ABSTRACT
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.
Subject(s)
Chlamydia Infections , Mass Screening , Primary Health Care , Humans , Female , United States , Male , Chlamydia Infections/diagnosis , Adult , Adolescent , Young Adult , Middle Aged , RegistriesABSTRACT
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.
Subject(s)
Central Nervous System Neoplasms , Proton Therapy , Humans , Proton Therapy/methods , Proton Therapy/adverse effects , Central Nervous System Neoplasms/radiotherapy , Child , Adolescent , Young Adult , Treatment Outcome , AdultABSTRACT
PURPOSE: The COVID-19 pandemic not only exacerbated existing disparities in health care in general but likely worsened disparities in access to primary care. Our objective was to quantify the nationwide decrease in primary care visits and increase in telehealth utilization during the pandemic and explore whether certain groups of patients were disproportionately affected. METHODS: We used a geographically diverse primary care electronic health record data set to examine the following 3 outcomes: (1) change in total visit volume, (2) change in in-person visit volume, and (3) the telehealth conversion ratio defined as the number of pandemic telehealth visits divided by the total number of prepandemic visits. We assessed whether these outcomes were associated with patient characteristics including age, gender, race, ethnicity, comorbidities, rurality, and area-level social deprivation. RESULTS: Our primary sample included 1,652,871 patients from 408 practices. During the pandemic we observed decreases of 7% and 17% in total and in-person visit volume and a 10% telehealth conversion ratio. The greatest decreases in visit volume were observed among pediatric patients (-24%), Asian patients (-11%), and those with more comorbidities (-9%). Telehealth usage was greatest among Hispanic or Latino patients (17%) and those living in urban areas (12%). CONCLUSIONS: Decreases in primary care visit volume were partially offset by increasing telehealth use for all patients during the COVID-19 pandemic, but the magnitude of these changes varied significantly across all patient characteristics. These variations have implications not only for the long-term consequences of the COVID-19 pandemic, but also for planners seeking to ready the primary care delivery system for any future systematic disruptions.
Subject(s)
COVID-19 , Primary Health Care , SARS-CoV-2 , Telemedicine , Humans , COVID-19/epidemiology , Telemedicine/statistics & numerical data , Primary Health Care/statistics & numerical data , Female , Male , Adult , Middle Aged , Adolescent , Aged , Child , Child, Preschool , Young Adult , Infant , United States , Pandemics , Healthcare Disparities/statistics & numerical data , Healthcare Disparities/ethnology , Health Services Accessibility/statistics & numerical data , Electronic Health Records/statistics & numerical data , Infant, NewbornABSTRACT
PURPOSE: COVID-19 is a condition that can lead to other chronic conditions. These conditions are frequently diagnosed in the primary care setting. We used a novel primary care registry to quantify the burden of post-COVID conditions among adult patients with a COVID-19 diagnosis across the United States. METHODS: We used the American Family Cohort, a national primary care registry, to identify study patients. After propensity score matching, we assessed the prevalence of 17 condition categories individually and cumulatively, comparing patients having COVID-19 in 2020-2021 with (1) historical control patients having influenza-like illness in 2018 and (2) contemporaneous control patients seen for wellness or preventive visits in 2020-2021. RESULTS: We identified 28,215 patients with a COVID-19 diagnosis and 235,953 historical control patients with influenza-like illness. The COVID-19 group had higher prevalences of breathing difficulties (4.2% vs 1.9%), type 2 diabetes (12.0% vs 10.2%), fatigue (3.9% vs 2.2%), and sleep disturbances (3.5% vs 2.4%). There were no differences, however, in the postdiagnosis monthly trend in cumulative morbidity between the COVID-19 patients (trend = 0.026; 95% CI, 0.025-0.027) and the patients with influenza-like illness (trend = 0.026; 95% CI, 0.023-0.027). Relative to contemporaneous wellness control patients, COVID-19 patients had higher prevalences of breathing difficulties and type 2 diabetes. CONCLUSIONS: Our findings show a moderate burden of post-COVID conditions in primary care, including breathing difficulties, fatigue, and sleep disturbances. Based on clinical registry data, the prevalence of post-COVID conditions in primary care practices is lower than that reported in subspecialty and hospital settings.
Subject(s)
COVID-19 , Influenza, Human , Primary Health Care , Registries , SARS-CoV-2 , Humans , COVID-19/epidemiology , Male , Female , United States/epidemiology , Primary Health Care/statistics & numerical data , Middle Aged , Influenza, Human/epidemiology , Adult , Aged , Prevalence , Chronic Disease/epidemiologyABSTRACT
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.
Subject(s)
Entropy , Evolution, Molecular , Intrinsically Disordered Proteins/chemistry , Intrinsically Disordered Proteins/metabolism , Uridine Diphosphate Glucose Dehydrogenase/chemistry , Uridine Diphosphate Glucose Dehydrogenase/metabolism , Allosteric Regulation/drug effects , Amino Acid Sequence , Humans , Intrinsically Disordered Proteins/antagonists & inhibitors , Models, Molecular , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Protein Conformation , Protein Folding , Protein Unfolding , Proteome/chemistry , Proteome/metabolism , Substrate Specificity , Uridine Diphosphate Glucose Dehydrogenase/antagonists & inhibitorsABSTRACT
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.
