Glycemic control is associated with dyslipidemia over time in youth with type 2 diabetes: The SEARCH for diabetes in youth study.

BACKGROUND: Dyslipidemia has been documented in youth with type 2 diabetes. There is a paucity of studies examining dyslipidemia over time in youth with type 2 diabetes and associated risk factors. OBJECTIVE: To evaluate lipids at baseline and follow-up and associated risk factors in youth with type 2 diabetes. METHODS: We studied 212 youth with type 2 diabetes at baseline and after an average of 7 years of follow-up in the SEARCH for Diabetes in Youth Study. Abnormal lipids were defined as high-density lipoprotein cholesterol (HDL-C) < 35, low-density lipoprotein cholesterol (LDL-C) > 100, or triglycerides >150 (all mg/dl). We evaluated participants for progression to abnormal lipids (normal lipids at baseline and abnormal at follow-up), regression (abnormal lipids at baseline and normal at follow-up), stable normal, and stable abnormal lipids over time for HDL-C, LDL-C, and triglycerides. Associations between hemoglobin A1c (HbA1c) and adiposity over time (area under the curve [AUC]) with progression and stable abnormal lipids were evaluated. RESULTS: HDL-C progressed, regressed, was stable normal, and stable abnormal in 12.3%, 11.3%, 62.3%, and 14.2% of participants, respectively. Corresponding LDL-C percentages were 15.6%, 12.7%, 42.9%, and 28.8% and triglycerides were 17.5%, 10.8%, 55.7%, and 16.0%. Each 1% increase in HbA1c AUC was associated with a 13% higher risk of progression and stable abnormal triglycerides and a 20% higher risk of progression and stable abnormal LDL-C. Higher adiposity AUC was marginally (p = 0.049) associated with abnormal HDL-C. CONCLUSIONS: Progression and stable abnormal LDL-C and triglycerides occur in youth with type 2 diabetes and are associated with higher HbA1c.

The Type 1 Diabetes-Resistance Locus Idd22 Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice.

Type 1 diabetes (T1D) has a strong genetic component. The insulin dependent diabetes (Idd)22 locus was identified in crosses of T1D-susceptible NOD mice with the strongly T1D-resistant ALR strain. The NODcALR-(D8Mit293-D8Mit137)/Mx (NOD-Idd22) recombinant congenic mouse strain was generated in which NOD mice carry the full Idd22 confidence interval. NOD-Idd22 mice exhibit almost complete protection from spontaneous T1D and a significant reduction in insulitis. Our goal was to unravel the mode of Idd22-based protection using in vivo and in vitro models. We determined that Idd22 did not impact immune cell diabetogenicity or ß cell resistance to cytotoxicity in vitro. However, NOD-Idd22 mice were highly protected against adoptive transfer of T1D. Transferred CTLs trafficked to the pancreatic lymph node and proliferated to the same extent in NOD and NOD-Idd22 mice, yet the accumulation of pathogenic CTLs in the islets was significantly reduced in NOD-Idd22 mice, correlating with disease resistance. Pancreatic endothelial cells from NOD-Idd22 animals expressed lower levels of adhesion molecules, even in response to inflammatory stimuli. Lower adhesion molecule expression resulted in weaker adherence of T cells to NOD-Idd22 endothelium compared with NOD-derived endothelium. Taken together, these results provide evidence that Idd22 regulates the ability of ß cell-autoreactive T cells to traffic into the pancreatic islets and may represent a new target for pharmaceutical intervention to potentially prevent T1D.

Combined Alkali-Organoammonium Structure Direction of High-Charge-Density Heteroatom-Containing Aluminophosphate Molecular Sieves.

The charge density mismatch concept was applied to the synthesis of high-charge-density silicoaluminophosphate SAPO-69 (OFF) and SAPO-79 (ERI) and zincoaluminophosphate PST-16 (CGS), PST-17 (BPH), PST-19 (SBS), and ZnAPO-88 (MER) molecular sieves. Combined alkali-organoammonium structure direction in these systems is thus enabled. Structure direction is treated from the perspective of stabilizing an ionic framework, the relationships between reaction charge density (OH- /H3 PO4 ), alkali and organoammonium content, and ionicity of tetrahedral framework atoms in successful structure direction are presented.

Distress sounds of thorny catfishes emitted underwater and in air: characteristics and potential significance.

