Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set.

BACKGROUND: A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. PATIENTS AND METHODS: This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. RESULTS: Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). CONCLUSION: In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. CLINICAL TRIAL NUMBER: NCT02889978.

Nurses' and physicians' experiences with diabetes consultations and the use of dialogue tools in the DiaPROM pilot trial: A qualitative study.

AIM: To explore nurses' and physicians' experiences with diabetes consultations in general and the use of dialogue tools in the Diabetes Patient-Related Outcome Measures (DiaPROM) pilot trial. METHODS: We used a qualitative explorative design by conducting semi-structured in-depth interviews with five nurses and nine physicians engaged in the DiaPROM pilot trial. The pilot trial aimed to test an intervention utilizing the patient-reported Problem Areas In Diabetes (PAID) scale and person-centred communication skills as dialogue tools in clinical consultations with adults with type 1 diabetes. We used thematic analysis to analyse the data. RESULTS: We generated three themes (each including two subthemes) from the analysis of participants' experiences: (1) 'Conflicting demands and priorities' (subthemes: 'Balancing guideline recommendations with patients' main concerns' and 'Experiencing that patients need more support to disclose their emotional concerns'); (2) 'Insights about using dialogue tools' (subthemes: 'The benefits and challenges of using the PAID as a dialogue tool' and 'Communication techniques are helpful'); and (3) 'Facilitating new interventions is challenging' (subthemes: 'Unclear roles and responsibilities in the multidisciplinary teamwork' and 'The capacity sets the limit, not the willingness'). CONCLUSIONS: Our findings indicate that the physicians and nurses experienced substantial challenges related to time and resources in the use of dialogue tools to support people's emotional concerns in clinical diabetes consultations. Thus, there is a need for healthcare organizations to adjust priorities to focus on the emotional burden of diabetes if the multidisciplinary diabetes teams are to successfully integrate psychosocial support into routine diabetes care.

Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.

Dendritic cell phenotype in severe asthma reflects clinical responsiveness to glucocorticoids.

BACKGROUND: Subsets of patients with severe asthma remain symptomatic despite prolonged, high-dose glucocorticoid therapy. We hypothesized that the clinical glucocorticoid sensitivity of these asthmatics is reflected in differences in peripheral blood dendritic cell subsets. OBJECTIVE: To compare peripheral blood leucocyte populations using flow cytometry at baseline and after 2 weeks of systemic glucocorticoid (steroid) treatment to identify immunological differences between steroid-sensitive (SS) and steroid-resistant (SR) asthmatics. METHODS: Adult severe asthmatics (SS n = 12; SR n = 23) were assessed for their response to 2 weeks of therapy with oral prednisolone. Peripheral blood was obtained before and after therapy and stained for lymphocyte (CD3, CD19, CD4, CD8 and Foxp3) and dendritic cell markers (Lineage negative [CD3, CD14, CD16, CD19, CD20, CD56], HLA-DR+, CD304, CD11c, ILT3 and CD86). RESULTS: A higher median frequency of myeloid DCs (mDCs) but not plasmacytoid DCs (pDCs) was observed in the blood of SR as compared to SS asthmatics (P = .03). Glucocorticoid therapy significantly increased median B cell, but not T cell numbers in both cohorts, with a trend for increased numbers of Foxp3+ Tregs in SS (P = .07), but not SR subjects. Oral prednisolone therapy significantly reduced the median numbers and frequencies of total DCs and pDCs in both SS and SR asthmatics. Interestingly, the expression of HLA-DR and ILT3 was also reduced on pDCs in all patients. In contrast, therapy increased the median frequency of mDCs in SS, but reduced it in SR asthmatics. CONCLUSIONS: Myeloid DC frequency is elevated in SR compared with SS asthmatics, and mDC shows a differential response to oral prednisolone therapy.

The actin binding protein scinderin acts in PC12 cells to tether dense-core vesicles prior to secretion.

Mechanistic understanding of the control of vesicle motion from within a secretory cell to the site of exocytosis remains incomplete. In this work, we have used total internal reflection (TIRF) microscopy to examine the mobility of secretory vesicles at the plasma membrane. Under resting conditions, we found vesicles showed little lateral mobility. Anchoring of vesicles in this membrane proximal compartment could be disrupted with latrunculin A, indicating an apparent actin dependent process. A candidate intermediary between vesicles and the actin skeleton is the actin binding protein scinderin. Co-transfection of an shRNA construct against scinderin blocked secretion, and also increased the mobility of vesicles in the membrane-proximal section of the cell, indicating a dual role for scinderin in secretion; tethering vesicles to the cytoskeleton, as well as liberating them following stimulation through the previously described calcium dependent actin severing activity. Analysis of lipid dependence indicates that scinderin exhibits calcium dependent binding to phosphatidyl-inositol monophosphate, providing a possible mechanism for vesicle binding.

