Objective Linguistic Markers Associated with Callous-Unemotional Traits in Early Childhood.

BACKGROUND: Callous-unemotional (CU) traits are associated with interpersonal difficulties and risk for severe conduct problems (CP). The ability to communicate thoughts and feelings is critical to social success, with language a promising treatment target. However, no prior studies have examined objective linguistic correlates of childhood CU traits in early childhood, which could give insight into underlying risk mechanisms and novel target treatments. METHODS: We computed lexical (positive emotion, sad, and anger words) and conversational (interruptions and speech rate) markers produced by 131 children aged 5-6 years (M = 5.98; SD = 0.54, 58.8% female) and their parents while narrating wordless storybooks during two online visits separated by 6-8 weeks (M = 6.56, SD = 1.11; two books, order counterbalanced). Audio recordings were diarized, time-aligned, and orthographically transcribed using WebTrans. Conversational markers were calculated using R and word frequencies were calculated using Linguistic Inquiry and Word Count (LIWC) software. We examined links between child CU traits and linguistic markers, and explored whether relationships were moderated by child sex. RESULTS: Higher CU traits were associated with fewer positive emotion words produced by parents and children. Higher CU traits were also associated with greater concordance in the degree of interruptions and expression of anger emotion words by parents and children. CONCLUSIONS: Results suggest that objective linguistic correlates of CU traits are detectable during early childhood, which could inform adjunctive treatment modules that improve outcomes by precisely tracking and targeting subtle communication patterns.

Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma.

The sub-ventricular zone (SVZ) is the most well-characterized neurogenic area in the mammalian brain. We previously showed that in 65% of patients with glioblastoma (GBM), the SVZ is a reservoir of cancer stem-like cells that contribute to treatment resistance and emergence of recurrence. Here, we built a single-nucleus RNA-sequencing-based microenvironment landscape of the tumor mass (T_Mass) and the SVZ (T_SVZ) of 15 GBM patients and 2 histologically normal SVZ (N_SVZ) samples as controls. We identified a mesenchymal signature in the T_SVZ of GBM patients: tumor cells from the T_SVZ relied on the ZEB1 regulatory network, whereas tumor cells in the T_Mass relied on the TEAD1 regulatory network. Moreover, the T_SVZ microenvironment was predominantly characterized by tumor-supportive microglia, which spatially co-exist and establish heterotypic interactions with tumor cells. Lastly, differential gene expression analyses, predictions of ligand-receptor and incoming/outgoing interactions, and functional assays revealed that the IL-1ß/IL-1RAcP and Wnt-5a/Frizzled-3 pathways are therapeutic targets in the T_SVZ microenvironment. Our data provide insights into the biology of the SVZ in GBM patients and identify specific targets of this microenvironment.

Validation of the brain injury associated visual impairment - impact questionnaire (BIVI-IQ).

PURPOSE: The Brain Injury associated Visual Impairment - Impact Questionnaire (BIVI-IQ) was developed to assess the impact of post-stroke visual impairment. The development of the questionnaire used robust methods involving stroke survivors and clinicians. The aim of this study was to assess the validity of the BIVI-IQ in a stroke population. METHODS: Stroke survivors with visual impairment were recruited from stroke units, outpatient clinics and non-healthcare settings. Participants were asked to complete questionnaire sets on three separate occasions; the BIVI-IQ at each visit with additional questionnaires at baseline and visit 2. Vision assessment and anchor questions from participants and clinicians were collected. The analysis included assessment of missing data, acceptability, Rasch model analysis, test-retest reliability, construct validity (NEI VFQ-25, EQ-5D-5L) and responsiveness to change. RESULTS: 316 stroke survivors completed at least one questionnaire of the 326 recruited. Mean age was 67 years and 64% were male. Adequate fit statistics to the Rasch model were reached (χ2 = 73.12, p = 0.02) with two items removed and thresholds of two adjusted, indicating validity and unidimensionality. Excellent test-retest reliability was demonstrated (ICC = 0.905) with a 3-month interval. Construct validity was demonstrated with a strong significant correlation to the NEI VFQ-25 (r = 0.837, p < 0.01). The BIVI-IQ also demonstrated responsiveness to change with significant differences identified between groups based on participant and clinician anchor questions (X2 = 23.29, p < 0.001; X2 = 24.56, p < 0.001). CONCLUSION: The BIVI-IQ has been shown to be valid and practical for 'everyday' use by clinicians and researchers to monitor vision-related quality of life in stroke survivors with visual impairment.

