% CI, 1.29-6.30). No outcomes were significantly different between surgical routes among women with no vaginal parity or obesity. Mean operative time was significantly longer for RH. CONCLUSION: VH is a surgical option for patients with the conditions perceived as contraindications for vaginal surgery evaluated herein.

Do Undiagnosed Suicide Decedents Have Symptoms of a Mental Disorder?

BACKGROUND: Psychological autopsy studies consistently report that the rate of detected mental disorders among suicide decedents is below 100%. This implies three possibilities: (a) a subset of suicide decedents did not have a mental disorder at the time of death; (b) all suicide decedents suffered from a mental disorder, but some were undetected due to methodological limitations; and/or (c) suicide decedents with an undetected mental disorder displayed significant and perhaps subclinical features of a mental disorder. OBJECTIVE: In this article, we examined these possibilities by evaluating the differences in symptoms and stressors between suicide decedents who were undiagnosed and those diagnosed with a mental disorder at the time of death. METHOD: We reviewed 130 case studies of community-based suicide decedents originally described in Robins' (1981) psychological autopsy study. RESULTS: Without exception, suicide decedents in Robins' sample suffered either from a clearly diagnosable mental disorder or displayed features indicative of a significant, even if subclinical, presentation of a mental disorder. Undiagnosed and diagnosed suicide decedents did not significantly differ with regards to demographics, violence of suicide method, suicide attempt history, the number and intensity of stressful life events preceding death, and whether their death was a murder-suicide. CONCLUSION: Although clearly not all who suffer from mental disorders will die by suicide, these findings imply that all who die by suicide appear to exhibit, at minimum, subclinical psychiatric symptoms with the great majority showing prominent clinical symptoms. We conclude with clinical implications and recommendations for future study.

Concomitant expression of far upstream element (FUSE) binding protein (FBP) interacting repressor (FIR) and its splice variants induce migration and invasion of non-small cell lung cancer (NSCLC) cells.

Transcription factors integrate a variety of oncogenic input information, facilitate tumour growth and cell dissemination, and therefore represent promising therapeutic target structures. Because over-expression of DNA-interacting far upstream element binding protein (FBP) supports non-small cell lung cancer (NSCLC) migration, we asked whether its repressor, FBP-interacting repressor (FIR) is functionally inactivated and how FIR might affect NSCLC cell biology. Different FIR splice variants were highly expressed in the majority of NSCLCs, with the highest levels in tumours carrying genomic gains of chromosome 8q24.3, which contained the FIR gene locus. Nuclear FIR expression was significantly enriched at the invasion front of primary NSCLCs, but this did not correlate with tumour cell proliferation. FIR accumulation was associated with worse patient survival and tumour recurrence; in addition, FIR over-expression significantly correlated with lymph node metastasis in squamous cell carcinomas (SCCs). In vitro, we applied newly developed methods and modelling approaches for the quantitative and time-resolved description of the pro-migratory and pro-invasive capacities of SCC cells. siRNA-mediated silencing of all FIR variants significantly reduced the speed and directional movement of tumour cells in all phases of migration. Furthermore, sprouting efficiency and single cell invasiveness were diminished following FIR inhibition. Interestingly, the silencing of FIR isoforms lacking exon 2 (FIR(Δexon2)) alone was sufficient to reduce lateral migration and invasion. In summary, by using scale-spanning data derived from primary human tissues, quantitative cellular analyses and mathematical modelling, we have demonstrated that concomitant over-expression of FIR and its splice variants drives NSCLC migration and dissemination.

The medical complications associated with purging.

OBJECTIVE: Purging behaviors, including self-induced vomiting, laxative abuse, and diuretic abuse, are present across many of the eating disorders. Here we review the major medical complications of these behaviors. METHOD: Although we identified over 100 scholarly articles describing medical complications associated with purging, most papers involved case studies or small, uncontrolled samples. Given the limited evidence base, we conducted a qualitative (rather than systematic) review to identify medical complications that have been attributed to purging behaviors. RESULTS: Medical conditions affecting the teeth, esophagus, gastrointestinal system, kidneys, skin, cardiovascular system, and musculoskeletal system were identified, with self-induced vomiting causing the most medical complications. DISCUSSION: Purging behavior can be associated with severe medical complications across all body systems. Mental health professionals should refer patients with purging behaviors to medical providers for screening and treatment as needed. The medical work-up for individuals with eating disorders should include a comprehensive metabolic panel, complete blood count, and a full body exam including the teeth to prevent severe complications. Medical providers should screen patients for purging behaviors and associated medical complications, even in the absence of an eating disorder diagnosis, to increase the detection of eating disorders. Recognizing the link between purging and medical complications can aid in identifying potential eating disorders, particularly those that often elude detection such as purging disorder.

