bluuebunny/crossref_metadata_2025_split huggingface dataset:
Model‐based treatment optimization of a novel VEGFR inhibitor
Authors: Keizer Ron J. , Gupta Anubha , Shumaker Robert , Beijnen Jos H. , Schellens Jan H. M. , Huitema Alwin D. R. 
Published: February 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Drugs targeting the VEGF‐pathway often show increase in blood pressure (BP) and proteinuria as dose limiting toxicity. However, high dose levels are also considered crucial for anti‐tumour activity. In preclinical models, lenvatinib affects tumour cell proliferation and tumour vascularization, while therapeutic effects were observed in phase I and II trials.WHAT THIS STUDY ADDS• Adverse event guided dose titration, including treatment with anti‐hypertensive treatment and dose de‐escalations can be expected to keep about 80% of patients on treatment with lenvatinib for 16 weeks. Additionally, within subject dose escalation in subjects not experiencing toxicity can considerably increase dose intensity.AIM To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK–PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment.METHODS A previously developed PK–PD model for lenvatinib (E7080) was updated and parameters were re‐estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de‐escalation. Additionally, a within‐patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred.RESULTS Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day−1. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day−1, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%).CONCLUSIONS The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE‐guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome.
Burkitt lymphoma: staging and response evaluation
Authors: Sandlund John T. 
Published: February 2012

SummaryThe refinements in both the staging and response evaluation of children with Burkitt lymphoma (BL) have contributed to the improvements in treatment outcome observed over the past 40 years. Ziegler and Magrath designed a staging system in the 1970s for children with BL in equatorial Africa. Currently, the most widely used staging system around the world is that described by Murphy in 1980, which was developed for children with non‐Hodgkin lymphoma (NHL) of any histology. There are opportunities for refinement in this system, particularly with respect to certain extra‐nodal sites, such as skin and bone. The findings obtained at diagnosis with novel technologies (functional imaging [e.g., positron emission tomography [PET]] and minimal residual disease [MRD] technology), which are more sensitive with respect to disease detection than historic modalities, also need to be considered. Technological advances have also had impact on the assessment of response evaluation. Standard x‐rays were routinely used in the 1960s; nuclear imaging became widely used in the 1970s; computerized axial tomography was incorporated in the 1980s; PET imaging was incorporated and, in many cases, has replaced gallium/bone scans since 2000; and MRD technology has been explored in some of the most recent clinical trials. There is clearly a need for more clinical data on the use of PET and MRD technology in the determination of response evaluation of children with BL as well as other histological subtypes of NHL. An international working group is currently addressing the refinement of both disease staging and response evaluation in children with NHL.
A 15q24 microdeletion in transient myeloproliferative disease (TMD) and acute megakaryoblastic leukaemia (AMKL) implicates PML and SUMO3 in the leukaemogenesis of TMD/AMKL
Authors: Haemmerling Susanne , Behnisch Wolfgang , Doerks Tobias , Korbel Jan O. , Bork Peer , Moog Ute , Hentze Sabine , Grasshoff Ute , Bonin Michael , Rieß Olaf , Janssen Johannes W. G. , Jauch Anna , Bartram Claus R. , Reinhardt Dirk , Koch Karin A. , Bandapalli Obul R. , Kulozik Andreas E. 
Published: February 2012

SummaryTransient myeloproliferative disorder (TMD) of the newborn and acute megakaryoblastic leukaemia (AMKL) in children with Down syndrome (DS) represent paradigmatic models of leukaemogenesis. Chromosome 21 gene dosage effects and truncating mutations of the X‐chromosomal transcription factor GATA1 synergize to trigger TMD and AMKL in most patients. Here, we report the occurrence of TMD, which spontaneously remitted and later progressed to AMKL in a patient without DS but with a distinct dysmorphic syndrome. Genetic analysis of the leukaemic clone revealed somatic trisomy 21 and a truncating GATA1 mutation. The analysis of the patient's normal blood cell DNA on a genomic single nucleotide polymorphism (SNP) array revealed a de novo germ line 2·58 Mb 15q24 microdeletion including 41 known genes encompassing the tumour suppressor PML. Genomic context analysis of proteins encoded by genes that are included in the microdeletion, chromosome 21‐encoded proteins and GATA1 suggests that the microdeletion may trigger leukaemogenesis by disturbing the balance of a hypothetical regulatory network of normal megakaryopoiesis involving PML, SUMO3 and GATA1. The 15q24 microdeletion may thus represent the first genetic hit to initiate leukaemogenesis and implicates PML and SUMO3 as novel components of the leukaemogenic network in TMD/AMKL.
Modelling approaches for relating effects of change in river flow to populations of Atlantic salmon and brown trout
Authors: ARMSTRONG J. D. , NISLOW K. H. 
Published: February 2012