Aotearoa genomic data repository: An ahuru mowai for taonga species sequencing data.

The Aotearoa Genomic Data Repository (AGDR) is an initiative to provide a secure within-nation option for the storage, management and sharing of non-human genomic data generated from biological and environmental samples originating in Aotearoa New Zealand. This resource has been developed to follow the principles of Maori Data Sovereignty, and to enable the right of kaitiakitanga (guardianship), so that iwi, hapu and whanau (tribes, kinship groups and families) can effectively exercise their responsibilities as guardians over biological entities that they regard as taonga (precious or treasured). While the repository is designed to facilitate the sharing of data-making it findable by researchers and interoperable with data held in other genomic repositories-the decision-making process regarding who can access the data is entirely in the hands of those holding kaitiakitanga over each data set. No data are made available to the requesting researcher until the request has been approved, and the conditions for access (which can vary by data set) have been agreed to. Here we describe the development of the AGDR, from both a cultural perspective, and a technical one, and outline the processes that underpin its operation.

Born into an isolating world: family-centred care for babies born to mothers with COVID-19.

Background: The benefits of facilitating breastmilk feeding and close contact between mother and neonate (family-centred care; FCC) in the perinatal period are well-established. The aim of this study was to determine how the delivery of FCC practices were impacted for neonates born to mothers with perinatal SARS-CoV-2 infection during the COVID-19 pandemic. Methods: Neonates born to mothers with confirmed SARS-CoV-2 infection during pregnancy were identified from the 'EsPnIC Covid paEdiatric NeonaTal REgistry' (EPICENTRE) multinational cohort between 10 March 2020 and 20 October 2021. The EPICENTRE cohort collected prospective data on FCC practices. Rooming-in and breastmilk feeding practice were the main outcomes, and factors influencing each were determined. Other outcomes included mother-baby physical contact prior to separation and the pattern of FCC components relative to time and local site guidelines. Findings: 692 mother-baby dyads (13 sites, 10 countries) were analysed. 27 (5%) neonates were positive for SARS-CoV-2 (14 (52%) asymptomatic). Most sites had policies that encouraged FCC during perinatal SARS-CoV-2 infection for most of the reporting period. 311 (46%) neonates roomed-in with their mother during the admission. Rooming-in increased over time from 23% in March-June 2020 to 74% in January-March 2021 (boreal season). 330 (93%) of the 369 separated neonates had no FCC physical contact with their mother prior, and 319 (86%) were asymptomatic. Maternal breastmilk was used for feeding in 354 (53%) neonates, increasing from 23% to 70% between March-June 2020 and January-March 2021. FCC was most impacted when mothers had symptomatic COVID-19 at birth. Interpretation: This is the largest report of global FCC practice during the COVID-19 pandemic to date. The COVID-19 pandemic may have impacted FCC despite low perinatal transmission rates. Fortunately, clinicians appear to have adapted to allow more FCC delivery as the COVID-19 pandemic progressed. Funding: The National Health and Medical Research Council (Australia): Grant ID 2008212 (DGT), Royal Children's Hospital Foundation: Grant ID 2019-1155 (EJP), Victorian Government Operational Infrastructure Support Program.

Milk triglycerides from dairy cows abomasally infused with increasing amounts of high-oleic sunflower fatty acids.