Relieving menstrual obstruction: surgical correction of vaginal agenesis.

INTRODUCTION AND HYPOTHESIS: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome includes vaginal agenesis with varied uterine development. The objective of this video is to illustrate our surgical technique to create a cervical and vaginal canal to relieve menstrual obstruction for a teenager with a functional uterus and vaginal agenesis. METHODS: Using vaginal dissection and a mini laparotomy, a sound placed through the fundus of the uterus created an endocervical and vaginal channel to relieve her menstrual obstruction. A Foley catheter stented the cervical canal and a red rubber chest tube catheter stented the vagina until epithelization was achieved. RESULTS: No complications were encountered. The patient was examined with intermittent hysteroscopy with gentle dilation of the cervix. She had the red rubber catheter removed at 3 months, and she started using a small dilator. Her menses were suppressed with a gonadotropin releasing-hormone agonist allowing for complete healing. She is now 17. Her vaginal canal is well-epithelialized. Hysteroscopy confirmed a patent endocervical canal and uterine cavity. CONCLUSION: MRKH is rare. A small percentage of affected women has a functional endometrium requiring intervention for menstrual obstruction. Full vaginal reconstruction may be considered, but creation of a small canal to provide menstrual relief can be a temporary solution in those not desiring sexual function.

Management of a vesicovaginal fistula using holmium laser ablation.

INTRODUCTION AND HYPOTHESIS: The objective was to demonstrate a surgical technique for the management of a small vesicovaginal fistula (VVF) involving a combination of cystoscopic holmium laser ablation and vaginal repair. METHODS: A 55-year-old morbidly obese female presented with complaints of menometrorrhagia and complex adnexal mass. She underwent an attempted robotic hysterectomy, which was converted to open hysterectomy, omentectomy, and lymphadenectomy owing to an intraoperative diagnosis of endometrioid carcinoma of the endometrium and dense pelvic adhesions. Postoperatively, the patient developed intermittent urinary leakage associated with position change. On evaluation, a speculum examination did not reveal any fistulous tract or leakage of fluid in the vagina. A tampon test was positive, but no evidence of a fistula was noted on a CT urogram. Cystourethroscopy was performed and identified a small VVF. The patient subsequently underwent repair of her VVF using a combination of cystoscopic holmium laser ablation and transvaginal excision of the suspected fistula opening. RESULTS: About 2 weeks after the surgery, a tampon test was negative and cystourethroscopy revealed healing bladder mucosa. The patient remains fistula-free at 12 months post-operatively. CONCLUSION: Holmium laser ablation combined with partial vaginal excision may be considered as a management option for a small VVF.

Routinized Assessment of Suicide Risk in Clinical Practice: An Empirically Informed Update.

OBJECTIVE: Empirically informed suicide risk assessment frameworks are useful in guiding the evaluation and treatment of individuals presenting with suicidal symptoms. Joiner et al. (1999) formulated one such framework, which has provided a concise heuristic for the assessment of suicide risk. The purpose of this review is to ensure compatibility of this suicide risk assessment framework with the growing literature on suicide-related behaviors. METHODS: This review integrates recent literature on suicide risk factors and clinical applications into the existing model. Further, we present a review of risk factors not previously included in the Joiner et al. (1999) framework, such as the interpersonal theory of suicide variables of perceived burdensomeness, thwarted belongingness, and capability for suicide (Joiner, 2005; Van Orden et al., 2010) and acute symptoms of suicidality (i.e., agitation, irritability, weight loss, sleep disturbances, severe affective states, and social withdrawal). RESULTS: These additional indicators of suicide risk further facilitate the classification of patients into standardized categories of suicide risk severity and the critical clinical decision making needed for the management of such risk. CONCLUSIONS: To increase the accessibility of empirically informed risk assessment protocols for suicide prevention and treatment, an updated suicide risk assessment form and decision tree are provided.

Cysteinate protonation and water hydrogen bonding at the active-site of a nickel superoxide dismutase metallopeptide-based mimic: implications for the mechanism of superoxide reduction.