Abstract  Modelling approaches for relating discharge to the biology of Atlantic salmon, Salmo salar L., and brown trout, Salmo trutta L., growing in rivers are reviewed. Process‐based and empirical models are set within a common framework of input of water flow and output of characteristics of fish, such as growth and survival, which relate directly to population dynamics. A continuum is envisaged incorporating various contributions of process and empirical structure as practical and appropriate to specific goals. This framework is compared with, and shown to differ from, approaches whose output is in the form of quantity and form of habitat (or usable area) based on its frequency of use by fish, which then is assumed to have some relationship with fish performance. A simple conceptual modelling approach is also developed to relate water flow to fish population characteristics to assess the likelihood of simple relationships between flow and usable area thresholds. Basic predictions of the model are tested against empirical data from a long‐term individual‐based study of juvenile S. salar and resident brook trout, Salvelinus fontinalis (Mitchell), in West Brook, Massachusetts. For this system, growth rates of both species increased linearly with flow during spring, summer and autumn months and bore no relation to Q95 or wetted‐width discontinuities. Winter is identified as a season during which water might be abstracted most safely, but cautiously given sparse knowledge of wild salmonid fish at this time of year. These results, together with the fundamental conceptual problems inherent in usable area‐based approaches, suggest that models that relate directly to fish performance outcomes may be more robust as a basis for flow prescriptions. However, this utility will depend strongly on our ability to generalise from a limited set of empirical studies and to use the results of these studies of management actions to inform and improve future models.
Improved clonality detection in Hodgkin lymphoma using the BIOMED‐2‐based heavy and kappa chain assay: a paraffin‐embedded tissue study
Authors: Tapia Gustavo , Sanz Carolina , Mate José L , Muñoz‐Mármol Ana M , Ariza Aurelio 
Published: February 2012

Tapia G, Sanz C, Mate J L, Muñoz‐Mármol A M & Ariza A  (2012) Histopathology 60, 768–773 Improved clonality detection in Hodgkin lymphoma using the BIOMED‐2‐based heavy and kappa chain assay: a paraffin‐embedded tissue studyAims:  Although BIOMED‐2 polymerase chain reaction (PCR) standardization protocols allow clonality detection in nearly 100% of non‐Hodgkin B cell lymphomas, they have not been widely validated for Hodgkin lymphoma (HL). Our aim was to assess BIOMED‐2 protocol sensitivity when using non‐microdissected, formalin‐fixed, paraffin‐embedded (FFPE) tissue from HL cases.Methods and results:  We studied 69 consecutive HL cases, of which 61 corresponded to classic HL (cHL) and eight to nodular lymphocyte‐predominant HL (NLPHL). CD30‐positive cell numbers (<10, 10–25 or >25 per ×200 field), background CD20‐positive cell density (low or high) and tumour cell immunophenotype were evaluated. IGH and IGK clonality was assessed on FFPE tissue following BIOMED‐2 protocols. Of the 58 assessable cHL cases, 15 (25.9%) exhibited IGH and/or IGK clonality; IGH clonality was shown by nine (15.5%) and IGK clonality by 12 (20.7%). Clonality detection rates in cHL improved as CD30‐positive Reed–Sternberg (RS) cell density increased and CD20‐positive B cell density decreased, although these correlations did not reach statistical significance. Of the eight NLPHL cases studied, none showed clonal rearrangement.Conclusions:  Combined study of IGH and IGK rearrangement according to BIOMED‐2 protocols improves clonality detection rate (up to 25% of cases) in HL, even when working on non‐microdissected FFPE tissue.
‘You need to let your voice be heard’: research participants' views on research
Authors: McDonald K. E. , Kidney C. A. , Patka M. 
Published: February 2012

AbstractBackground  Persons with intellectual and developmental disabilities have had regrettably few opportunities to voice their opinions on aspects of research with which they have had direct experience. Understanding and responding to these views can contribute to policies and practices that increasingly treat people as they desire to be treated.Methods  We conducted individual interviews and focus groups with 16 adults with intellectual and developmental disabilities to examine their perspectives on participating in research.Results  Our analysis indicates that adults with intellectual and developmental disabilities want to engage in research to improve their quality of life and to have greater access to a worthwhile activity through more active participation. Our results also highlight trust as a critical ingredient in the success of research with this group.Conclusions  Our findings suggest that despite ethical challenges, researchers can and should pursue research that has the potential to improve the lives of persons with intellectual and developmental disabilities. Such research is more likely to be both ethical and successful if researchers pay attention to enhancing autonomy and person‐centredness, while at the same time engendering participant trust.
Event sequencing of forced intramuscular medication in England
Authors: BOWERS L. , ROSS J. , OWITI J. , BAKER J. , ADAMS C. , STEWART D. 
Published: February 2012