Thorny catfishes produce stridulation (SR) sounds using their pectoral fins and drumming (DR) sounds via a swimbladder mechanism in distress situations when hand held in water and in air. It has been argued that SR and DR sounds are aimed at different receivers (predators) in different media. The aim of this study was to analyse and compare sounds emitted in both air and water in order to test different hypotheses on the functional significance of distress sounds. Five representatives of the family Doradidae were investigated. Fish were hand held and sounds emitted in air and underwater were recorded (number of sounds, sound duration, dominant and fundamental frequency, sound pressure level and peak-to-peak amplitudes). All species produced SR sounds in both media, but DR sounds could not be recorded in air for two species. Differences in sound characteristics between media were small and mainly limited to spectral differences in SR. The number of sounds emitted decreased over time, whereas the duration of SR sounds increased. The dominant frequency of SR and the fundamental frequency of DR decreased and sound pressure level of SR increased with body size across species. The hypothesis that catfish produce more SR sounds in air and more DR sounds in water as a result of different predation pressure (birds versus fish) could not be confirmed. It is assumed that SR sounds serve as distress sounds in both media, whereas DR sounds might primarily be used as intraspecific communication signals in water in species possessing both mechanisms.

Integrated care system leadership: a rapid realist review.

PURPOSE: Given the complex nature of integrated care systems (ICSs), the geographical spread and the large number of organisations involved in partnership delivery, the importance of leadership cannot be overstated. This paper aims to present novel findings from a rapid realist review of ICS leadership in England. The overall review question was: how does leadership in ICSs work, for whom and in what circumstances? DESIGN/METHODOLOGY/APPROACH: Development of initial programme theories and associated context-mechanism-outcome configurations (CMOCs) were supported by the theory-gleaning activities of a review of ICS strategies and guidance documents, a scoping review of the literature and interviews with key informants. A refined programme theory was then developed by testing these CMOCs against empirical data published in academic literature. Following screening and testing, six CMOCs were extracted from 18 documents. The study design, conduct and reporting were informed by the Realist And Metanarrative Evidence Syntheses: Evolving Standards (RAMESES) training materials (Wong et al., 2013). FINDINGS: The review informed four programme theories explaining that leadership in ICSs works when ICS leaders hold themselves and others to account for improving population health, a sense of purpose is fostered through a clear vision, partners across the system are engaged in problem ownership and relationships are built at all levels of the system. RESEARCH LIMITATIONS/IMPLICATIONS: Despite being a rigorous and comprehensive investigation, stakeholder input was limited to one ICS, potentially restricting insights from varied geographical contexts. In addition, the recent establishment of ICSs meant limited literature availability, with few empirical studies conducted. Although this emphasises the importance and originality of the research, this scarcity posed challenges in extracting and applying certain programme theory elements, particularly context. ORIGINALITY/VALUE: This review will be of relevance to academics and health-care leaders within ICSs in England, offering critical insights into ICS leadership, integrating diverse evidence to develop new evidence-based recommendations, filling a gap in the current literature and informing leadership practice and health-care systems.

Vitamin D Oral Replacement in Children With Obesity Related Asthma: VDORA1 Randomized Clinical Trial.

Children with asthma and obesity are more likely to have lower vitamin D levels, but the optimal replacement dose is unknown in this population. The objective of this study is identifying a vitamin D dose in children with obesity-related asthma that safely achieves serum vitamin D levels of ≥ 40 ng/mL. This prospective multisite randomized controlled trial recruited children/adolescents with asthma and body mass index ≥ 85% for age/sex. Part 1 (dose finding), evaluated 4 oral vitamin D regimens for 16 weeks to identify a replacement dose that achieved serum vitamin D levels ≥ 40 ng/mL. Part 2 compared the replacement dose calculated from part 1 (50,000 IU loading dose with 8,000 IU daily) to standard of care (SOC) for 16 weeks to identify the proportion of children achieving target serum 25(OH)D level. Part 1 included 48 randomized participants. Part 2 included 64 participants. In Part 1, no SOC participants achieved target serum level, but 50-72.7% of participants in cohorts A-C achieved the target serum level. In part 2, 78.6% of replacement dose participants achieved target serum level compared with none in the SOC arm. No related serious adverse events were reported. This trial confirmed a 50,000 IU loading dose plus 8,000 IU daily oral vitamin D as safe and effective in increasing serum 25(OH)D levels in children/adolescents with overweight/obesity to levels ≥ 40 ng/mL. Given the critical role of vitamin D in many conditions complicating childhood obesity, these data close a critical gap in our understanding of vitamin D dosing in children.

