Underlying Reasons for Primary Care Visits Where Chlamydia Testing Was Performed in the United States, 2019 to 2022.

BACKGROUND: In the United States, most chlamydia cases are reported from non-sexually transmitted disease clinics, and there is limited information focusing on the reasons for chlamydia testing in private settings. These analyses describe clinical visits to primary care providers where chlamydia testing was performed to help discern between screening and diagnostic testing for chlamydia. METHODS: Using the largest primary care clinical registry in the United States, the PRIME registry, chlamydia tests were identified using Current Procedural Terminology procedure codes and categorized as diagnostic testing for sexually transmitted infection (STI)-related symptoms, screening for chlamydia, or "other," based on Classification of Diseases, Tenth Revision Evaluation and Management codes selected for visits. RESULTS: Of 120,013 clinical visits with chlamydia testing between January 1, 2019, and December 31, 2022, 70.4% were women; 20.6% were with STI-related symptoms, 59.9% were for screening, and 19.5% for "other" reasons. Of those 120,013 clinical visits with chlamydia testing, the logit model showed that patients were significantly more likely to have STI-related symptoms if they were female than male, non-Hispanic Black than non-Hispanic White, aged 15 to 24 years than aged ≥45 years, and resided in the South than in the Northeast. CONCLUSION: It is important to know what proportion of chlamydial infections is identified through screening programs and to have this information stratified by demographics. The inclusion of laboratory results could further facilitate a better understanding of the impact of chlamydia screening programs on the identification and treatment of chlamydia in private office settings in the United States.

The effectiveness and safety of proton beam radiation therapy in children and young adults with Central Nervous System (CNS) tumours: a systematic review.

BACKGROUND: Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment. METHODS: A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed. RESULTS: Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported. CONCLUSIONS: This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-CRD42016036802.

The entropic force generated by intrinsically disordered segments tunes protein function.

Protein structures are dynamic and can explore a large conformational landscape1,2. Only some of these structural substates are important for protein function (such as ligand binding, catalysis and regulation)3-5. How evolution shapes the structural ensemble to optimize a specific function is poorly understood3,4. One of the constraints on the evolution of proteins is the stability of the folded 'native' state. Despite this, 44% of the human proteome contains intrinsically disordered peptide segments greater than 30 residues in length6, the majority of which have no known function7-9. Here we show that the entropic force produced by an intrinsically disordered carboxy terminus (ID-tail) shifts the conformational ensemble of human UDP-α-D-glucose-6-dehydrogenase (UGDH) towards a substate with a high affinity for an allosteric inhibitor. The function of the ID-tail does not depend on its sequence or chemical composition. Instead, the affinity enhancement can be accurately predicted based on the length of the intrinsically disordered segment, and is consistent with the entropic force generated by an unstructured peptide attached to the protein surface10-13. Our data show that the unfolded state of the ID-tail rectifies the dynamics and structure of UGDH to favour inhibitor binding. Because this entropic rectifier does not have any sequence or structural constraints, it is an easily acquired adaptation. This model implies that evolution selects for disordered segments to tune the energy landscape of proteins, which may explain the persistence of intrinsic disorder in the proteome.

Distinct subpopulations of D1 medium spiny neurons exhibit unique transcriptional responsiveness to cocaine.

