Phase II study of second-line therapy with DTIC, BCNU, cisplatin and tamoxifen (Dartmouth regimen) chemotherapy in patients with malignant melanoma previously treated with dacarbazine

This study assessed response rates to combination dacarbazine (DTIC), BCNU (carmustine), cisplatin and tamoxifen (DBPT) chemotherapy in patients with progressive metastatic melanoma previously treated with DTIC, as an evaluation of DBPT as a second-line regimen, and as an indirect comparison of DBPT with DTIC. Thirty-five consecutive patients received DBPT. The patients were divided into two groups. Group 1 comprised 17 patients with progressive disease (PD) on DTIC + tamoxifen therapy who were switched directly to DBPT. Group 2 comprised 18 patients not immediately switched to DBPT and included patients who had either a partial response (PR; one patient) or developed stable disease (SD; four patients) with DTIC, or received adjuvant DTIC (nine patients). All except four patients had received tamoxifen at the time of initial DTIC treatment. Median times since stopping DTIC were 22 days (range 20–41) and 285 days (range 50–1240) in Groups 1 and 2 respectively. In Group 1, one patient developed SD for 5 months and the remainder had PD. In Group 2, there were two PRs, four patients with SD (4, 5, 6, and 6 months), and 11 with PD. These results indicate that the DBPT regimen is not of value in melanoma primarily refractory to DTIC. There were responses in patients not directly switched from DTIC to DBPT, suggesting combination therapy may be of value in a small subgroup of melanoma patients. © 2000 Cancer Research Campaig

Identification of the factors associated with outcomes in a condition management programme

<p>Background: A requirement of the Government’s Pathways to Work (PtW) agenda was to introduce a Condition Management Programme (CMP). The aim of the present study was to identify the differences between those who engaged and made progress in this telephone-based biopsychosocial intervention, in terms of their health, and those who did not and to determine the client and practitioner characteristics and programme elements associated with success in a programme aimed at improving health.</p> <p>Methods: Data were obtained from the CMP electronic spreadsheets and clients paper-based case records. CMP standard practice was that questionnaires were administered during the pre- and post-assessment phases over the telephone. Each client’s record contains their socio-demographic data, their primary health condition, as well as the pre- and post-intervention scores of the health assessment tool administered. Univariate and multivariate statistical analysis was used to investigate the relationships between the database variables. Clients were included in the study if their records were available for analysis from July 2006 to December 2007.</p> <p> Results: On average there were 112 referrals per month, totalling 2016 referrals during the evaluation period. The majority (62.8%) of clients had a mental-health condition. Successful completion of the programme was 28.5% (575 “completers”; 144 “discharges”). Several factors, such as age, health condition, mode of contact, and practitioner characteristics, were significant determinants of participation and completion of the programme. The results showed that completion of the CMP was associated with a better mental-health status, by reducing the number of clients that were either anxious, depressed or both, before undertaking the programme, from 74% to 32.5%.</p> <p>Conclusions: Our findings showed that an individual's characteristics are associated with success in the programme, defined as completing the intervention and demonstrating an improved health status. This study provides some evidence that the systematic evaluation of such programmes and interventions could identify ways in which they could be improved.</p&gt

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Psychologists’ dilemmas in career counselling practice

In this study, we explored main dilemmas psychologists face in career counselling in two main professional settings: employment and education. Participants included 24 experienced Portuguese psychologists, working in employment (n = 14) and educational (n = 10) settings. We used consensual qualitative research to conduct and analyse semi-structured interviews. Results revealed dilemmas’ in five domains: neutrality, assessment, dual loyalty, role boundaries, and confidentiality, with the typical dilemma in the domain of neutrality. Differences between groups were found in the domains of dual loyalty and role boundaries.Dans cette étude, nous avons exploré les principaux dilemmes rencontrés par les psychologues dans le conseil en orientation dans deux milieux professionnels centraux: le placement et l’éducation. Parmi les participants figuraient 24 psychologues portugais expérimentés travaillant dans des contextes de placement (n = 14) et d’éducation (n = 10). Nous avons utilisé la recherche qualitative consensuelle pour mener et analyser les entretiens semi-structurés. Les re´sultats ont révé lé des dilemmes dans cinq domaines: la neutralité, l’évaluation, la double loyauté, les limites du rôle, et la confidentialité, avec le dilemme typique dans le domaine de la neutralité. Les différences entre les groupes ont été identifiees dans les domaines de la double loyauté et les limites du rôle.In dieser Studie untersuchten wir die hauptsä chlichen Dilemmata, mit denen Psychologen in der Berufsberatung in zwei wesentlichen professionellen Einrichtungen konfrontiert sind: Beruf und Bildung. Zu den Teilnehmern geho ¨rten 24 erfahrene portugiesische Psychologen, die in Einrichtungen von Beruf (n = 14) und Bildung (n = 10) arbeiteten. Wir verwendeten einvernehmliche qualitative Forschung um semi-strukturierte Interviews durchzufu¨hren und zu analysieren. Die Ergebnisse zeigten Dilemmata in fünf Bereichen: Neutralität, Beurteilung, doppelte Loyalität, Rollengrenzen und Vertraulichkeit, mit dem typischen Dilemma in der Domäne der Neutralität. Unterschiede zwischen den Gruppen wurden in den Bereichen der doppelten Loyalität und Rollengrenzen gefunden