Accessible summary
In many countries staff are allowed to inject psychiatric inpatients against their will with psychotropic medication.
This study, conducted in England, found such injections were given to 9% of patients, usually in response to aggressive behaviour or medication refusal.
In most cases the forced injections ended a crisis, but the study concludes that there are opportunities for staff to use alternative approaches.
AbstractIn most inpatient psychiatric care systems it is permissible in certain situations for staff to forcibly inject patients with psychotropic medication. The aim of this study is to describe what precedes and follows a coerced intramuscular injection within a nursing shift. Data were collected on the sequence of conflict (aggression, absconding, etc.) and containment (seclusion, restraint, etc.) for the first 2 weeks of 522 acute admissions on 84 wards in 31 UK hospitals. Injections were given to 9% of patients. Aggression, regular medication refusal and pro re nata (PRN) medication refusal preceded injections. The giving of coerced medication concluded most crises. Coerced medication effectively resolves crises in the short term. Staff should offer oral PRN as an alternative, unless this is unsafe. Where only verbal violence has occurred staff should try to resolve the crisis without enforcing medication. More research on the best way to respond to inpatients' medication refusal is required.
Managing distressed and disturbed patients: the thoughts and feelings experienced by Italian nurses
Authors: CAMUCCIO C. A. , CHAMBERS M. , VÄLIMÄKI M. , FARRO D. , ZANOTTI R. 
Published: February 2012

Accessible summary
The aim of the research was to examine the thoughts and feelings experienced by Italian nurses when caring for distressed and aggressive patients in acute psychiatric settings.
Fear was the prevalent feeling experienced by nurses: fear of being harmed by the patient and fear of harming the patient and fear of damaging the therapeutic relationship.
When managing distressed and aggressive patients, the nursing team have to share similar feelings and be emotionally in tune with each other.
The paper offers clear explanations of nurses' feelings, the reasons for their fear and the importance of effective team working during a crisis.
AbstractThis paper reports on a qualitative study to identify Italian nurses' feelings and emotions towards the management of distressed and disturbed psychiatric patients in acute inpatient settings. Four focus groups were carried out involving 33 nurses from seven acute psychiatric services in a region of Italy. Data were analysed using content analysis. Findings highlight that fear is the prevailing feeling experienced by nurses in the management of distressed patients. This includes both fear of being physically harmed and concerns about doing harm or damage to patients. The unpredictability of aggressive behaviour from unknown patients was described as especially frightening. Known patients, namely those previously admitted to the unit, induced less fear, as their behaviour was considered more predictable. Patients with dual diagnosis were also a worry for many nurses, who considered themselves lacking in the personal relational skills needed to manage an individual in crisis. Nurses reported that they try to understand the reasons for a patient's aggressive behaviour and are empathetic to his or her suffering. When such empathy is lacking, nurses experience conflicting feelings of counter‐aggressiveness. The paper concludes by emphasizing the need to increase availability of education related to patient management, in particular team working and its internal relationships.
Self‐esteem among German nurses: does academic education make a difference?
Authors: VAN ECKERT S. , GAIDYS U. , MARTIN C. R. 
Published: February 2012

Accessible summary
Self‐esteem is not typically associated with nurses.
An academic nurse training can potentially increase self‐esteem.
Promoting self‐esteem in nurses should be part of academic as well as non‐academic education.
AbstractSelf‐esteem is not typically associated with the nursing profession. However, the concept is indispensible for job satisfaction and good‐quality patient care. Many healthcare systems are confronted with declining numbers of qualified nurses, and desperately seek suitable strategies to recruit and retain sufficient trainees and junior staff. This investigation examined self‐esteem in 212 German nurses using the Rosenberg Self‐Esteem Scale. Nurses with an academic degree displayed a statistically significant higher level of self‐esteem than nurses without academic education (P < 0.01). The type of professional training may therefore have a direct effect on the self‐esteem, thus offering a myriad of potential benefits to both nurses and patients. Self‐esteem is a quality relevant to this profession and, as such, the findings of research in this area should be reflected in the design of nurse training curricula.
A comparison between colonic submucosa and mucosa to detect Lewy pathology in Parkinson’s disease
Authors: Pouclet H. , Lebouvier T. , Coron E. , Des Varannes S. B. , Neunlist M. , Derkinderen P. 
Published: February 2012