Drugs of abuse increase extracellular concentrations of dopamine in the nucleus accumbens (NAc), resulting in transcriptional alterations that drive long-lasting cellular and behavioral adaptations. While decades of research have focused on the transcriptional mechanisms by which drugs of abuse influence neuronal physiology and function, few studies have comprehensively defined NAc cell type heterogeneity in transcriptional responses to drugs of abuse. Here, we used single nucleus RNA-seq (snRNA-seq) to characterize the transcriptome of over 39,000 NAc cells from male and female adult Sprague-Dawley rats following acute or repeated cocaine experience. This dataset identified 16 transcriptionally distinct cell populations, including two populations of medium spiny neurons (MSNs) that express the Drd1 dopamine receptor (D1-MSNs). Critically, while both populations expressed classic marker genes of D1-MSNs, only one population exhibited a robust transcriptional response to cocaine. Validation of population-selective transcripts using RNA in situ hybridization revealed distinct spatial compartmentalization of these D1-MSN populations within the NAc. Finally, analysis of published NAc snRNA-seq datasets from non-human primates and humans demonstrated conservation of MSN subtypes across rat and higher order mammals, and further highlighted cell type-specific transcriptional differences across the NAc and broader striatum. These results highlight the utility in using snRNA-seq to characterize both cell type heterogeneity and cell type-specific responses to cocaine and provides a useful resource for cross-species comparisons of NAc cell composition.

Active site serine-193 modulates activity of human aromatic amino acid decarboxylase.

Aromatic amino acid decarboxylase is a pyridoxal 5'-phosphate-dependent enzyme responsible for the synthesis of the neurotransmitters, dopamine and serotonin. Here, by a combination of bioinformatic predictions and analyses, phosphorylation assays, spectroscopic investigations and activity measurements, we determined that Ser-193, a conserved residue located at the active site, can be phosphorylated, increasing catalytic efficiency. In order to determine the molecular basis for this functional improvement, we determined the structural and kinetic properties of the site-directed variants S193A, S193D and S193E. While S193A retains 27% of the catalytic efficiency of wild-type, the two acidic side chain variants are impaired in catalysis with efficiencies of about 0.15% with respect to the wild-type. Thus, even if located at the active site, Ser-193 is not essential for enzyme activity. We advance the idea that this residue is fundamental for the correct architecture of the active site in terms of network of interactions triggering catalysis. This role has been compared with the properties of the Ser-194 of the highly homologous enzyme histidine decarboxylase whose catalytic loop is visible in the spatial structure, allowing us to propose the validation for the effect of the phosphorylation. The effect could be interesting for AADC deficiency, a rare monogenic disease, whose broad clinical phenotype could be also related to post translational AADC modifications.

Foundational Collective Actions for Achieving Agile High-Quality Primary Care in the United States.

In 2021, the National Academy of Science, Engineering, and Medicine Committee on Implementing High-Quality Primary Care published its recommendations to expand the provision of high-quality primary care in the USA. These include paying for primary care teams to care for people, ensuring that high-quality primary care is available, training primary care teams where people live and work, and designing information technology that serves the patient, family, and care team. Many of these recommendations echo those of prior calls for action, including the Institute of Medicine's 1996 report. However, the 2021 report recognizes the importance of implementation in its final recommendation of ensuring that high-quality primary care is implemented in the USA. We consider the NASEM recommendations in terms of the complexity of the task of supporting interconnected implementation activities that occur in local contexts. With this vantage point, we identify foundational collective actions, including the creation of an accountable leadership entity, payment reform, and community networks. We then discuss the creation of a monitoring mechanism to assess and support sustained action.

Variation in Family Physicians' Experiences Across Different Electronic Health Record Platforms: a Descriptive Study.

BACKGROUND: Electronic health records (EHRs) have been connected to excessive workload and physician burnout. Little is known about variation in physician experience with different EHRs, however. OBJECTIVE: To analyze variation in reported usability and satisfaction across EHRs. DESIGN: Internet-based survey available between December 2021 and October 2022 integrated into American Board of Family Medicine (ABFM) certification process. PARTICIPANTS: ABFM-certified family physicians who use an EHR with at least 50 total responding physicians. MEASUREMENTS: Self-reported experience of EHR usability and satisfaction. KEY RESULTS: We analyzed the responses of 3358 physicians who used one of nine EHRs. Epic, athenahealth, and Practice Fusion were rated significantly higher across six measures of usability. Overall, between 10 and 30% reported being very satisfied with their EHR, and another 32 to 40% report being somewhat satisfied. Physicians who use athenahealth or Epic were most likely to be very satisfied, while physicians using Allscripts, Cerner, or Greenway were the least likely to be very satisfied. EHR-specific factors were the greatest overall influence on variation in satisfaction: they explained 48% of variation in the probability of being very satisfied with Epic, 46% with eClinical Works, 14% with athenahealth, and 49% with Cerner. CONCLUSIONS: Meaningful differences exist in physician-reported usability and overall satisfaction with EHRs, largely explained by EHR-specific factors. User-centric design and implementation, and robust ongoing evaluation are needed to reduce physician burden and ensure excellent experience with EHRs.