High-resolution powder X-ray data reveal the T(6) hexameric form of bovine insulin.

A series of bovine insulin samples were obtained as 14 polycrystalline precipitates at room temperature in the pH range 5.0-7.6. High-resolution powder X-ray diffraction data were collected to reveal the T6 hexameric insulin form. Sample homogeneity and reproducibility were verified by additional synchrotron measurements using an area detector. Pawley analyses of the powder patterns displayed pH- and radiation-induced anisotropic lattice modifications. The pronounced anisotropic lattice variations observed for T6 insulin were exploited in a 14-data-set Rietveld refinement to obtain an average crystal structure over the pH range investigated. Only the protein atoms of the known structure with PDB code 2a3g were employed in our starting model. A novel approach for refining protein structures using powder diffraction data is presented. In this approach, each amino acid is represented by a flexible rigid body (FRB). The FRB model requires a significantly smaller number of refinable parameters and restraints than a fully free-atom refinement. A total of 1542 stereochemical restraints were imposed in order to refine the positions of 800 protein atoms, two Zn atoms and 44 water molecules in the asymmetric unit using experimental data in the resolution range 18.2-2.7 Å for all profiles.

Knowledge of breast density and awareness of related breast cancer risk.

Little is known about women's knowledge of breast density or between-race differences in this knowledge. In the current study, we examined knowledge of breast density and awareness of its role as a breast cancer risk factor among women who had previously taken part in a breast imaging study. Seventy-seven women (54.5 % Black) returned a survey assessing perceptions and accuracy of breast density knowledge, knowledge of one's own breast density, and breast cancer risk awareness. White women had greater perceived knowledge of breast density compared to Black women; however, differences in the accuracy of definitions of breast density were due to education. Black women were less likely to know how dense their own breasts were. Black and White women both lacked awareness that having dense breast increased breast cancer risk. The results highlight the need to disseminate information regarding breast density to women, while ensuring that the information is equally accessible to both Black and White women.

Household Food Insecurity and Fear of Hypoglycemia in Adolescents and Young Adults With Diabetes and Parents of Youth With Diabetes.

OBJECTIVE: To evaluate the relation between household food insecurity (HFI) and fear of hypoglycemia among young adults with type 1 and type 2 diabetes and adolescents with type 1 diabetes and their parents. RESEARCH DESIGN AND METHODS: We analyzed cross-sectional data of 1,676 young adults with youth-onset diabetes (84% type 1, 16% type 2) and 568 adolescents (<18 years old; mean age 15.1 years) with type 1 diabetes from the SEARCH for Diabetes in Youth study. Adult participants and parents of adolescent participants completed the U.S. Household Food Security Survey Module. Adults, adolescents, and parents of adolescents completed the Hypoglycemia Fear Survey, where answers range from 1 to 4. The outcomes were mean score for fear of hypoglycemia and the behavior and worry subscale scores. Linear regression models identified associations between HFI and fear of hypoglycemia scores. RESULTS: Adults with type 1 diabetes experiencing HFI had higher fear of hypoglycemia scores (0.22 units higher for behavior, 0.55 units for worry, 0.40 units for total; all P < 0.0001) than those without HFI. No differences by HFI status were found for adolescents with type 1 diabetes. Parents of adolescents reporting HFI had a 0.18 unit higher worry score than those not reporting HFI (P < 0.05). Adults with type 2 diabetes experiencing HFI had higher fear of hypoglycemia scores (0.19 units higher for behavior, 0.35 units for worry, 0.28 units for total; all P < 0.05) than those in food secure households. CONCLUSIONS: Screening for HFI and fear of hypoglycemia among people with diabetes can help providers tailor diabetes education for those who have HFI and therefore fear hypoglycemia.

Short-term changes in ultrasound tomography measures of breast density and treatment-associated endocrine symptoms after tamoxifen therapy.

