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Introduction: Case-finding algorithms can be applied to administrative healthcare records to identify people with diseases, including people with HIV (PWH). When supplementing an existing registry of a low prevalence disease, near-perfect specificity helps minimize impacts of adding in algorithm-identified false positive cases. We evaluated the performance of algorithms applied to healthcare records to supplement an HIV registry in British Columbia (BC), Canada., Methods: We applied algorithms based on HIV-related diagnostic codes to healthcare practitioner and hospitalization records. We evaluated 28 algorithms in a validation sub-sample of 7,124 persons with positive HIV tests (2,817 with a prior negative test) from the STOP HIV/AIDS data linkage-a linkage of healthcare, clinical, and HIV test records for PWH in BC, resembling a disease registry (1996-2020). Algorithms were primarily assessed based on their specificity-derived from this validation sub-sample-and their impact on the estimate of the total number of PWH in BC as of 2020., Results: In the validation sub-sample, median age at positive HIV test was 37 years (Q1: 30, Q3: 46), 80.1% were men, and 48.9% resided in the Vancouver Coastal Health Authority. For all algorithms, specificity exceeded 97% and sensitivity ranged from 81% to 95%. To supplement the HIV registry, we selected an algorithm with 99.89% (95% CI: 99.76% - 100.00%) specificity and 82.21% (95% CI: 81.26% - 83.16%) sensitivity, requiring five HIV-related healthcare practitioner encounters or two HIV-related hospitalizations within a 12-month window, or one hospitalization with HIV as the most responsible diagnosis. Upon adding PWH identified by this highly-specific algorithm to the registry, 8,774 PWH were present in BC as of March 2020, of whom 333 (3.8%) were algorithm-identified., Discussion: In the context of an existing low prevalence disease registry, the results of our validation study demonstrate the value of highly-specific case-finding algorithms applied to administrative healthcare records to enhance our ability to estimate the number of PWH living in BC., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JSGM is the Executive Director and Physician-in-Chief of the BC Centre for Excellence in HIV/AIDS, a provincial program serving all BC health authorities, and based at St. Paul’s Hospital-Providence Health Care. JM’s Treatment as Prevention® (TasP®) research, paid to his institution, has received support from the BC Ministry of Health, Health Canada, Public Health Agency of Canada, Genome BC, Vancouver Coastal Health and VGH Foundation. Institutional grants have been provided by Gilead, Merck and ViiV Healthcare. JSGM received no specific funding for this work and has no competing interests. VDL is funded by a grant from the Canadian Institutes of Health Research, the Canadian Foundation for AIDS Research (CANFAR Innovation Grant – 30-101), and has received honoraria for the CROI Ambassador Program from ViiV Healthcare. KK is funded by a Michael Smith Health Research BC Research Trainee Fellowship (grant number: #RT-2022-2559), a CTN Postdoctoral Fellowship (no grant number), and a Canadian Institutes of Health Research Postdoctoral Fellowship (grant number: HIV 181935). The other authors declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Emerson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Accidental overdoses are now the leading cause of death among people with HIV (PWH) in British Columbia (BC). We examined the utilization and retention of opioid agonist therapy (OAT). Adult PWH (≥19 years) with ≥ 1 OAT dispensation in BC between 2008 and 2020 were included (n = 1,515). OAT treatment episodes were formed based on specific criteria for slow-release oral morphine (SROM), methadone, injectable OAT (iOAT), and buprenorphine/naloxone. Retention in treatment was defined as any episode lasting ≥ 12 months. Logistic regression with generalized estimating equations modeled retention-associated factors. There was a 56.6% decline in OAT retention over time. Buprenorphine treatment exhibited significantly lower odds of retention (OR: 0.58; 95% CI: 0.36-0.92) compared to methadone. Conversely, no significant change in retention odds was observed for SROM (0.72; 0.33-1.54) and iOAT (0.81; 0.31-2.12). Factors associated with increased odds of retention included a 10-year increase in age (1.69; 1.46-1.95), previous retention history (1.96; 1.40-2.73), achieving OAT therapeutic dose (8.22; 6.67-10.14), and suppressed HIV viral load (1.35; 1.10-1.67). Individuals with a lifetime HCV diagnosis receiving iOAT were more likely to retain (3.61; 1.20-10.83). Each additional year on OAT during the study period was associated with a 4% increase in the odds of retention. A significant proportion of PWH had a history of OAT prescribing but experienced low retention rates. Retention outcomes were more positive for SROM and iOAT. The association between OAT medication type and retention odds may be particularly influenced by HCV diagnosis. Optimal management of opioid use disorder among PWH, with an emphasis on attaining the therapeutic dose is crucial., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Julio S. G. Montaner is the Executive Director and Physician-in-Chief of the BC Centre for Excellence in HIV/AIDS, a provincial program serving all BC health authorities, and based at St. Paul’s Hospital-Providence Health Care. JM’s Treatment as Prevention® (TasP®) research, paid to his institution, has received support from the BC Ministry of Health, Health Canada, Public Health Agency of Canada, Genome BC, Vancouver Coastal Health and VGH Foundation. Institutional grants have been provided by Gilead, Merck and ViiV Healthcare., (© 2023 The Authors.)