Measuring Trust in Primary Care.

Policy Points Trust in primary care clinicians is essential for effective patient care and is associated with better health outcomes, but it is rarely assessed, and existing measures have not been thoroughly evaluated. This scoping review reveals that research assessing patients' trust in primary care clinicians largely stopped more than a decade ago but offers candidate measures for future testing, implementation, and policy applications. CONTEXT: Trust is a fundamental aspect of any human relationship, and medical care is no exception. An ongoing, trusting relationship between clinicians and patients has shown demonstrable value to primary care. However, there is currently no measure of trust in general use, and none endorsed for use by most value-based payment programs. This review searched the literature for any existing measures of patient trust in primary care clinicians and assessed their potential to be implemented as a patient-reported outcome measure. METHODS: A keyword search on PubMed along with scanning references was conducted to find any trust measures in health care. Measures that did not address primary care clinicians were eliminated and the remaining measures were then assessed for their utility to primary care. RESULTS: This purposeful, scoping review found four tested measures for assessing patients' trust in primary care clinicians that are candidates for general use. Of these four, the revised Trust in Physicians Scale and Wake Forest Physician Trust Scale are the most tested and viable options. CONCLUSION: Renewed national interest in trust in health care should focus on the capacity to measure it. This review informs the effort to test trust measures for use in research, practice improvement, and value-based payment. Measuring trust, how it relates to outcomes, and learning how it is produced or lost are key to assisting practices and health systems toward earning it.

Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4.

Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed that microbial-specific indoles regulated intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is a ligand for PXR in vivo, and IPA downregulated enterocyte TNF-α while it upregulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2(-/-)) mice showed a distinctly "leaky" gut physiology coupled with upregulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier were corrected in Nr1i2(-/-)Tlr4(-/-) mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway that involves luminal sensing and signaling by TLR4.

An analysis of the resource use and costs of febrile neutropenia events in pediatric cancer patients in Australia.

BACKGROUND: Febrile neutropenia (FN) in children with cancer generally requires in-hospital care, but low-risk patients may be successfully managed in an outpatient setting, potentially reducing the overall healthcare costs. Updated data on the costs of FN care are lacking. METHODS: A bottom-up microcosting analysis was conducted from the healthcare system perspective using data collected alongside the Australian PICNICC (Predicting Infectious Complications of Neutropenic sepsis In Children with Cancer) study. Inpatient costs were accessed from hospital administrative records and outpatient costs from Medicare data. Costs were stratified by risk status (low/high risk) according to the PICNICC criteria. Estimated mean costs were obtained through bootstrapping and using a linear model to account for multiple events across individuals and other clinical factors that may impact costs. RESULTS: The total costs of FN care were significantly higher for FN events classified as high-risk ($17,827, 95% confidence interval [CI]: $17,193-$18,461) compared to low-risk ($10,574, 95% CI: $9818-$11,330). In-hospital costs were significantly higher for high-risk compared to low-risk events, despite no differences in the cost structure, mean cost per day, and pattern of resource use. Hospital length of stay (LOS) was the only modifiable factor significantly associated with total costs of care. Excluding antineoplastics, antimicrobials are the most commonly used medications in the inpatient and outpatient setting for the overall period of analysis. CONCLUSION: The FN costs are driven by in-hospital admission and LOS. This suggests that the outpatient management of low-risk patients is likely to reduce the in-hospital cost of treating an FN event. Further research will determine if shifting the cost to the outpatient setting remains cost-effective overall.