Community-based nutrition intervention to promote oral health and restore healthy body weight in refugee children: a scoping review.

OBJECTIVE: To determine the scope and quality of evidence on the effectiveness of community-based nutrition interventions to promote oral health and restore healthy body weight in school-aged refugee children. BASIC RESEARCH DESIGN: Scoping review using a systematic approach. MAIN OUTCOME MEASURES: Oral health and body weight. RESULTS: Four primary studies, two evaluation studies and one systematic review met the inclusion criteria. No nutrition interventions or reviews to promote oral health in school-aged refugee children were found. There is limited weak evidence for the effectiveness of community-based nutrition interventions to restore healthy body weight in refugee settings. A systematic review also reported weak evidence of correction of child body weight as a result of community-based nutrition interventions in refugee camps. CONCLUSION: This scoping review found no community-based nutrition interventions for school-aged refugee children to promote oral health and restore healthy body weight. There is limited and weak evidence for the effectiveness of community-based nutrition interventions to restore healthy body weight in refugee settings. There is a need to conduct an early phase study to develop and co-produce community-based nutrition interventions to promote oral health and healthy body weight for children residing in long-term refugee situations and to investigate the feasibility for their implementation.

PeP-SCOT a health coaching intervention for people in prisons: the development of the intervention protocol.

There is a need for an alternative approach for health promotion prisons since previous work has indicated that health education, while improving health knowledge, does not result in behaviour change. Evidence has suggested that a health coaching assists in this regard. However, the question remained whether this approach would be appropriate and possible in prisons? This paper presents the public health strategies used to work in partnership with prison management to address challenges and accept opportunities as a health coaching intervention protocol was developed for oral health and wellbeing in the prison setting.

Using the simplified case mix tool (sCMT) to identify cost in special care dental services to support commissioning.

To commission dental services for vulnerable (special care) patient groups effectively, consistently and fairly an evidence base is needed of the costs involved. The simplified Case Mixed Tool (sCMT) can assess treatment mode complexity for these patient groups. OBJECTIVE: To determine if the sCMT can be used to identify costs of service provision. CLINICAL SETTING: Patients (n=495) attending the Sussex Community NHS Trust Special Care Dental Service for care were assessed using the sCMT. MAIN MEASURES: sCMT score and costs (staffing, laboratory fees, etc.) besides patient age, whether a new patient and use of general anaesthetic/intravenous sedation. METHOD: Statistical analysis (adjusted linear regression modelling) compared sCMT score and costs then sensitivity analyses of the costings to age, being a new patient and sedation use were undertaken. Regression tables were produced to present estimates of service costs. RESULTS: Costs increased with sCMT total scale and single item values in a predictable manner in all analyses except for 'cooperation'. Costs increased with the use of IV sedation; with each rising level of the sCMT, and with complexity in every sCMT category, except cooperation. CONCLUSION: Costs increased with increase in complexity of treatment mode as measured by sCMT scores. Measures such as the sCMT can provide predictions of the resource allocations required when commissioning special care dental services.

Injuries at the Whistler Sliding Center: a 4-year retrospective study.

BACKGROUND: The Whistler Sliding Centre (WSC) in British Columbia, Canada, has played host to many events including the 2010 Winter Olympics. This study was performed to better understand sliding sport incident (crash, coming off sled, etc) and injury prevalence and provide novel insights into the effect of slider experience and track-specific influences on injury risk and severity. METHODS: Track documentation and medical records over 4 years (2007 track inception to 2011) were used to form 3 databases, including over 43,200 runs (all sliding disciplines). Statistics were generated relating incident and injury to start location, crash location and slider experience as well as to understand injury characteristics. RESULTS: Overall injury rate was found to be 0.5%, with more severe injury occurring in <0.1% of the total number of runs. More frequent and severe injuries were observed at lower track locations. Of 2605 different sliders, 73.6% performed 1-29 runs down the track. Increased slider experience was generally found to reduce the frequency of injury. Lacerations, abrasions and contusions represented 52% of all injuries. A fatality represented the most severe injury on the track and was the result of track ejection. CONCLUSIONS: By investigating the influence of start location, incident location and slider experience on incident and injury frequency and severity, a better understanding has been achieved of the inherent risks involved in sliding sports. Incident monitoring, with particular focus on track ejection, should be an emphasis of sliding tracks.

Docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer: a randomized phase II study.

BACKGROUND: Docetaxel/cisplatin/infusional 5-fluorouracil (5-FU; DCF) is a standard chemotherapy regimen for patients with advanced gastric cancer (GC). This phase II study evaluated docetaxel/oxaliplatin (TE), docetaxel/oxaliplatin/5-FU (TEF), and docetaxel/oxaliplatin/capecitabine (TEX) in patients with advanced GC. PATIENTS AND METHODS: Patients with metastatic or locally recurrent gastric adenocarcinoma (including carcinoma of the gastro-oesophageal junction) were randomly assigned (1 : 1 : 1) to TE, TEF, or TEX. Each regimen was tested at two doses before full evaluation at optimized dose levels. The primary end point was progression-free survival (PFS). Overall survival (OS), tumour response, and safety were also assessed. A therapeutic index (median PFS relative to the incidence of febrile neutropenia) was calculated for each regimen and compared with DCF (historical data). RESULTS: Overall, 248 patients were randomly assigned to receive optimized dose treatment. Median PFS was longer with TEF (7.66 [95% confidence interval (CI): 6.97-9.40] months) versus TE (4.50 [3.68-5.32] months) and TEX (5.55 [4.30-6.37] months). Median OS was 14.59 (95% CI: 11.70-21.78) months for TEF versus 8.97 (7.79-10.87) months for TE and 11.30 (8.08-14.03) months for TEX. The rate of tumour response (complete or partial) was 46.6% (95% CI 35.9-57.5) for TEF versus 23.1% (14.3-34.0) for TE and 25.6% (16.6-36.4) for TEX. The frequency and type of adverse events (AEs) were similar across the three arms. Common grade 3/4 AEs were fatigue (21%), sensory neuropathy (14%), and diarrhoea (13%). Febrile neutropenia was reported in 2% (TEF), 14% (TE), and 9% (TEX) of patients. The therapeutic index was improved with TEF versus TEX, TE, or DCF. CONCLUSION: These results suggest that TEF is worthy of evaluation as an arm in a phase III trial or as a backbone regimen for new targeted agents in advanced GC. CLINICALTRIALS.GOV: Identifier Trial registration number: NCT00382720.

Stepped care treatment delivery for depression: a systematic review and meta-analysis.

BACKGROUND: In stepped care models patients typically start with a low-intensity evidence-based treatment. Progress is monitored systematically and those patients who do not respond adequately step up to a subsequent treatment of higher intensity. Despite the fact that many guidelines have endorsed this stepped care principle it is not clear if stepped care really delivers similar or better patient outcomes against lower costs compared with other systems. We performed a systematic review and meta-analysis of all randomized trials on stepped care for depression. METHOD: We carried out a comprehensive literature search. Selection of studies, evaluation of study quality and extraction of data were performed independently by two authors. RESULTS: A total of 14 studies were included and 10 were used in the meta-analyses (4580 patients). All studies used screening to identify possible patients and care as usual as a comparator. Study quality was relatively high. Stepped care had a moderate effect on depression (pooled 6-month between-group effect size Cohen's d was 0.34; 95% confidence interval 0.20-0.48). The stepped care interventions varied greatly in number and duration of treatment steps, treatments offered, professionals involved, and criteria to step up. CONCLUSIONS: There is currently only limited evidence to suggest that stepped care should be the dominant model of treatment organization. Evidence on (cost-) effectiveness compared with high-intensity psychological therapy alone, as well as with matched care, is required.

Comparison of energy metabolism in liver grafts from donors after circulatory death and donors after brain death during cold storage and reperfusion.