Objective: Routinely collected health administrative data can be used to efficiently assess disease burden in large populations, but it is important to evaluate the validity of these data. The objective of this study was to develop and validate International Classification of Disease 10th revision (ICD -10) algorithms that identify laboratory-confirmed influenza or laboratory-confirmed respiratory syncytial virus (RSV) hospitalizations using population-based health administrative data from Ontario, Canada., Study Design and Setting: Influenza and RSV laboratory data from the 2014-15, 2015-16, 2016-17 and 2017-18 respiratory virus seasons were obtained from the Ontario Laboratories Information System (OLIS) and were linked to hospital discharge abstract data to generate influenza and RSV reference cohorts. These reference cohorts were used to assess the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the ICD-10 algorithms. To minimize misclassification in future studies, we prioritized specificity and PPV in selecting top-performing algorithms., Results: 83,638 and 61,117 hospitalized patients were included in the influenza and RSV reference cohorts, respectively. The best influenza algorithm had a sensitivity of 73% (95% CI 72% to 74%), specificity of 99% (95% CI 99% to 99%), PPV of 94% (95% CI 94% to 95%), and NPV of 94% (95% CI 94% to 95%). The best RSV algorithm had a sensitivity of 69% (95% CI 68% to 70%), specificity of 99% (95% CI 99% to 99%), PPV of 91% (95% CI 90% to 91%) and NPV of 97% (95% CI 97% to 97%)., Conclusion: We identified two highly specific algorithms that best ascertain patients hospitalized with influenza or RSV. These algorithms may be applied to hospitalized patients if data on laboratory tests are not available, and will thereby improve the power of future epidemiologic studies of influenza, RSV, and potentially other severe acute respiratory infections., Competing Interests: The authors have declared that no competing interests exist.

The present study examined the association of residential instability with hospitalizations among homeless and vulnerably housed individuals over a 4-year time period. Survey data were linked to administrative records on hospitalizations. Specifically, we used data from the Health and Housing in Transition study, a prospective cohort study that tracked the health and housing status of homeless and vulnerably housed individuals in Canada. Responses from Vancouver-based participants (n = 378) from baseline and 3 follow-ups were linked to their administrative health records on hospitalizations (Discharge Abstract Database - Hospital Separation Files; 2008-2012). A generalized estimating equations model was used to examine associations between the number of residential moves and any hospitalizations during each year (none versus ≥ 1 hospitalizations). Analyses included demographic and health variables. Survey data were collected via structured interviews. Hospitalizations were derived from provincial administrative health records. A higher number of residential moves were associated with hospitalization over the study period (adjusted odds ratio: 1.14; 95% confidence interval: 1.01, 1.28). Transgender, female gender, perceived social support, better self-reported mental health, and having ≥ 3 chronic health conditions also predicted having been hospitalized over the study period, whereas high school/higher education was negatively associated with hospitalizations. Our results indicate that residential instability is associated with increased risk of hospitalization, illustrating the importance of addressing housing as a social determinant of health.