Treatment of breakthrough and prevention of refractory chemotherapy-induced nausea and vomiting in pediatric cancer patients: Clinical practice guideline update.

This clinical practice guideline update provides recommendations for treating breakthrough chemotherapy-induced nausea and vomiting (CINV) and preventing refractory CINV in pediatric patients. Two systematic reviews of randomized controlled trials in adult and pediatric patients informed the recommendations. In patients with breakthrough CINV, escalation of antiemetic agents to those recommended for chemotherapy of the next higher level of emetogenic risk is strongly recommended. A similar recommendation to escalate therapy is made to prevent refractory CINV in patients who did not experience complete breakthrough CINV control and are receiving minimally or low emetogenic chemotherapy. A strong recommendation to use antiemetic agents that controlled breakthrough CINV for the prevention of refractory CINV is also made.

How the Gender Wage Gap for Primary Care Physicians Differs by Compensation Approach : A Microsimulation Study.

BACKGROUND: The physician gender wage gap may be due, in part, to productivity-based compensation models that undervalue female practice patterns. OBJECTIVE: To determine how primary care physician (PCP) compensation by gender differs when applying existing productivity-based and alternative compensation models. DESIGN: Microsimulation. SETTING: 2016 to 2019 national clinical registry of 1222 primary care practices. PARTICIPANTS: Male and female PCPs matched on specialty, years since medical school graduation, practice site, and sessions worked. MEASUREMENTS: Net annual, full-time-equivalent compensation for male versus female PCPs, under productivity-based fee-for-service, panel size-based capitation without or with risk adjustment, and hybrid payment models. Microsimulation inputs included patient and visit characteristics and overhead expenses. RESULTS: Among 1435 matched male (n = 881) and female (n = 554) PCPs, female PCP panels included patients who were, on average, younger, had lower diagnosis-based risk scores, were more often female, and were more often uninsured or insured by Medicaid rather than by Medicare. Under productivity-based payment, female PCPs earned a median of $58 829 (interquartile range [IQR], $39 553 to $120 353; 21%) less than male PCPs. This gap was similar under capitation ($58 723 [IQR, $42 141 to $140 192]). It was larger under capitation risk-adjusted for age alone ($74 695 [IQR, $42 884 to $152 423]), for diagnosis-based scores alone ($114 792 [IQR, $49 080 to $215 326] and $89 974 [IQR, $26 175 to $173 760]), and for age-, sex-, and diagnosis-based scores ($83 438 [IQR, $28 927 to $129 414] and $66 195 [IQR, $11 899 to $96 566]). The gap was smaller and nonsignificant under capitation risk-adjusted for age and sex ($36 631 [IQR, $12 743 to $73 898]). LIMITATION: Panel attribution based on office visits. CONCLUSION: The gender wage gap varied by compensation model, with capitation risk-adjusted for patient age and sex resulting in a smaller gap. Future models might better align with primary care effort and outcomes. PRIMARY FUNDING SOURCE: None.

Crystallographic snapshots of ternary complexes of thermophilic secondary alcohol dehydrogenase from Thermoanaerobacter pseudoethanolicus reveal the dynamics of ligand exchange and the proton relay network.