Subject(s)
Cocaine , Male , Female , Rats , Animals , Mice , Cocaine/pharmacology , Medium Spiny Neurons , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Rats, Sprague-Dawley , Neurons/metabolism , Receptors, Dopamine D1/genetics , Receptors, Dopamine D1/metabolism , Nucleus Accumbens/metabolism , Mice, Inbred C57BL , Mice, Transgenic , MammalsABSTRACT
ABSTRACT: As physical therapists and exercise professionals, we have an obligation to promote health and well-being through participation in sport and recreational/physical activity. We play an active role in facilitating and encouraging movement for a large percentage of the population, including our transgender patients/clients. It is integral that we include transgender individuals in supportive and inclusive atmospheres of play, and it is critical for us to lead the conversation around the inclusion of the transgender community in recreational activities and sport. This commentary provides evidence for the physical therapy community to support, advocate for, and include all populations as we promote healthy habits through sport.
Subject(s)
Fear , Sports , Transgender Persons , Humans , Transgender Persons/psychology , Female , Male , Athletes/psychology , Health PromotionABSTRACT
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.
ABSTRACT
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.
Subject(s)
Leadership , Quality of Health Care , Humans , United States , Primary Health CareABSTRACT
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.
ABSTRACT
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.
Subject(s)
Physicians , Trust , Humans , Primary Health CareABSTRACT
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.
Subject(s)
Intestines/immunology , Receptors, Steroid/immunology , Tight Junctions/immunology , Toll-Like Receptor 4/immunology , Adherens Junctions/genetics , Adherens Junctions/immunology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antibodies/immunology , CD3 Complex/immunology , Caco-2 Cells , Cell Line , Female , HEK293 Cells , Humans , Indoles , Indomethacin/pharmacology , Inflammation/immunology , Intestines/microbiology , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Microbiota/immunology , Pregnane X Receptor , RNA Interference , RNA, Messenger , RNA, Small Interfering , Receptors, Steroid/genetics , Reperfusion Injury/immunology , Signal Transduction/immunology , Tight Junctions/genetics , Toll-Like Receptor 4/genetics , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
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.
Subject(s)
Antineoplastic Agents , Febrile Neutropenia , Neoplasms , Aged , Child , Humans , Australia , National Health Programs , Neoplasms/complications , Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Febrile Neutropenia/drug therapyABSTRACT
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.
Subject(s)
Antiemetics , Antineoplastic Agents , Neoplasms , Adult , Child , Humans , Antiemetics/adverse effects , Antineoplastic Agents/adverse effects , Nausea/chemically induced , Nausea/drug therapy , Nausea/prevention & control , Neoplasms/complications , Neoplasms/drug therapy , Vomiting/chemically induced , Vomiting/drug therapy , Vomiting/prevention & controlABSTRACT
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.
Subject(s)
Capitation Fee , Physicians, Primary Care , Aged , Female , Humans , Male , Medicare , Primary Health Care , Salaries and Fringe Benefits , United StatesABSTRACT
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.
Subject(s)
Protons , Thermoanaerobacter , Alcohol Dehydrogenase/chemistry , Alcohol Oxidoreductases , Binding Sites , Crystallography, X-Ray , Dimethyl Sulfoxide , Ligands , NADP/metabolism , Pentanols , Thermoanaerobacter/metabolism , ZincABSTRACT
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.
Subject(s)
Benchmarking , Mortality/trends , Neoplasms/epidemiology , Neoplasms/mortality , Registries/statistics & numerical data , Adolescent , Adult , Australia/epidemiology , Canada/epidemiology , Child , Child, Preschool , Denmark/epidemiology , Female , Follow-Up Studies , Humans , Incidence , Infant , Infant, Newborn , Male , Norway/epidemiology , Prognosis , Survival Rate , Sweden/epidemiology , United Kingdom/epidemiology , Young AdultABSTRACT
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.
Subject(s)
Tyrosine Phenol-Lyase , Catalytic Domain , Citrobacter freundii/genetics , Citrobacter freundii/metabolism , Kinetics , Methionine , Mutagenesis, Site-Directed , Phenylalanine/metabolism , Tyrosine/metabolism , Tyrosine Phenol-Lyase/chemistry , Tyrosine Phenol-Lyase/genetics , Tyrosine Phenol-Lyase/metabolismABSTRACT
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.
Subject(s)
Family Practice/methods , Patient Acceptance of Health Care/statistics & numerical data , Cohort Studies , Family Practice/standards , Family Practice/statistics & numerical data , Humans , Longitudinal Studies , Medicare/economics , Medicare/statistics & numerical data , United StatesABSTRACT
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.