Importance: More than 50% of lifetime mental health disorders develop by early adolescence, and yet it is not well understood how early childhood social-emotional functioning varies in populations or how differences in functioning may be associated with emerging mental health conditions., Objectives: To identify profiles of social-emotional functioning at kindergarten school entry (age 5 years) and to examine to what extent profiles are related to early-onset mental health conditions (ages 6-14 years)., Design, Setting, and Participants: This prospective cohort study followed up a population cohort of 34 552 children in British Columbia, Canada, from birth (born 1996-1998) to age 14 years (last follow-up, December 31, 2011). Data were analyzed from the Developmental Trajectories cohort that links British Columbia child development data from the Early Development Instrument (EDI) to British Columbia Ministry of Health and Ministry of Education records. Data were analyzed between May and September 2017., Exposures: Early childhood social-emotional functioning (defined as social competence, internalizing, and externalizing symptoms) rated by the children's kindergarten teachers., Main Outcomes and Measures: Occurrences of physician-assessed mental health conditions throughout childhood and early adolescence, including depression, anxiety, conduct disorder, and attention-deficit/hyperactivity disorder (ADHD), calculated from billing codes from the International Classification of Diseases, Ninth Revision recorded in provincial health insurance data., Results: Data from 34 323 children (mean [SD] age, 5.7 [0.3] years; 17 538 [51.1%] were boys) were analyzed at kindergarten and followed up to age 14 years (15 204 completed follow-up). Latent profile analysis identified 6 unique social-emotional functioning profiles at school entry, with 41.6% of children (n = 14 262) exhibiting comparative vulnerabilities in internalizing or externalizing behaviors. Prevalence of mental health conditions from ages 6 to 14 years was 4.0% for depression, 7.0% for anxiety, 5.5% for conduct disorder, 7.1% for ADHD, and 5.4% for multiple conditions. Zero-inflated Poisson analyses showed an association between social-emotional functioning profiles at kindergarten school entry and physician-assessed mental health conditions by age 14 years (range of adjusted odds ratios: depression, 1.10 [95% CI, 0.76-1.60] to 2.93 [95% CI, 1.93-4.44]; anxiety, 1.00 [95% CI, 0.74-1.36] to 1.73 [95% CI, 1.11-2.70]; conduct disorder, 2.17 [95% CI, 1.41-3.34] to 6.91 [95% CI, 4.90-9.74]; ADHD, 1.46 [95% CI, 1.11-1.93] to 8.72 [95% CI, 6.46-11.78]; and multiple conditions, 1.20 [95% CI, 0.88-1.63] to 6.81 [95% CI, 4.91-9.44]). Children with higher teacher ratings of aggression and hyperactivity had more frequent consultations for conduct disorder, ADHD, and multiple conditions., Conclusions and Relevance: This study's findings suggest that more than 40% of children enter the school system with relative vulnerabilities in social-emotional functioning that are associated with early-onset mental health conditions. The results raise important questions for using population-level early childhood development monitoring in the context of universal and proactive mental health strategies.

MDM2 is a regulator of cell growth processes that acts by binding to the tumor suppressor protein p53 and ultimately restraining its activity. While inactivation of p53 by mutation is commonly observed in human cancers, a substantial percentage of tumors express wild type p53. In many of these cases, MDM2 is overexpressed, and it is believed that suppression of MDM2 activity could yield therapeutic benefits. Therefore, we have been focusing on the p53-MDM2 interaction as the basis of a drug discovery program and have been able to develop a series of small molecule inhibitors. We herein report a high resolution NMR structure of a complex between the p53-binding domain of MDM2 and one of these inhibitors. The form of MDM2 utilized was an engineered hybrid between the human and Xenopus sequences, which provided a favorable combination of relevancy and stability. The inhibitor is found to bind in the same site as does a highly potent peptide fragment of p53. The inhibitor is able to successfully mimic the peptide by duplicating interactions in three subpockets normally made by amino acid sidechains, and by utilizing a scaffold that presents substituents with rigidity and spatial orientation comparable to that provided by the alpha helical backbone of the peptide. The structure also suggests opportunities for modifying the inhibitor to increase its potency.

Nuclear magnetic resonance (NMR) methods were employed to study the interaction of the cytokine Interleukin-2 (IL-2) with the alpha-subunit of its receptor (IL-2Ralpha), and to help understand the behavior of small molecule inhibitors of this interaction. Heteronuclear (1)H-(15)N HSQC experiments were used to identify the interaction surface of (15)N-enriched Interleukin-2 ((15)N-IL-2) in complex with human IL-2Ralpha. In these experiments, chemical shift and line width changes in the heteronuclear single-quantum coherence (HSQC) spectra upon binding of (15)N-IL-2 enabled classification of NH atoms as either near to, or far from, the IL-2Ralpha interaction surface. These data were complemented by hydrogen/deuterium (H/D) exchange measurements, which illustrated enhanced protection of slowly-exchanging IL-2 NH protons near the site of interaction with IL-2Ralpha. The interaction surface defined by NMR compared well with the IL-2Ralpha binding site identified previously using mutagenesis of human and murine IL-2. Two low molecular weight inhibitors of the IL-2/IL-2Ralpha interaction were studied: one (a cyclic peptide derivative) was found to mimic a part of the cytokine and bind to IL-2Ralpha; the other (an acylphenylalanine derivative) was found to bind to IL-2. For the interaction between IL-2 and the acylphenylalanine, chemical shift perturbations of (15)N and (15)NH backbone resonances were tracked as a function of ligand concentration. The perturbation pattern observed for this complex revealed that the acylphenylalanine is a competitive inhibitor-it binds to the same site on IL-2 that interacts with IL-2Ralpha.