Three-dimensional structures of I86A and C295A mutant secondary alcohol dehydrogenase (SADH) from Thermoanaerobacter pseudoethanolicus were determined by x-ray crystallography. The tetrameric structure of C295A-SADH soaked with NADP+ and dimethyl sulfoxide (DMSO) was determined to 1.85 Å with an Rfree of 0.225. DMSO is bound to the tetrahedral zinc in each subunit, with ligands from SG of Cys-37, NE2 of His-59, and OD2 of Asp-150. The nicotinamide ring of NADP is hydrogen-bonded to the N of Ala-295 and the O of Val-265 and Gly-293. The O of DMSO is connected to a network of hydrogen bonds with OG of Ser-39, the 3'-OH of NADP, and ND1 of His-42. The structure of I86A-SADH soaked with 2-pentanol and NADP+ contains (R)-2-pentanol bound in each subunit, ligated to the tetrahedral zinc, and connected to the proton relay network. The structure of I86A-SADH soaked with 3-methylcyclohexanol and NADP+ has alcohol bound in three subunits. Two of the sites have the alcohol ligated to the zinc in an axial position, with OE2 of Glu-60 in the other axial position of a trigonal bipyramidal complex. One site has 3-methylcyclohexanol bound noncovalently, with the zinc in an inverted tetrahedral geometry with Glu-60. The fourth site also has the zinc in a trigonal bipyramidal complex with axial Glu-60 and water ligands. These structures demonstrate that ligand exchange of SADH involves pentacoordinate and inverted zinc complexes with Glu-60. Furthermore, we see a network of hydrogen bonds connecting the substrate oxygen to the external solvent that is likely to play a role in the mechanism of SADH.

International variation in childhood cancer mortality rates from 2001 to 2015: Comparison of trends in the International Cancer Benchmarking Partnership countries.

Despite improved survival rates, cancer remains one of the most common causes of childhood death. The International Cancer Benchmarking Partnership (ICBP) showed variation in cancer survival for adults. We aimed to assess and compare trends over time in cancer mortality between children, adolescents and young adults (AYAs) and adults in the six countries involved in the ICBP: United Kingdom, Denmark, Australia, Canada, Norway and Sweden. Trends in mortality between 2001 and 2015 in the six original ICBP countries were examined. Age standardised mortality rates (ASR per million) were calculated for all cancers, leukaemia, malignant and benign central nervous system (CNS) tumours, and non-CNS solid tumours. ASRs were reported for children (age 0-14 years), AYAs aged 15 to 39 years and adults aged 40 years and above. Average annual percentage change (AAPC) in mortality rates per country were estimated using Joinpoint regression. For all cancers combined, significant temporal reductions were observed in all countries and all age groups. However, the overall AAPC was greater for children (-2.9; 95% confidence interval = -4.0 to -1.7) compared to AYAs (-1.8; -2.1 to -1.5) and adults aged >40 years (-1.5; -1.6 to -1.4). This pattern was mirrored for leukaemia, CNS tumours and non-CNS solid tumours, with the difference being most pronounced for leukaemia: AAPC for children -4.6 (-6.1 to -3.1) vs AYAs -3.2 (-4.2 to -2.1) and over 40s -1.1 (-1.3 to -0.8). AAPCs varied between countries in children for all cancers except leukaemia, and in adults over 40 for all cancers combined, but not in subgroups. Improvements in cancer mortality rates in ICBP countries have been most marked among children aged 0 to 14 in comparison to 15 to 39 and over 40 year olds. This may reflect better care, including centralised service provision, treatment protocols and higher trial recruitment rates in children compared to older patients.

M379A Mutant Tyrosine Phenol-lyase from Citrobacter freundii Has Altered Conformational Dynamics.

The M379A mutant of Citrobacter freundii tyrosine phenol-lyase (TPL) has been prepared. M379A TPL is a robust catalyst to prepare a number of tyrosines substituted at the 3-position with bulky groups that cannot be made with wild type TPL. The three dimensional structures of M379A TPL complexed with L-methionine and 3-bromo-DL-phenylalanine have been determined by X-ray crystallography. Methionine is bound as a quinonoid complex in a closed active site in 3 of 4 chains of homotetrameric M379A TPL. M379A TPL reacts with L-methionine about 8-fold slower than wild type TPL. The temperature dependence shows that the slower reaction is due to less positive activation entropy. The structure of the M379A TPL complex of 3-bromo-DL-phenylalanine has a quinonoid complex in two subunits, with an open active site conformation. The effects of the M379A mutation on TPL suggest that the mutant enzyme has altered the conformational dynamics of the active site.