BACKGROUND: Donation after circulatory death (DCD) liver grafts have supplemented the donor organ pool, but certain adverse outcomes have prevented exploration of the full potential of such organs. The aim of this study was to determine key differences in basic energy metabolism between DCD and donation after brainstem death (DBD) grafts. METHODS: Microdialysis samples from DCD and DBD allograft parenchyma from cold storage to 48 h after reperfusion were analysed by colorimetric methods. Interstitial lactate, pyruvate and glycerol levels were measured and the lactate/pyruvate ratio was calculated to estimate energy depletion of the grafts. Histological features of ischaemia and reperfusion injury were assessed. RESULTS: Donor age, extent of steatosis and cold ischaemia time were comparable between ten DCD and 20 DBD organs. DCD grafts had higher levels of interstitial lactate (median 11.6 versus 1.2 mmol/l; P = 0.015) and increased lactate/pyruvate ratio (792 versus 38; P = 0.001) during cold storage. There was no significant difference in glycerol levels between DCD and DBD grafts (225.1 versus 127.5 µmol/l respectively; P = 0.700). Rapid restoration of energy levels with lactate clearance, increased pyruvate levels and reduced lactate/pyruvate ratio was seen following reperfusion of functioning DCD grafts, parallel with levels in DBD grafts. Histology revealed more pronounced glycogen depletion in DCD grafts. Three allografts that failed owing to primary non-function showed energy exhaustion with severe glycogen depletion. CONCLUSION: Liver grafts from DCD donors exhibited depletion of intracellular energy reserves during cold storage. Failed allografts showed severe energy depletion. Modified organ preservation techniques to minimize organ injury related to altered energy metabolism may enable better utilization of donor organs after circulatory death.

Netmums: a phase II randomized controlled trial of a guided Internet behavioural activation treatment for postpartum depression.

BACKGROUND: Despite the high prevalence of postnatal depression (PND), few women seek help. Internet interventions may overcome many of the barriers to PND treatment use. We report a phase II evaluation of a 12-session, modular, guided Internet behavioural activation (BA) treatment modified to address postnatal-specific concerns [Netmums Helping With Depression (NetmumsHWD)]. METHOD: To assess feasibility, we measured recruitment and attrition to the trial and examined telephone session support and treatment adherence. We investigated sociodemographic and psychological predictors of treatment adherence. Effectiveness outcomes were estimated with the Edinburgh Postnatal Depression Scale (EPDS), Generalized Anxiety Disorder-7, Work and Social Adjustment Scale, Postnatal Bonding Questionnaire, and Social Provisions Scale. RESULTS: A total of 249 women were recruited via a UK parenting site, Netmums.com. A total of 83 women meeting DSM-IV criteria for major depressive disorder were randomized to NetmumsHWD (n = 41) or treatment-as-usual (TAU; n = 42). Of the 83 women, 71 (86%) completed the EPDS at post-treatment, and 71% (59/83) at the 6-month follow-up. Women completed an average of eight out of 12 telephone support sessions and five out of 12 modules. Working women and those with less support completed fewer modules. There was a large effect size favouring women who received NetmumsHWD on depression, work and social impairment, and anxiety scores at post-treatment compared with women in the TAU group, and a large effect size on depression at 6 months post-treatment. There were small effect sizes for postnatal bonding and perceived social support. CONCLUSIONS: A supported, modular, Internet BA programme can be feasibly delivered to postpartum women, offering promise to improve depression, anxiety and functioning.

Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects.

The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ≥ 30 kg m(-2) and binge eating scale scores ≥ 19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day(-1) GSK1521498, 5 mg day(-1) GSK1521498 or placebo (N=21 per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety and pharmacokinetics. The primary analysis was the comparison of change scores in the higher-dose treatment group versus placebo using analysis of covariance at each relevant time point. GSK1521498 (2 mg and 5 mg) was not different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, GSK1521498 5 mg day(-1) caused a significant reduction in hedonic responses to sweetened dairy products and reduced calorific intake, particularly of high-fat foods during ad libitum buffet meals, with some of these effects correlating with systemic exposure of GSK1521498. There were no significant effects of GSK1521498 2 mg day(-1) on eating behaviour, indicating dose dependency of pharmacodynamics. GSK1521498 was generally well tolerated and no previously unidentified safety signals were detected. The potential for these findings to translate into clinically significant effects in the context of binge eating and weight regain prevention requires further investigation.

A comparison of maternal calcium and magnesium levels in pre-eclamptic and normotensive pregnancies: an observational case-control study.