Although breast density decline with tamoxifen therapy is associated with greater therapeutic benefit, limited data suggest that endocrine symptoms may also be associated with improved breast cancer outcomes. However, it is unknown whether endocrine symptoms are associated with reductions in breast density after tamoxifen initiation. We evaluated treatment-associated endocrine symptoms and breast density change among 74 women prescribed tamoxifen in a 12-month longitudinal study. Treatment-associated endocrine symptoms and sound speed measures of breast density, assessed via novel whole breast ultrasound tomography (m/s), were ascertained before tamoxifen (T0) and at 1-3 (T1), 4-6 (T2), and 12 months (T3) after initiation. CYP2D6 status was genotyped, and tamoxifen metabolites were measured at T3. Using multivariable linear regression, we estimated mean change in breast density by treatment-associated endocrine symptoms adjusting for age, race, menopausal status, body mass index, and baseline density. Significant breast density declines were observed in women with treatment-associated endocrine symptoms (mean change (95% confidence interval) at T1:-0.26 m/s (-2.17,1.65); T2:-2.12 m/s (-4.02,-0.22); T3:-3.73 m/s (-5.82,-1.63); p-trend = 0.004), but not among women without symptoms (p-trend = 0.18) (p-interaction = 0.02). Similar declines were observed with increasing symptom frequency (p-trends for no symptoms = 0.91; low/moderate symptoms = 0.03; high symptoms = 0.004). Density declines remained among women with detectable tamoxifen metabolites or intermediate/efficient CYP2D6 metabolizer status. Emergent/worsening endocrine symptoms are associated with significant, early declines in breast density after tamoxifen initiation. Further studies are needed to assess whether these observations predict clinical outcomes. If confirmed, endocrine symptoms may be a proxy for tamoxifen response and useful for patients and providers to encourage adherence.

Structural studies of human insulin cocrystallized with phenol or resorcinol via powder diffraction.

The effects of the ligands phenol and resorcinol on the crystallization of human insulin have been investigated as a function of pH. Powder diffraction data were used to characterize several distinct polymorphic forms. A previously unknown polymorph with monoclinic symmetry (P2(1)) was identified for both types of ligand with similar characteristics [the unit-cell parameters for the insulin-resorcinol complex were a = 114.0228 (8), b = 335.43 (3), c = 49.211 (6) Å, ß = 101.531 (8)°].

Prevalence and impact of initial misclassification of pediatric type 1 diabetes mellitus.

PURPOSE: To characterize rates of initial misclassification of type 1 diabetes mellitus as type 2/unspecified diabetes mellitus in a cohort of children/adolescents and to examine the impact of misclassification on the risk of diabetes-related complications. METHODS: An 11-year dataset (1996-2006) was analyzed. Inclusion criteria included age 17 years and younger, enrollees in South Carolina State Medicaid, and diagnosis of type 2/unspecified or type 1 diabetes mellitus for at least two visits, 15 days apart. Survival analysis was used to assess the association of "misclassification" with the incidence of diabetic ketoacidosis (DKA), and the cumulative incidence of neuropathy, nephropathy, and cardiovascular complications, after controlling for individual risk factors and comorbid conditions. RESULTS: A total of 1130 individuals meeting the inclusion criteria were studied for a median of 7 years. Of the 1130 individuals, 669 (59.2%) maintained a diagnosis of type 2/unspecified diabetes mellitus, 205 (18.1%) were consistently diagnosed as type 1 diabetes mellitus, and the remaining 256 individuals (22.7%) were misclassified. Insulin treatment was used in 100% of the type 1 diabetes mellitus group and 73% of the misclassified group. Compared with the type 2 diabetes mellitus group, being misclassified was associated with earlier development of DKA (adjusted hazard ratio [aHR] 5.08, 95% confidence interval [CI] 3.09-8.37), neuropathy (aHR 1.94, CI 1.31-2.88), and nephropathy (aHR 1.72, CI 1.19-2.50), whereas being consistently classified with type 1 diabetes mellitus was associated only with earlier development of DKA (aHR 4.96, CI 2.56-9.61). CONCLUSIONS: Proper categorization of pediatric diabetes can be challenging, especially with comorbid obesity. Failure to ascertain type 1 diabetes mellitus in a timely manner in a pediatric population may increase the risk of substandard care and diabetes-related complications.

Facilitators and barriers to pediatric clinical trial recruitment and retention in rural and community settings: A scoping review of the literature.