AbstractBackground  Lewy bodies and neurites (LN), the two pathological hallmarks of Parkinson’s disease (PD), are found in the enteric nervous system (ENS). Previously, we have shown that whole mounts of submucosa obtained after microdissection of colonic biopsies can be used for the detection of LN in the submucosal plexus (SMP) of PD patients. Recent reports suggest that Lewy pathology may extend beyond the submucosa to involve the digestive mucosa. The aim of the present research was to determine whether the analysis of the mucosa obtained after microdissection may help improve the sensitivity of colonic biopsies to detect Lewy pathology in the colon of PD patients.Methods  Nine PD patients and 10 controls were included. Four biopsies were taken from the sigmoid/descending colon junction during the course of a rectosigmoidoscopy (short colonoscopy) in PD patients and during a total colonoscopy for colorectal screening in controls. Biopsies were microdissected, the mucosa was separated from the submucosa and both structures were analyzed by immunohistochemistry. Immunohistochemical analysis was performed using antibodies against phosphorylated alpha‐synuclein to detect LN and neurofilaments NF200 kDa to label the neuronal structures.Key Results  Lewy neurites were present in the SMP of four patients and in the mucosa of three patients. Remarkably, among the patients who displayed LN within their mucosa, one was devoid of Lewy pathology in his SMP. No LN were observed in the mucosa and the SMP of controls.Conclusions & Inferences  The parallel analysis of colonic mucosa, along with the SMP, can help detect Lewy pathology in PD.
Magnetic mineral transport and sorting in the swash‐zone: northern Lake Erie, Canada
Authors: GALLAWAY ERIC , TRENHAILE ALAN S. , CIOPPA MARIA T. , HATFIELD ROBERT G. 
Published: February 2012

AbstractA combined field and laboratory study in northern Lake Erie has provided new insights into the origin and dynamics of heavy mineral placer deposits on beaches consisting primarily of non‐magnetic sediment. Work was conducted on the cross‐shore and longshore transport of heavy magnetic minerals using magnetic susceptibility and fluorescent paints to trace the movement, in the field, of samples of magnetic (magnetite) and non‐magnetic (quartz and calcite) grains, respectively. Laboratory experiments examined how the burial of small, dense magnetic minerals is affected by the grain size of the non‐magnetic host material, and how grain burial affects magnetic susceptibility measurements at the surface. The field experiments demonstrated that the magnetic mineral tracers were buried rapidly beneath coarser, non‐magnetic grains under low to moderate wave conditions, and subsequently were unable to move in the longshore or cross‐shore directions. The laboratory experiments showed that the magnetic susceptibility rapidly decreased with the rate and depth of burial of the magnetic minerals, and that magnetic grain burial was most effective beneath coarser rather than finer non‐magnetic sand and, for the latter sediments, under less rather than more energetic conditions. The results imply that magnetic mineral concentrations develop in this area through magnetic grain burial under fairly mild conditions, and subsequent settling, exposure and concentration in the upper swash zone during more energetic periods, when the non‐magnetic grains are eroded. It is probably during these erosional periods, when the magnetic minerals are exposed in fairly homogeneous deposits, that longshore and cross‐shore transport takes place.
Suboptimal patterns of provider initiated HIV testing and counselling, antiretroviral therapy eligibility assessment and referral in primary health clinic attendees in Blantyre, Malawi*
Authors: MacPherson Peter , Lalloo David G. , Choko Augustine T. , Mann Gillian H. , Squire Stephen Bertel , Mwale Daniel , Manda Eddie , Makombe Simon D. , Desmond Nicola , Heyderman Robert , Corbett Elizabeth L. 
Published: February 2012

AbstractObjective:  To understand reasons for suboptimal and delayed uptake of antiretroviral therapy (ART) by describing the patterns of HIV testing and counselling (HTC) and outcomes of ART eligibility assessments in primary clinic attendees.Methods:  All clinic attendances and episodes of HTC were recorded at two clinics in Blantyre. A cohort of newly diagnosed HIV‐positive adults (>15 years) was recruited and exit interviews undertaken. Logistic regression models were constructed to investigate factors associated with referral to start ART. Qualitative interviews were conducted with providers and patients.Results:  There were 2398 episodes of HTC during 18 021 clinic attendances (13.3%) between January and April 2011. The proportion of clinic attendees undergoing HTC was lowest in non‐pregnant women (6.3%) and men (8.5%), compared with pregnant women (47.2%). Men had more advanced HIV infection than women (79.7% WHO stage 3 or 4 vs. 56.4%). Problems with WHO staging and access to CD4 counts affected ART eligibility assessments; only 48% completed ART eligibility assessment, and 54% of those reporting WHO stage 3/4 illnesses were not referred to start ART promptly. On multivariate analysis, HIV‐positive pregnant women were significantly less likely to be referred directly for ART initiation (adjusted OR: 0.29, 95% CI: 0.13–0.63).Conclusions:  These data show that provider‐initiated testing and counselling (PITC) has not yet been fully implemented at primary care clinics. Suboptimal ART eligibility assessments and referral (reflecting the difficulties of WHO staging in primary care) mean that simplified eligibility assessment tools are required to reduce unnecessary delay and attrition in the pre‐ART period. Simplified initiation criteria for pregnant women, as being introduced in Malawi, should improve linkage to ART.