Family Practices in Transforming Clinical Practice Initiative Showed No Changes in Medicare Costs or Utilization.

BACKGROUND: The Centers for Medicare and Medicaid Services proposed that the Transforming Clinical Practice Initiative (TCPI) would improve health outcomes for patients, reduce utilization of institutional services, and generate significant savings for payers by the end of September 2019. OBJECTIVE: The objective of this study was to investigate whether participation in TCPI's Practice Transformation Networks (PTNs) was associated with improved cost and utilization outcomes for Medicare patients of family medicine-based practices in the first 2 years, that is, 2016-2017, of the Initiative. STUDY DESIGN: A quasi-experimental design with a longitudinal cohort of family medicine-based practices and a propensity-matched comparison sample. SUBJECTS: A total of 761 PTN practices and 3451 non-PTN practices. MEASURES: To measure practice-level patient outcomes, we attributed patients to practice based on the plurality of office visits. We obtained Medicare claims from 2011 to 2017 to assess PTN participation effects for Medicare Part A and B costs, hospital admission, and emergency department visit rates using a Difference-in-Differences design, adjusting for baseline characteristics. RESULTS: The differences in Medicare Part A and B costs (-1.71%, P=0.25), annual rates of hospitalization (-0.59%, P=0.12) and emergency department visit (-0.29%, P=0.46) were not significantly lower among PTN practices (N=761) than among propensity score-matched non-PTN practices (N=3541). CONCLUSIONS: TCPI's transforming efforts, such as the outcomes examined in the study, might need a longer time frame to manifest and require evaluation after the full 4-year participation period. The indistinguishable effect of PTN participation may also be attributed to the fact that non-PTN practices might have participated in other initiatives that changed their care and curbed health care utilization and costs consequently.

The crystal structure of the S154Y mutant carbonyl reductase from Leifsonia xyli explains enhanced activity for 3,5-bis(trifluoromethyl)acetophenone reduction.

Carbonyl reductase from Leifsonia xyli (LXCAR, UniProtKB - T2FLN4) can stereoselectively catalyze the reduction of 3,5-bis(trifluoromethyl)acetophenone (BTAP) to its corresponding alcohol, (R)-[3,5-bis(trifluoromethyl)phenyl]ethanol ((R)-BTPE), which is a valuable chiral intermediate for the synthesis of antiemetic drugs, Aprepitant and Fosaprepitant. Moreover, this protein was found to have a broad spectrum of substrate specificity and can asymmetrically catalyze the reduction of a variety of ketones and keto esters. Even though molecular modelling of this protein was done by Wang et al. (2014), a crystal structure has not yet obtained. In this study, a single mutant, S154Y, which was shown to have higher catalytic activity toward BTAP than that of the wild type, was overexpressed in Escherichia coli BL21 (DE3), purified, and crystallized. The crystal structure of LXCAR-S154Y explains how the mutant enzyme can work with BTAP more efficiently than wild type carbonyl reductase. Furthermore, the structure explains why LXCAR-S154Y can use either NADH or NADPH efficiently as a cofactor, as well as elucidates a proton relay system present in the enzyme.

The Y430F mutant of Salmonella d-ornithine/d-lysine decarboxylase has altered stereospecificity and a putrescine allosteric activation site.