Children in rural settings are under-represented in clinical trials, potentially contributing to rural health disparities. We performed a scoping review describing available literature on barriers and facilitators impacting participation in pediatric clinical trials in rural and community-based (nonclinical) settings. Articles identified via PubMed, CINAHL, Embase, and Web of Science were independently double-screened at title/abstract and full-text levels to identify articles meeting eligibility criteria. Included articles reported on recruitment or retention activities for US-based pediatric clinical studies conducted in rural or community-based settings and were published in English through January 2021. Twenty-seven articles describing 31 studies met inclusion criteria. Most articles reported on at least one study conducted in an urban or suburban or unspecified community setting (n = 23 articles; 85%); fewer (n = 10; 37%) reported on studies that spanned urban and rural settings or were set in rural areas. More studies discussed recruitment facilitators (n = 25 studies; 81%) and barriers (n = 19; 61%) versus retention facilitators (n = 15; 48%) and barriers (n = 8; 26%). Descriptions of recruitment and retention barriers and facilitators were primarily experiential or subjective. Recruitment and retention facilitators were similar across settings and included contacts/reminders, community engagement, and relationship-building, consideration of participant logistics, and incentives. Inadequate staff and resources were commonly cited recruitment and retention barriers. Few studies have rigorously examined optimal ways to recruit and retain rural participants in pediatric clinical trials. To expand the evidence base, future studies examining recruitment and retention strategies should systematically assess and report rurality and objectively compare relative impact of different strategies.

Rapid Reductions in Breast Density following Tamoxifen Therapy as Evaluated by Whole-Breast Ultrasound Tomography.

PURPOSE: Women whose mammographic breast density declines within 12-18 months of initiating tamoxifen for chemoprevention or adjuvant treatment show improved therapeutic responses compared with those whose density is unchanged. We tested whether measuring changes in sound speed (a surrogate of breast density) using ultrasound tomography (UST) could enable rapid identification of favorable responses to tamoxifen. METHODS: We evaluated serial density measures at baseline and at 1 to 3, 4 to 6, and 12+ months among 74 women (aged 30-70 years) following initiation of tamoxifen for clinical indications, including an elevated risk of breast cancer (20%) and diagnoses of in situ (39%) or invasive (40%) breast carcinoma, enrolled at Karmanos Cancer Institute and Henry Ford Health System (Detroit, MI, USA). For comparison, we evaluated an untreated group with screen negative mammography and frequency-matched on age, race, and menopausal status (n = 150), at baseline and 12 months. Paired t-tests were used to assess differences in UST sound speed over time and between tamoxifen-treated and untreated patients. RESULTS: Sound speed declined steadily over the 12 month period among patients receiving tamoxifen (mean (SD): -3.0 (8.2) m/s; p = 0.001), whereas density remained unchanged in the untreated group (mean (SD): 0.4 (7.1) m/s; p = 0.75 (relative change between groups: p = 0.0009)). In the tamoxifen group, we observed significant sound speed reductions as early as 4-6 months after tamoxifen initiation (mean (SD): -2.1 (6.8) m/s; p = 0.008). Sound speed reductions were greatest among premenopausal patients (P-interaction = 0.0002) and those in the middle and upper tertiles of baseline sound speed (P-interaction = 0.002). CONCLUSIONS: UST can image rapid declines in sound speed following initiation of tamoxifen. Given that sound speed and mammographic density are correlated, we propose that UST breast imaging may capture early responses to tamoxifen, which in turn may have utility in predicting therapeutic efficacy.

What settings have been linked to SARS-CoV-2 transmission clusters?

Background: Concern about the health impact of novel coronavirus SARS-CoV-2 has resulted in widespread enforced reductions in people's movement ("lockdowns"). However, there are increasing concerns about the severe economic and wider societal consequences of these measures. Some countries have begun to lift some of the rules on physical distancing in a stepwise manner, with differences in what these "exit strategies" entail and their timeframes. The aim of this work was to inform such exit strategies by exploring the types of indoor and outdoor settings where transmission of SARS-CoV-2 has been reported to occur and result in clusters of cases. Identifying potential settings that result in transmission clusters allows these to be kept under close surveillance and/or to remain closed as part of strategies that aim to avoid a resurgence in transmission following the lifting of lockdown measures. Methods: We performed a systematic review of available literature and media reports to find settings reported in peer reviewed articles and media with these characteristics. These sources are curated and made available in an editable online database. Results: We found many examples of SARS-CoV-2 clusters linked to a wide range of mostly indoor settings. Few reports came from schools, many from households, and an increasing number were reported in hospitals and elderly care settings across Europe. Conclusions: We identified possible places that are linked to clusters of COVID-19 cases and could be closely monitored and/or remain closed in the first instance following the progressive removal of lockdown restrictions. However, in part due to the limits in surveillance capacities in many settings, the gathering of information such as cluster sizes and attack rates is limited in several ways: inherent recall bias, biased media reporting and missing data.