The triglyceride composition of milk fat largely determines the manufacturing characteristics of products containing milk fat. Increasing oleic acid content of milk fat might be desirable for human nutrition and also for butter and whipping cream, among other product applications. The objective of this research was to determine the effects of increasing intestinally available oleic acid (provided via abomasal infusion) on the profile of milk triglycerides. A control and 4 increasing doses of free fatty acids from high oleic sunflower oil (HOSFA) were infused into the abomasum of 4 lactating dairy cows in a changeover experimental design with periods of 7 d. Treatments were (1) control (no fatty acids infused), (2) HOSFA (250 g/d), (3) HOSFA (500 g/d), (4) HOSFA (750 g/d), and (5) HOSFA (1,000 g/d). All treatments included meat solubles and Tween 80 as emulsifiers. Infusion of HOSFA increased oleic acid and decreased short- and medium-chain fatty acids in milk fat. Statistical analysis of results showed linear changes in most of the milk triglycerides analyzed. The most significant changes as the result of increasing HOSFA infusion were a decrease in triglycerides with saturated fatty acids (butyrin-caprylin-palmitin, butyrin-laurin-olein, butyrin-myristin-palmitin, butyrin-palmitin-palmitin, caproin-myristin-palmitin, butyrin-palmitin-stearin, caproin-palmitin-palmitin) and an increase in dioleyl triglycerides (with butyric, lauric, myristic and palmitic acids) and triolein. The synthesis of triglyceride is position-specific and does not follow a random distribution model.

Recent advancements and application of in vitro models for predicting inhalation toxicity in humans.

Animals have been indispensable in testing chemicals that can pose a risk to human health, including those delivered by inhalation. In recent years, the combination of societal debate on the use of animals in research and testing, the drive to continually enhance testing methodologies, and technology advancements have prompted a range of initiatives to develop non-animal alternative approaches for toxicity testing. In this review, we discuss emerging in vitro techniques being developed for the testing of inhaled compounds. Advanced tissue models that are able to recreate the human response to toxic exposures alongside examples of their ability to complement in vivo techniques are described. Furthermore, technology being developed that can provide multi-organ toxicity assessments are discussed.

Difficult airway management algorithms: a directed review.

The primary aim of this study was to identify, describe and compare the content of existing difficult airway management algorithms. Secondly, we aimed to describe the literature reporting the implementation of these algorithms. A directed search across three databases (MEDLINE, Embase and Scopus) was performed. All articles were screened for relevance to the research aims and according to pre-determined exclusion criteria. We identified 38 published airway management algorithms. Our results show that most facemask employ a four-step process as represented by a flow chart, with progression from tracheal intubation, facemask ventilation and supraglottic airway device use, to a rescue emergency surgical airway. The identified algorithms are overwhelmingly similar, yet many use differing terminology. The frequency of algorithm publication has increased recently, yet adherence and implementation outcome data remain limited. Our results highlight the lack of a single algorithm that is universally endorsed, recognised and applicable to all difficult airway management situations.

A discourse of disconnection--challenges to clinical engagement and collaborative dental commissioning.

AIM: While doctors are moving centre-stage into managerial and leadership commissioning roles, the role of clinicians in NHS dental commissioning has retained a mainly representative model. In this paper we describe the discourse of 'rank and file' dental practitioners and the implications of this for clinical engagement and clinical leadership in dentistry. METHOD: As part of an NIHR study of NHS dental contracting a questionnaire was sent to 925 practitioners. The questionnaire included a free text box inviting further comment. We received 113 lengthy narratives in 333 (43%) of the questionnaires returned and so undertook a discourse analysis of this data--focusing on the use of language, shared meaning and how practitioners portrayed their identity and activities. RESULTS: Three discursive repertoires were identified: professional subordination; a disconnected hierarchy; and a strained collegiality. Underpinning these repertoires was the sense of disjuncture between the macro-level (managerial) and micro-level (practice), and the problematic nature of clinical leadership in a profession where dentists' common identity is fractured by their individual clinical and business practice. CONCLUSIONS: This paper presents an insight into the views of dental practitioners in their own words, and the challenges of engaging dental practitioners in a new commissioning era.

'It's something you have to put up with'--service users' experiences of in utero transfer: a qualitative study.