Four overlapping peptide fragments of human c-Raf-1 (residues 55-132, 55-117, 77-132, and 77-117) were expressed in Escherichia coli as carboxyl-terminal extensions of maltose binding protein (MBP). The MBP-Raf fusions were purified by affinity chromatography on amylose resin and tested for binding to Ras.GTP indirectly by measuring their ability to inhibit the stimulation of Ras GTPase activity by GTPase activating protein (GAP120) in vitro. MBP-Raf(55-132) was a potent inhibitor in this assay (50% inhibition at 100 nM concentration), but the other fusion proteins had no measurable effect. The fusion partners were cleaved with Factor Xa protease and separated by gel filtration. The 8960-dalton Raf(55-132) fragment retained full activity as a competitive inhibitor of GAP120. It also blocked Ras-stimulated germinal vesicle breakdown in frog oocytes. Raf(55-132) was further characterized by circular dichroism and nuclear magnetic resonance spectroscopy. The results indicate that this fragment of c-Raf-1 adopts a highly structured, monomeric conformation in solution.

Sequence-specific 1H and 15N resonance assignments have been determined for the major cold shock protein (CspA) from Escherichia coli with recently developed three-dimensional triple-resonance NMR experiments. By use of these assignments, five antiparallel beta-strands were identified from analysis of NMR data. Strands 1-4 have a classical 3-2-1-4 Greek key beta-sheet topology and there are two beta-bulges, at positions Lys10-Trp11 and Gly65-Asn66. Three-dimensional structures of CspA were generated from NMR data by using simulated annealing with molecular dynamics. The overall chain fold of CspA is a beta-barrel structure, with a tightly packed hydrophobic core. Two-dimensional isotope-edited pulsed-field gradient 15N-1H heteronuclear single-quantum coherence spectroscopy was used to characterize the 15N-1H fingerprint spectrum with and without a 24-base oligodeoxyribonucleotide, 5'-AACGGTTTGACGTACAGACCATTA-3'. Protein-DNA complex formation perturbs a subset of the amide resonances that are located mostly on one face of the CspA molecule. This portion of the CspA molecular surface includes two putative RNA-binding sequence motifs which contribute to an unusual cluster of eight surface aromatic side chains: Trp11, Phe12, Phe18, Phe20, Phe31, His33, Phe34, and Tyr42. These surface aromatic groups, and also residues Lys16, Ser44, and Lys60 located on this same face of CspA, are highly conserved in the family of CspA homologues. These isotope-edited pulsed-field gradient NMR data provide a low-resolution mapping of a DNA-binding epitope on CspA.

A combination of one- and two-dimensional NMR experiments has been used to identify and spatially locate the heme pocket residues in the paramagnetic, low spin, met-cyano complex of elephant myoglobin. In addition to assigning resonances of the conserved residues, we have also assigned Gln64 (E7) and an aromatic ring designated PheA whose side chain is inserted into the heme pocket, as found earlier for elephant carbonmonoxy-myoglobin and oxy-myoglobin (Yu, L. P., La Mar, G. N., and Mizukami, H. (1990) Biochemistry 29, 2578-2585). The assigned conserved proximal side residues (Leu89(F4), Ala90(F5), His93(F8), His97(FG3), Ile99(FG5), Leu104(G5), Phe138(H15), and Tyr146(H23)) and conserved distal side residues (Phe43(CD1), Thr67(E10), Val68(E11), and Ala71(E14)) in elephant met-cyano-myoglobin are found to have orientations similar to those in sperm whale met-cyano-myoglobin. The observed dipolar connectivities and dipolar shift pattern for the substituted Gln64(E7) place the Gln in the heme pocket oriented toward the iron, as found for His64(E7). The conserved structural elements demand that the inserted PheA originate from the B-helix (i.e. Phe27 or Phe33). Dipolar contacts between the inserted PheA and the conserved residues Phe43(CD1), Val68(E11), Ile107(G8), and Gln64(E7), place PheA in the position occupied by the B10 residue in sperm whale myoglobin (Mb), with the larger size of the PheA side chain as compared to the replaced Leu being accommodated by the vacancy that occurs in sperm whale Mb. The paramagnetic induced relaxation places PheA in van der Waals contact with the bound ligand. Hence we conclude that the B10 position of elephant Mb is occupied by a Phe, and this substitution relative to sperm whale Mb is responsible for the low autoxidation rate and low reduction potential of elephant Mb. A reduced autoxidation rate has been reported for a sperm whale synthetic point mutant Leu29(B10) --> Phe (Carver, T. E., Brantley, R. E., Jr., Singleton, E. W., Arduini, R. M., Quillin, M. L., Phillips, G. N., and Olson, J. S. (1992) J. Biol. Chem. 267, 14443-14450). The published sequence of elephant Mb places B-helix Phe residues at position 27(B8) and 33(B14), but a Phe at neither of these positions can account for the observed NMR properties. Since a large proportion of the substitutions in elephant relative to sperm whale Mb, and some of the least conservative, occur in the B-helix, neither a structurally perturbed B-helix nor an error in the sequence can be discounted.