A Novel Marker, Based on Ultrasound Tomography, for Monitoring Early Response to Neoadjuvant Chemotherapy.

OBJECTIVE: To evaluate the combination of tumor volume and sound speed as a potential imaging marker for assessing neoadjuvant chemotherapy (NAC) response. METHODS: This study was carried out under an IRB-approved protocol (written consent required). Fourteen patients undergoing NAC for invasive breast cancer were examined with ultrasound tomography (UST) throughout their treatment. The volume (V) and the volume-averaged sound speed (VASS) of the tumors and their changes were measured for each patient. Time-dependent response curves of V and VASS were constructed individually for each patient and then as averages for the complete versus partial response groups in order to characterize differences between the two groups. Differences in group means were assessed for statistical significance using t-tests. Differences in shapes of group curves were evaluated with Kolmogorov-Smirnoff tests. RESULTS: On average, tumor volume and sound speed in the partial response group showed a gradual decline in the first 60 days of treatment, while the complete response group showed a much steeper decline (P < 0.05). The shapes of the response curves of the two groups, corresponding to the entire treatment period, were also found to be significantly different (P < 0.05). Furthermore, large simultaneous drops in volume and sound speed in the first 3 weeks of treatment were characteristic only of the complete responders (P < 0.05). CONCLUSION: This study demonstrates the feasibility of using UST to monitor NAC response, warranting future studies to better define the potential of UST for noninvasive, rapid identification of partial versus complete responders in women undergoing NAC.

Three biomarker tests to help diagnose preterm labour: a systematic review and economic evaluation.