Tyrosine-430 of d-ornithine/d-lysine decarboxylase (DOKDC) is located in the active site, and was suggested to be responsible for the D-stereospecificity of the enzyme. We have prepared the Y430F mutant form of Salmonella enterica serovar typhimurium DOKDC and evaluated its catalytic activity with D- and l-lysine and ornithine. The kinetic results show that the Y430F mutant has measurable decarboxylase activity with both D- and l-lysine and ornithine, which wild type DOKDC does not. Spectroscopic experiments show that these amino acids bind to form external aldimine complexes with the pyridoxal-5'-phosphate with λmax = 425 nm. In addition, we have obtained crystal structures of Y430F DOKDC bound to HEPES, putrescine, d-ornithine, d-lysine, and d-arginine. The d-amino acids bind in the crystals to form equilibrium mixtures of gem-diamine and external aldimine complexes. Furthermore, the crystal structures reveal an unexpected allosteric product activator site for putrescine located on the 2-fold axis between the two active sites. Putrescine binds by donating hydrogen bonds from the ammonium groups to Asp-361 and Gln-358 in the specificity helix of both chains. Addition of 0.1-1 mM putrescine eliminates the lag in steady state kinetics and abolishes the sigmoid kinetics. The catalytic loop was modeled with AlphaFold2, and the model shows that Glu-181 can form additional hydrogen bonds with the bound putrescine, likely stabilizing the catalytic closed conformation.

Predicting relapse or recurrence of depression: systematic review of prognostic models.

BACKGROUND: Relapse and recurrence of depression are common, contributing to the overall burden of depression globally. Accurate prediction of relapse or recurrence while patients are well would allow the identification of high-risk individuals and may effectively guide the allocation of interventions to prevent relapse and recurrence. AIMS: To review prognostic models developed to predict the risk of relapse, recurrence, sustained remission, or recovery in adults with remitted major depressive disorder. METHOD: We searched the Cochrane Library (current issue); Ovid MEDLINE (1946 onwards); Ovid Embase (1980 onwards); Ovid PsycINFO (1806 onwards); and Web of Science (1900 onwards) up to May 2021. We included development and external validation studies of multivariable prognostic models. We assessed risk of bias of included studies using the Prediction model risk of bias assessment tool (PROBAST). RESULTS: We identified 12 eligible prognostic model studies (11 unique prognostic models): 8 model development-only studies, 3 model development and external validation studies and 1 external validation-only study. Multiple estimates of performance measures were not available and meta-analysis was therefore not necessary. Eleven out of the 12 included studies were assessed as being at high overall risk of bias and none examined clinical utility. CONCLUSIONS: Due to high risk of bias of the included studies, poor predictive performance and limited external validation of the models identified, presently available clinical prediction models for relapse and recurrence of depression are not yet sufficiently developed for deploying in clinical settings. There is a need for improved prognosis research in this clinical area and future studies should conform to best practice methodological and reporting guidelines.

Physicians' Choice of Board Certification Activity Is Unaffected by Baseline Quality of Care: The TRADEMaRQ Study.

PURPOSE: Physicians' use of self-assessment to guide quality improvement or board certification activities often does not correlate with more objective measures, and they may spend valuable time on activities that support their strengths instead of addressing gaps. Our objective was to study whether viewing quality measures, with peer comparisons, would affect the selection of certification activities. METHODS: We conducted a cluster-randomized controlled trial-the Trial of Data Exchange for Maintenance of certification and Raising Quality (TRADEMaRQ)-with 4 partner organizations during 2015-2017. Physicians were presented their quality data within their online certification portfolios before (intervention) vs after (control) they chose board certification activities. The primary outcome was whether the selected activity addressed a quality gap (a quality area in which the physician scored below the mean for the study population). RESULTS: Of 2,570 invited physicians, 254 physicians completed the study: 130 in the intervention group and 124 in the control group. Nearly one-fifth of participating physicians did not complete any certification activities during the study. A sizable minority of those in the intervention group, 18.4%, never reviewed their quality dashboard. Overall, just 27.2% of completed certification activities addressed a quality gap, and there was no significant difference in this outcome in the intervention group vs the control group in either bivariate or adjusted analyses (odds ratio = 1.28; 95% CI, 0.90-1.82). CONCLUSIONS: Physicians did not use quality performance data in choosing certification activities. Certification boards are being pressed to make their programs relevant to practice, less burdensome, and supportive of quality improvement in alignment with value-based payment models. Using practice data to drive certification choices would meet these goals.