OBJECTIVE: The purpose of this study was to gain in-depth insight and enhance understanding of service users' experiences of the in utero transfer (IUT) process, in order to inform policy and improve the current service provision of maternal care. DESIGN: Qualitative descriptive study using semi-structured interviews. SETTING: Participant's home or hospital in the Midlands, UK. POPULATION: Fifteen women transferred in utero to a tertiary level maternity hospital; five male partners and two grandmothers. METHODS: Audio-recorded individual or paired semi-structured interviews transcribed verbatum and analysed thematically using nvivo 9. MAIN OUTCOME MEASURES: Facilitators and barriers of the IUT experience. RESULTS: Findings suggest that IUT is an emotional experience that financially disadvantages patients and their families. Male partners were perceived to be most negatively affected by the experience. The quality of the IUT experience was influenced by a range of factors, including the lack of proximity to home and the lack of information. Patients had little knowledge or awareness of IUT, and most felt unprepared for displacement. Despite this, there was resigned acceptance that IUT was a necessary rather than adverse experience. CONCLUSIONS: The experience of IUT for service users could be enhanced by ensuring that they are better informed about the process and the circumstances that necessitate displacement, that they are better informed about the hospital to which they are being transferred, and that they are transferred as close to home as possible. Efforts to minimise the emotional and socio-economic impact of IUT on women and their families also need to be considered.

The impact of prostate cancer on men's everyday life.

Prostate cancer impacts on the daily lives of men, particularly their physical and emotional health, relationships and social life. This paper highlights how men cope with disease and treatment and the strategies they employ to manage their diagnosis alongside daily life. Twenty-seven men were interviewed at different stages in their disease pathway: nine men prior to radiotherapy, eight men at 6-8 months post radiotherapy and 10 men at 12-18 months post radiotherapy. A grounded theory approach was used to collect and analyse the data. Regardless of the point at which they were interviewed four areas emerged as important to the men: the pathway to diagnosis; the diagnosis; the impact of prostate cancer and its treatment on daily life; and living with prostate cancer. Prostate cancer was diagnosed using the prostate-specific antigen (PSA) test, rectal examination and biopsy. Many men did not understand the consequences of a high PSA reading before they undertook the test. Painful investigative biopsies were viewed as the worst part of the disease experience. Radiotherapy was considered less invasive than other treatments, although preparatory regimes were associated with stress and inconvenience. Men used various strategies to deal with treatment-induced threats to their masculinity in the long term.

Phase I trial of bortezomib (PS-341; NSC 681239) and "nonhybrid" (bolus) infusion schedule of alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory indolent B-cell neoplasms.

PURPOSE: This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). EXPERIMENTAL DESIGN: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. RESULTS: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses. CONCLUSIONS: The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies.

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells.

The relationship between mitochondrial metabolism and cell viability and differentiation in stem cells (SCs) remains poorly understood. In the present study, we compared mitochondrial physiology and metabolism between P19SCs before/after differentiation and present a unique fingerprint of the association between mitochondrial activity, cell differentiation and stemness. In comparison with their differentiated counterparts, pluripotency of P19SCs was correlated with a strong glycolytic profile and decreased mitochondrial biogenesis and complexity: round, low-polarized and inactive mitochondria with a closed permeability transition pore. This decreased mitochondrial capacity increased their resistance against dichloroacetate. Thus, stimulation of mitochondrial function by growing P19SCs in glutamine/pyruvate-containing medium reduced their glycolytic phenotype, induced loss of pluripotent potential, compromised differentiation and became P19SCs sensitive to dichloroacetate. Because of the central role of this type of SCs in teratocarcinoma development, our findings highlight the importance of mitochondrial metabolism in stemness, proliferation, differentiation and chemoresistance. In addition, the present work suggests the regulation of mitochondrial metabolism as a tool for inducing cell differentiation in stem line therapies.

In vivo corrosion, tumor outcome, and microarray gene expression for two types of muscle-implanted tungsten alloys.