Nickel-containing superoxide dismutase (NiSOD) is a mononuclear cysteinate-ligated nickel metalloenzyme that catalyzes the disproportionation of superoxide into dioxygen and hydrogen peroxide by cycling between Ni(II) and Ni(III) oxidation states. All of the ligating residues to nickel are found within the first six residues from the N-terminus, which has prompted several research groups to generate NiSOD metallopeptide-based mimics derived from the first several residues of the NiSOD sequence. To assess the viability of using these metallopeptide-based mimics (NiSOD maquettes) to probe the mechanism of SOD catalysis facilitated by NiSOD, we computationally explored the initial step of the O2(-) reduction mechanism catalyzed by the NiSOD maquette {Ni(II)(SOD(m1))} (SOD(m1) = HCDLP CGVYD PA). Herein we use spectroscopic (S K-edge X-ray absorption spectroscopy, electronic absorption spectroscopy, and circular dichroism spectroscopy) and computational techniques to derive the detailed active-site structure of {Ni(II)(SOD(m1))}. These studies suggest that the {Ni(II)(SOD(m1))} active-site possesses a Ni(II)-S(H(+))-Cys(6) moiety and at least one associated water molecule contained in a hydrogen-bonding interaction to the coordinated Cys(2) and Cys(6) sulfur atoms. A computationally derived mechanism for O2(-) reduction using the formulated active-site structure of {Ni(II)(SOD(m1))} suggests that O2(-) reduction takes place through an apparent initial outersphere hydrogen atom transfer (HAT) from the Ni(II)-S(H(+))-Cys(6) moiety to the O2(-) molecule. It is proposed that the water molecule aids in driving the reaction forward by lowering the Ni(II)-S(H(+))-Cys(6) pK(a). Such a mechanism is not possible in NiSOD itself for structural reasons. These results therefore strongly suggest that maquettes derived from the primary sequence of NiSOD are mechanistically distinct from NiSOD itself despite the similarities in the structure and physical properties of the metalloenzyme vs the NiSOD metallopeptide-based models.

Crystallographic and computational studies of luminescent, binuclear gold(I) complexes, Au(I)2(Ph2P(CH2)nPPh2)2I2 (n = 3-6).

Four crystalline dimers of the type, Au(I)(2)(µ-PnP)(2)I(2), where PnP is PPh(2)(CH(2))(n)PPh(2) with n = 3, 4, 5, and 6 have been prepared and characterized by single-crystal X-ray diffraction and by (31)P NMR and infrared spectroscopy. Au(I)(2)(µ-P3P)(2)I(2) and Au(I)(2)(µ-P6P)(2)I(2) are centrosymmetric dimers with the planar Au(I)P(2)I units oriented in antiparallel fashion. Remarkably, noncentrosymmetric Au(I)(2)(µ-P5P)(2)I(2) has its planar Au(I)P(2)I units oriented in parallel manner. Au(I)(2)(µ-P4P)(2)(µ-I)(2) is unique, since it contains four-coordinate gold centers that are bridged by both iodide and diphosphine ligands. All four compounds are luminescent as solids at room temperature. B3LYP, B2PLYP, and spectroscopically oriented configuration interaction (SORCI) calculations have been conducted to give insight into the electronic and geometric structures of the ground and first excited triplet states of the three trigonal-planar complexes. The emission energies for the trigonal planar complexes are more strongly correlated with changes in the Au-I bond length rather than changes in the P-Au-P angle.

Sequential oxidations of thiolates and the cobalt metallocenter in a synthetic metallopeptide: implications for the biosynthesis of nitrile hydratase.

Cobalt nitrile hydratases (Co-NHase) contain a catalytic cobalt(III) ion coordinated in an N2S3 first coordination sphere composed of two amidate nitrogens and three cysteine-derived sulfur donors: a thiolate (-SR), a sulfenate (-S(R)O(-)), and a sulfinate (-S(R)O2(-)). The sequence of biosynthetic reactions that leads to the post-translational oxidations of the metal and the sulfur ligands is unknown, but the process is believed to be initiated directly by oxygen. Herein we utilize cobalt bound in an N2S2 first coordination sphere by a seven amino acid peptide known as SODA (ACDLPCG) to model this oxidation process. Upon exposure to oxygen, Co-SODA is oxidized in two steps. In the first fast step (seconds), magnetic susceptibility measurements demonstrated that the metallocenter remains paramagnetic, that is, Co(2+), and sulfur K-edge X-ray absorption spectroscopy (XAS) is used to show that one of the thiolates is oxidized to sulfinate. In a second process on a longer time scale (hours), magnetic susceptibility measurements and Co K-edge XAS show that the metal is oxidized to Co(3+). Unlike other model complexes, additional slow oxidation of the second thiolate in Co-SODA is not observed, and a catalytically active complex is never formed. The likely reason is the absence of the axial thiolate ligand. In essence, the reactivity of Co-SODA can be described as between previously described models which either quickly convert to final product or are stable in air, and it offers a first glimpse into a possible oxidation pathway for nitrile hydratase biosynthesis.

Eyes Fixed on Heaven's Gate: An Empirical Examination of Blink Rate and Suicide.