OBJECTIVE: Supplementing pregnant women at high risk of developing pre-eclampsia with calcium may reduce the incidence of the disease. This study examines differences in serum and hair concentrations of calcium and magnesium between women with pre-eclamptic and normotensive pregnancies. DESIGN: Observational case-control study. SETTING: Two teaching hospitals in Cape Town, South Africa. POPULATION: Women with pre-eclamptic (N = 96) or normotensive (N = 96) pregnancies, who delivered a single, live infant. METHODS: Demographic and current pregnancy details were retrieved from clinical notes. Each participant completed a dietary questionnaire. Venous blood samples were taken from each participant to assess serum calcium and magnesium concentrations. Hair samples were obtained from all participants and calcium and magnesium levels were measured by inductively coupled plasma optical emission spectrometry (ICPOES). MAIN OUTCOME MEASURE: Hair and serum calcium and magnesium concentrations were compared between women with pre-eclamptic and normotensive pregnancies. RESULTS: Diet and socio-economic status in the two groups were similar. There was no significant difference in the hair calcium level between women with pre-eclamptic [1241 parts per million (ppm); range, 331-4654 ppm] and normotensive (1146 ppm; range, 480-4136 ppm) pregnancies (P = 0.5). Hair calcium levels in both groups were not affected by HIV infection. CONCLUSION: Woman with pre-eclampsia showed no difference in chronic calcium status relative to normotensive women. This finding does not support the current belief that the mechanism by which calcium supplementation reduces the risk of developing pre-eclampsia is by correcting a nutritional deficiency.

A theory led narrative review of one-to-one health interventions: the influence of attachment style and client-provider relationship on client adherence.

A theory-led narrative approach was used to unpack the complexities of the factors that enable successful client adherence following one-to-one health interventions. Understanding this could prepare the provider to anticipate different adherence behaviours by clients, allowing them to tailor their interventions to increase the likelihood of adherence. The review was done in two stages. A theoretical formulation was proposed to explore factors which influence the effectiveness of one-to-one interventions to result in client adherence. The second stage tested this theory using a narrative synthesis approach. Eleven studies across the health care arena were included in the synthesis and explored the interplay between client attachment style, client-provider interaction and client adherence with health interventions. It emerged that adherence results substantially because of the relationship that the client has with the provider, which is amplified or diminished by the client's own attachment style. This occurs because the client's attachment style shapes how they perceive and behave in relationships with the health-care providers, who become the 'secure base' from which the client accepts, assimilates and adheres with the recommended health intervention. The pathway from one-to-one interventions to adherence is explained using moderated mediation and mediated moderation models.

Weighing up the weighted case mix tool (WCMT): a psychometric investigation using confirmatory factor analysis.

OBJECTIVE: To assess the use of the WCMT in two Scottish health boards and to consider the impact of simplifying the tool to improve efficient use. DESIGN: A retrospective analysis of routine WCMT data (47,276 cases). CLINICAL SETTING: Public Dental Service (PDS) within NHS Lothian and Highland. METHOD: The WCMT consists of six criteria. Each criterion is measured independently on a four-point scale to assess patient complexity and the dental care for the disabled/impaired patient. Psychometric analyses on the data-set were conducted. Conventional internal consistency coefficients were calculated. Latent variable modelling was performed to assess the 'fit' of the raw data to a pre-specified measurement model. A Confirmatory Factor Analysis (CFA) was used to test three potential changes to the existing WCMT that included, the removal of the oral risk factor question, the removal of original weightings for scoring the Tool, and collapsing the 4-point rating scale to three categories. RESULTS: The removal of the oral risk factor question had little impact on the reliability of the proposed simplified CMT to discriminate between levels of patient complexity. The removal of weighting and collapsing each item's rating scale to three categories had limited impact on reliability of the revised tool. The CFA analysis provided strong evidence that a new, proposed simplified Case Mix Tool (sCMT) would operate closely to the pre-specified measurement model (the WMCT). CONCLUSIONS: A modified sCMT can demonstrate, without reducing reliability, a useful measure of the complexity of patient care. The proposed sCMT may be implemented within primary care dentistry to record patient complexity as part of an oral health assessment.

A multicenter, randomized phase 2 study to establish combinations of CBP501, cisplatin and nivolumab for ≥3rd-line treatment of patients with advanced pancreatic adenocarcinoma.