BACKGROUND: Preterm birth may result in short- and long-term health problems for the child. Accurate diagnoses of preterm births could prevent unnecessary (or ensure appropriate) admissions into hospitals or transfers to specialist units. OBJECTIVES: The purpose of this report is to assess the test accuracy, clinical effectiveness and cost-effectiveness of the diagnostic tests PartoSure™ (Parsagen Diagnostics Inc., Boston, MA, USA), Actim® Partus (Medix Biochemica, Espoo, Finland) and the Rapid Fetal Fibronectin (fFN)® 10Q Cassette Kit (Hologic, Inc., Marlborough, MA, USA) at thresholds ≠50 ng/ml [quantitative fFN (qfFN)] for women presenting with signs and symptoms of preterm labour relative to fFN at 50 ng/ml. METHODS: Systematic reviews of the published literature were conducted for diagnostic test accuracy (DTA) studies of PartoSure, Actim Partus and qfFN for predicting preterm birth, the clinical effectiveness following treatment decisions informed by test results and economic evaluations of the tests. A model-based economic evaluation was also conducted to extrapolate long-term outcomes from the results of the diagnostic tests. The model followed the structure of the model that informed the 2015 National Institute for Health and Care Excellence guidelines on preterm labour diagnosis and treatment, but with antenatal steroids use, as opposed to tocolysis, driving health outcomes. RESULTS: Twenty studies were identified evaluating DTA against the reference standard of delivery within 7 days and seven studies were identified evaluating DTA against the reference standard of delivery within 48 hours. Two studies assessed two of the index tests within the same population. One study demonstrated that depending on the threshold used, qfFN was more or less accurate than Actim Partus, whereas the other indicated little difference between PartoSure and Actim Partus. No study assessing qfFN and PartoSure in the same population was identified. The test accuracy results from the other included studies revealed a high level of uncertainty, primarily attributable to substantial methodological, clinical and statistical heterogeneity between studies. No study compared all three tests simultaneously. No clinical effectiveness studies evaluating any of the three biomarker tests were identified. One partial economic evaluation was identified for predicting preterm birth. It assessed the number needed to treat to prevent a respiratory distress syndrome case with a 'treat-all' strategy, relative to testing with qualitative fFN. Because of the lack of data, our de novo model involved the assumption that management of pregnant women fully adhered to the results of the tests. In the base-case analysis for a woman at 30 weeks' gestation, Actim Partus had lower health-care costs and fewer quality-adjusted life-years (QALYs) than qfFN at 50 ng/ml, reducing costs at a rate of £56,030 per QALY lost compared with qfFN at 50 ng/ml. PartoSure is less costly than Actim Partus while being equally effective, but this is based on diagnostic accuracy data from a small study. Treatment with qfFN at 200 ng/ml and 500 ng/ml resulted in lower cost savings per QALY lost relative to fFN at 50 ng/ml than treatment with Actim Partus. In contrast, qfFN at 10 ng/ml increased QALYs, by 0.002, and had a cost per QALY gained of £140,267 relative to fFN at 50 ng/ml. Similar qualitative results were obtained for women presenting at different gestational ages. CONCLUSION: There is a high degree of uncertainty surrounding the test accuracy and cost-effectiveness results. We are aware of four ongoing UK trials, two of which plan to enrol > 1000 participants. The results of these trials may significantly alter the findings presented here. STUDY REGISTRATION: The study is registered as PROSPERO CRD42017072696. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Infants may suffer from health problems if they are born early. If a mother has symptoms of labour before her baby is due, a test could be used to predict if the symptoms are real or a false alarm. A test could help the doctor to decide whether the mother needs treatment or to move to a specialist hospital or if she could be sent home (if it is a false alarm). Our report compares three tests [PartoSure™ (Parsagen Diagnostics Inc., Boston, MA, USA), Actim^® Partus (Medix Biochemica, Espoo, Finland) and the Fetal Fibronectin (fFN) Test (Hologic, Inc., Marlborough, MA, USA)] on how well they predict an early birth and how the costs and the long-term health outcomes of the child compare between and among tests. All the published literature reporting the accuracy of the three tests and their costs was reviewed. We developed a new cost-effectiveness model, which estimated the long-term health outcomes of the child based on the test results. Twenty of the studies reviewed looked at how good the tests were at predicting an early birth within the next 7 days, and six looked at predicting birth within 48 hours. The designs of the studies and the women taking part in the studies varied greatly. This meant that comparing the accuracy of the tests was very difficult and it would be unfair to decide which test was the best. Our model suggested no firm conclusions for the cost-effectiveness of fFN compared with Actim Partus. PartoSure appears to be less costly than Actim Partus and equally good at predicting preterm birth, but this is based on a study of very few patients. There were no data that allowed us to compare all three tests together. The accuracy of the results is uncertain, mainly because all the studies are very different. We are aware of four related UK trials that are currently ongoing that plan to include large numbers of women.

Effects of Parkinson's disease and dopamine on digit span measures of working memory.

RATIONALE: Parkinson's disease (PD) impairs working memory (WM)-the ability to maintain items in memory for short periods of time and manipulate them. There is conflicting evidence on the nature of the deficits caused by the disease, and the potential beneficial and detrimental effects of dopaminergic medication on different WM processes. OBJECTIVES: We hypothesised that PD impairs both maintenance and manipulation of items in WM and dopaminergic medications improve this in PD patients but impair it in healthy older adults. METHODS: We tested 68 PD patients ON and OFF their dopaminergic medication, 83 healthy age-matched controls, and 30 healthy older adults after placebo and levodopa administration. We used the digit span, a WM test with three components (forwards, backwards, and sequence recall) that differ in the amount of manipulation required. We analysed the maximum spans and the percentage of lists correctly recalled, which probe capacity of WM and the accuracy of the memory processes within this capacity, respectively. RESULTS: PD patients had lower WM capacity across all three digit span components, but only showed reduced percentage accuracy on the components requiring manipulation (backwards and sequence spans). Dopaminergic medication did not affect performance in PD patients. In healthy older adults, levodopa did not affect capacity, but did impair accuracy on one of the manipulation components (sequence), without affecting the other (backwards). CONCLUSIONS: This suggests that the deficit of maintenance capacity and manipulation accuracy in PD patients is not primarily a dopaminergic one and supports a potential "overdosing" of intact manipulation mechanisms in healthy older adults by levodopa.