Anecdotal and theoretical work suggests blink rate as an indicator of imminent suicide risk. We sought to empirically examine whether suicide decedents displayed a reduced blink rate in goodbye videos filmed before death, compared to several control groups. Independent raters coded blink rates from videos of 34 suicide decedents and four comparison groups: "mundane" product review, non-suicidal arousal, non-suicidal depression, and non-imminent risk of suicidal ideation. Mean blink rate was lower in the suicide decedent group relative to all comparison groups (ps < .001), except the depressed (p = .976) and suicidal ideation (p = .393) groups. Findings indicate blink rate may be reduced among individuals at imminent risk for suicide, exhibiting clinically-significant depressive symptoms, or experiencing suicidal ideation.

Modulation of luminescence by subtle anion-cation and anion-π interactions in a trigonal Au(I)···Cu(I) complex.

The trigonally coordinated [AuCu(PPh(2)py)(3)](BF(4))(2) (1) crystallizes in two polymorphs and a pseudopolymorph, each of which contains a trigonally coordinated cation with short Au(I)-Cu(I) separations of ∼2.7 Å. Under UV illumination, these crystals luminesce different colors ranging from blue to yellow. The structures of these cations are nearly superimposable, and the primary difference resides in the relative placement of the anions and solvate molecules. As confirmed by time-dependent density functional theory calculations, it is these interactions that are responsible for the differential emission properties.

Global Registries in Congenital Hyperinsulinism.

Congenital hyperinsulinism (HI) is the most frequent cause of severe, persistent hypoglycemia in newborn babies and children. There are many areas of need for HI research. Some of the most critical needs include describing the natural history of the disease, research leading to new and better treatments, and identifying and managing hypoglycemia before it is prolonged and causes brain damage or death. Patient-reported data provides a basis for understanding the day-to-day experience of living with HI. Commonly identified goals of registries include performing natural history studies, establishing a network for future product and treatment studies, and supporting patients and families to offer more successful and coordinated care. Congenital Hyperinsulinism International (CHI) created the HI Global Registry (HIGR) in October 2018 as the first global patient-powered hyperinsulinism registry. The registry consists of thirteen surveys made up of questions about the patient's experience with HI over their lifetime. An international team of HI experts, including family members of children with HI, advocates, clinicians, and researchers, developed the survey questions. HIGR is managed by CHI and advised by internationally recognized HI patient advocates and experts. This paper aims to characterize HI through the experience of individuals who live with it. This paper includes descriptive statistics on the birthing experience, hospitalizations, medication management, feeding challenges, experiences with glucose monitoring devices, and the overall disease burden to provide insights into the current data in HIGR and demonstrate the potential areas of future research. As of January 2022, 344 respondents from 37 countries consented to participate in HIGR. Parents or guardians of individuals living with HI represented 83.9% of the respondents, 15.3% were individuals living with HI. Data from HIGR has already provided insight into access challenges, patients' and caregivers' quality of life, and to inform clinical trial research programs. Data is also available to researchers seeking to study the pathophysiology of HI retrospectively or to design prospective trials related to improving HI patient outcomes. Understanding the natural history of the disease can also guide standards of care. The data generated through HIGR provides an opportunity to improve the lives of all those affected by HI.

Congenital Hyperinsulinism International: A Community Focused on Improving the Lives of People Living With Congenital Hyperinsulinism.

Congenital hyperinsulinism (HI) is a rare disease affecting newborns. HI causes severe hypoglycemia due to the overproduction of insulin. The signs and symptoms of hypoglycemia in HI babies is often not discovered until brain damage has already occurred. Prolonged hypoglycemia from HI can even lead to death. Disease management is often complex with a high burden on caregivers. Treatment options are extremely limited and often require long hospital stays to devise. Cascading from suboptimal treatments and diagnostic practices are a host of other problems and challenges that many with HI and their families experience including continued fear of hypoglycemia and feeding problems. The aim of this paper is (1) to describe the current challenges of living with HI including diagnosis and disease management told from the perspective of people who live with the condition (2), to provide family stories of life with HI, and (3) to share how a rare disease patient organization, Congenital Hyperinsulinism International (CHI) is working to improve the lives of HI patients and their families. CHI is a United States based nonprofit organization with a global focus. The paper communicates the programs the patient advocacy organization has put into place to support HI families through its virtual and in-person gatherings. The organization also helps individuals access diagnostics, medical experts, and treatments. CHI also raises awareness of HI to improve patient outcomes with information about HI and prolonged hypoglycemia in twenty-three languages. CHI drives innovation for new and better treatments by funding research pilot grants, conducting research through the HI Global Registry, and providing patient experience expertise to researchers developing new treatments. The organization is also the sponsor of the CHI Collaborative Research Network which brings medical and scientific experts together for the development of a patient-focused prioritized research agenda.