BACKGROUND: There is no standard of care for ≥ 3rd-line treatment of metastatic pancreatic adenocarcinoma (PDAC). CBP501 is a novel calmodulin-binding peptide that has been shown to enhance the influx of platinum agents into tumor cells and tumor immunogenicity. This study aimed to (1) confirm efficacy of CBP501/cisplatin/nivolumab for metastatic PDAC observed in a previous phase 1 study, (2) identify combinations that yield 35% 3-month progression-free survival rate (3MPFS) and (3) define the contribution of CBP501 to the effects of combination therapy. METHODS: CBP501 16 or 25 mg/m2 (CBP(16) or CBP(25)) was combined with 60 mg/m2 cisplatin (CDDP) and 240 mg nivolumab (nivo), administered at 3-week intervals. Patients were randomized 1:1:1:1 to (1) CBP(25)/CDDP/nivo, (2) CBP(16)/CDDP/nivo, (3) CBP(25)/CDDP and (4) CDDP/nivo, with randomization stratified by ECOG PS and liver metastases. A Fleming two-stage design was used, yielding a one-sided type I error rate of 2.5% and 80% power when the true 3MPFS is 35%. RESULTS: Among 36 patients, 3MPFS was 44.4% in arms 1 and 2, 11.1% in arm 3% and 33.3% in arm 4. Two patients achieved a partial response in arm 1 (ORR 22.2%; none in other arms). Median PFS and OS were 2.4, 2.1, 1.5 and 1.5 months and 6.3, 5.3, 3.7 and 4.9 months, respectively. Overall, all treatment combinations were well tolerated. Most treatment-related adverse events were grade 1-2. CONCLUSIONS: The combination CBP(25)/(16)/CDDP/nivo demonstrated promising signs of efficacy and a manageable safety profile for the treatment of advanced PDAC. CLINICAL TRIAL REGISTRATION: NCT04953962.

Screening and management of renal disease in human immunodeficiency virus-infected patients in Australia.

BACKGROUND: Renal disease has become one of the most important comorbidities observed in the human immunodeficiency virus (HIV)-infected patient cohort. Data are lacking on the current screening and management of renal disease in patients with HIV. We evaluated HIV-infected Australian adults in primary care to determine current practices. METHODS: This prospective, multicentre observational study included two rounds of data collection; the first was followed by an educational programme. Outcomes included screening for renal disease; management of risk factors for kidney disease and other comorbidities associated with renal disease. RESULTS: Fifty-three general practitioners participated with 733 patients enrolled. Most were male (94%); almost 40% were 41-50 years of age, and 6% and 84% were receiving antiretroviral therapy. Comorbidities were common; 19% had hypertension, 5% were diabetic, 32% were dyslipidaemic, and 40% were smokers. Estimated glomerular filtration rate was commonly measured in both rounds of data collection (96% vs 95%). Proteinuria was assessed less frequently; this improved after education (48% vs 71%). Almost 10% of patients tested had proteinuria on urinalysis. Of the 45 patients (6%) with renal impairment (estimated glomerular filtration rate <60 mL/min), none was referred for assessment by a renal specialist. CONCLUSIONS: This large observational study provides important information on renal disease in HIV-infected patients, an area with a paucity of clinical data. Current screening and management practices fall short of suggested guidelines. Failure to refer patients to specialists is a major deficiency. Improvements with education suggest the need to promote awareness of guidelines in primary care doctors.

Parkinson disease: an update.

Parkinson disease is a progressive neurologic disorder afflicting approximately 1 percent of Americans older than 60 years. The cardinal features of Parkinson disease are bradykinesia, rigidity, tremor, and postural instability. There are a number of neurologic conditions that mimic the disease, making it difficult to diagnose in its early stages. Physicians who rarely diagnose Parkinson disease should refer patients suspected of having it to physicians with more experience in making the diagnosis, and should periodically reevaluate the accuracy of the diagnosis. Treatment is effective in reducing motor impairment and disability, and should be started when a patient begins to experience functional impairment. The combination of carbidopa and levodopa is the most effective treatment, but dopamine agonists and monoamine oxidase-B inhibitors are also effective, and are less likely to cause dyskinesias. For patients taking carbidopa/levodopa who have motor complications, adjunctive therapy with a dopamine agonist, a monoamine oxidase-B inhibitor, or a catechol O-methyltransferase inhibitor will improve motor symptoms and functional status, but with an increase in dyskinesias. Deep brain stimulation is effective in patients who have poorly controlled symptoms despite optimal medical therapy. Occupational, physical, and speech therapy improve patient function. Fatigue, sleep disturbances, dementia, and depression are common in patients with Parkinson disease. Although these conditions are associated with significantly lower quality of life, they may improve with treatment.