Tungsten alloys are composed of tungsten microparticles embedded in a solid matrix of transition metals such as nickel, cobalt, or iron. To understand the toxicology of these alloys, male F344 rats were intramuscularly implanted with pellets of tungsten/nickel/cobalt, tungsten/nickel/iron, or pure tungsten, with tantalum pellets as a negative control. Between 6 and 12 months, aggressive rhabdomyosarcomas formed around tungsten/nickel/cobalt pellets, while those of tungsten/nickel/iron or pure tungsten did not cause cancers. Electron microscopy showed a progressive corrosion of the matrix phase of tungsten/nickel/cobalt pellets over 6 months, accompanied by high urinary concentrations of nickel and cobalt. In contrast, non-carcinogenic tungsten/nickel/iron pellets were minimally corroded and urinary metals were low; these pellets having developed a surface oxide layer in vivo that may have restricted the mobilization of carcinogenic nickel. Microarray analysis of tumors revealed large changes in gene expression compared with normal muscle, with biological processes involving the cell cycle significantly up-regulated and those involved with muscle development and differentiation significantly down-regulated. Top KEGG pathways disrupted were adherens junction, p53 signaling, and the cell cycle. Chromosomal enrichment analysis of genes showed a highly significant impact at cytoband 7q22 (chromosome 7) which included mouse double minute (MDM2) and cyclin-dependant kinase (CDK4) as well as other genes associated with human sarcomas. In conclusion, the tumorigenic potential of implanted tungsten alloys is related to mobilization of carcinogenic metals nickel and cobalt from corroding pellets, while gene expression changes in the consequent tumors are similar to radiation induced animal sarcomas as well as sporadic human sarcomas.

Water interaction in paper cellulose fibres as investigated by NMR pulsed field gradient.

In this paper, water diffusion coefficients were measured using NMR pulsed field gradient, on a variety of paper materials made from predominantly cellulose fibre and nanofibres, derived from wood, with different dimensions, internal porosity, and chemical composition. The moisture content ranged from 0.2 to 1.2g of water/g of dry fibre. Diffusion measurements were made both in the plane and through the thickness of the sheet. All data was generally well fitted by a simple two component diffusion model. For moisture contents less than 0.55 and 0.85g/g for measurements in the plane and through the thickness, respectively, it was found that both diffusion components increased approximately linearly with moisture content, with the faster diffusion coefficient being approximately five times larger than the smaller. The water appeared, within errors, to be evenly split between two components. The measured diffusion coefficients were not affected by fibre dimensions, internal structure or chemical composition, but were consistently higher when measured in the plane.

SU-E-I-67: Multi-Shot RESOLVE Compared to Single-Shot EPI Diffusion- Weighted MR Imaging Acquisition Scheme.

PURPOSE: The purpose of this project was to configure the parameters for optimal comparison of image quality differences between the prototype imaging technique, read-out-segmented EPI multi-shot (RESOLVE) and the clinically used single-shot EPI (SS-EPI) MRI sequence for Diffusion Weighted Imaging (DWI) in a saline phantom, followed by a normal rat brain. METHODS: Saline phantom (4.2 × 4.2 cm2 ) and a rat brain were imaged on the 1.5T ESPREE (Siemens, Germany) MRI magnet using a wrist coil. Both the SS-EPI and RESOLVE DWI were optimized with equal imaging parameters such as slice thickness/slice gap = 3.0/0 mm, field of view = 210 mm, phase resolution = 100%, and diffusion b values = 0, 600 s/mm2 while other parameters were given similar settings such as the base resolution, which had to be interpolated for the SS-EPI to 96i to match the RESOLVE as it was unable to be set at 192. Image quality was compared in terms of signal intensity, distortion, % ghosting and Apparent Diffusion Co-efficient (ADC) measurements from each sequence. RESULTS: A marked enhancement of overall image quality with superior detail was observed in each of the scans from the RESOLVE sequence when compared to the SS-EPI. Comparing the efficiency of both sequences in terms of image quality, RESOLVE demonstrated a better stable image with minimal distortion and ghosting. The phantom dimensions obtained from RESOLVE images matched the actual dimensions perfectly. RESOLVE images had signal intensities significantly higher than (2.4×) the SS-EPI images (p=0.0008) and ∼0.6 % times less ghosting compared to SS-EPI (p=0.82) which also exhibited distortion with reduced phantom dimensions (4.05 × 3.28 cm) from original. The ADC values computed were almost identical to be (p=0.32) from SS-EPI (2.21mm2 /sec) and RESOLVE (2.19mm2 /sec). CONCLUSIONS: The RESOLVE sequence has significantly superior image quality compared to SS-EPI at 1.5 T with reasonable scan times. DWI with RESLOVE acquisition scheme can be highly beneficial in obtaining distortion free images in routine clinical studies to characterize tumors and other pathological mechanisms with much greater detail than the current clinically used SS-EPI.

Optical microchip array biosensor for multiplexed detection of bio-hazardous agents.

An optical waveguide array biosensor suitable for rapid detection of multiple bio-hazardous agents is presented. SpectroSens™ optical microchip sensors contain multiple spatially-separated waveguide channels with integral high-precision Bragg gratings sensitive to changes in refractive-index; selective surface-functionalisation of discrete sensing channels with different antibodies as bio-recognition elements enables selective multi-analyte biological detection. Interactions between target antigens in the test sample and respective surface-immobilised antibodies result in localised changes in refractive-index; the biosensor response manifests as increases in wavelength of light reflected from specific sensing channels. Multiplexed, label-free detection of 8 different biological agents, encompassing bacterial spores, vegetative cells, viruses and proteinaceous toxins has been demonstrated in real-time. Selective detection of Bacillus atrophaeus (BG) spores, Escherichia coli cells, MS2 viruses and ovalbumin (OVA) protein (simulant bio-hazardous agents) was first demonstrated as proof-of-concept; subsequently, detection of Bacillus anthracis (BA) spores (UM23CL2 strain), Franciscella tularensis (FT) cells (live vaccine strain), Vaccinia viruses (heat-killed) and ricin toxin (bio-hazardous agents) was proven. Two optical microchip sensors, each comprising 8 sensing channels were packaged into a single disposable cartridge allowing simultaneous 16-channel data acquisition. The specific antibody deposition sequence used in this study enabled detection of either 4 simulants or 4 bio-hazardous agents using a single consumable. The final device, a culmination of the multidisciplinary convergence of the fields of biology, chemistry, optoelectronics and microfluidics, is man-portable and inherently robust. The performance characteristics of the SpectroSens™ technology platform highlight its potential for exploitation as a 'detect to warn/treat' biodetector in security and defence operations.

Adhesion, proliferation and differentiation of pluripotent stem cells on multi-walled carbon nanotubes.

This article studies the adhesion, growth and differentiation of stem cells on carbon nanotube matrices. Glass coverslips were coated with multi-walled carbon nanotube (MWNT) thin films using layer-by-layer self-assembling techniques. Pluripotent P19 mouse embryonal carcinoma stem cells were seeded onto uncoated or MWNT-coated glass coverslips and either maintained in an undifferentiated state or induced to differentiate by the addition of retinoic acid. The authors found that cell adhesion was increased on the MWNT-coated glass surfaces, and that the expression patterns of some differentiation markers were altered in cells grown on MWNTs. The results suggest that MWNTs will be useful in directing pluripotent stem cell differentiation for tissue engineering purposes.

Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms.

PURPOSE: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma). EXPERIMENTAL DESIGN: Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion. Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and pharmacodynamic studies were conducted. RESULTS: Sixteen patients were treated. The MTD was established as 1.3 mg/m(2) for bortezomib and 30 mg/m(2) for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%). Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results. CONCLUSIONS: The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non-Hodgkin's lymphoma, justifying phase II studies to determine the activity of this regimen more definitively.

Older men's experiences of community-based health checks in Knowsley, UK.

A study using both qualitative and quantitative methods was undertaken to examine the impact of community-based health checks on men in Knowsley, UK. The main objective was to understand whether community-based health checks targeted at specific geographical and age groups were an effective way of improving health in men. Interviews were conducted with 50 service users, and a completed postal questionnaire was received from 178 men who had attended during the service's pilot period. Results indicated that men were generally satisfied with both the content and structure of the health checks. Men spoke favourably of the service they had received, particularly in comparison to their previous experiences of primary care. They reported enjoying using a service that allowed them to examine their own health in a comfortable environment. Knowledge was provided to a group whose awareness of health matters was often poor, and the vast majority of men reported making a variety of positive lifestyle changes as a result of attending. Reported improvements to health included giving up smoking, reducing alcohol consumption, increasing exercise and eating more healthily. The study suggests that services of this nature deserve careful consideration by health care professionals and policy-makers.