The between and within day variation in gross efficiency

Before the influence of divergent factors on gross efficiency (GE) [the ratio of mechanical power output (PO) to metabolic power input (PI)] can be assessed, the variation in GE between days, i.e. the test–retest reliability, and the within day variation needs to be known. Physically active males (n = 18) performed a maximal incremental exercise test to obtain VO2max and PO at VO2max (PVO2max), and three experimental testing days, consisting of seven submaximal exercise bouts evenly distributed over the 24 h of the day. Each submaximal exercise bout consisted of six min cycling at 45, 55 and 65% PVO2max, during which VO2 and RER were measured. GE was determined from the final 3 min of each exercise intensity with: GE = (PO/PI) × 100%. PI was calculated by multiplying VO2 with the oxygen equivalent. GE measured during the individually highest exercise intensity with RER <1.0 did not differ significantly between days (F = 2.70, p = 0.08), which resulted in lower and upper boundaries of the 95% limits of agreement of 19.6 and 20.8%, respectively, around a mean GE of 20.2%. Although there were minor within day variations in GE, differences in GE over the day were not significant (F = 0.16, p = 0.99). The measurement of GE during cycling at intensities approximating VT is apparently very robust, a change in GE of ~0.6% can be reliably detected. Lastly, GE does not display a circadian rhythm so long as the criteria of a steady-state VO2 and RER <1.0 are applied

Exclusion Performance in Dwarf Goats (Capra aegagrus hircus) and Sheep (Ovis orientalis aries)

Using a comparative approach, we investigated the ability of dwarf goats and sheep to use direct and indirect information about the location of a food reward in an object-choice task. Subjects had to choose between two cups with only one covering a reward. Before making a choice, subjects received information about the baited (direct information) or non-baited cup (indirect information). Both goats and sheep were able to use direct information (presence of food) in the object choice task. After controlling for local enhancement, we found that goats rather than sheep were able to use indirect information (i.e., the absence of food) to find a reward. The actual test setup could not clarify whether individual goats were able to inferentially reason about the content of the baited cup when only shown the content of the non-baited cup or if they simply avoided the empty cup in that situation. As browsing species, feral and wild goats exhibit highly selective feeding behaviour compared to the rather unselective grazing sheep. The potential influence of this species-specific foraging flexibility of goats and sheep for using direct and indirect information to find a food reward is discussed in relation to a higher aversion to losses in food acquisition in goats compared to sheep

Understanding Global Change: From Documentation and Collaboration to Social Transformation

The conclusion to the book situates the chapters within four programs of anthropological research on climate change: (1) documentation of local impacts of and adaptations to climate change, (2) connections to socioeconomic and political contexts, (3) collaborations with nonanthropologists, and (4) activism and social transformation. The final section notes the persistent challenges to creating positive change and meaningful research outcomes. It highlights some examples of success and outlines future directions for politically engaged anthropological work around climate change

Inequality in treatment use among elderly patients with acute myocardial infarction: USA, Belgium and Quebec

<p>Abstract</p> <p>Background</p> <p>Previous research has provided evidence that socioeconomic status has an impact on invasive treatments use after acute myocardial infarction. In this paper, we compare the socioeconomic inequality in the use of high-technology diagnosis and treatment after acute myocardial infarction between the US, Quebec and Belgium paying special attention to financial incentives and regulations as explanatory factors.</p> <p>Methods</p> <p>We examined hospital-discharge abstracts for all patients older than 65 who were admitted to hospitals during the 1993–1998 period in the US, Quebec and Belgium with a primary diagnosis of acute myocardial infarction. Patients' income data were imputed from the median incomes of their residential area. For each country, we compared the risk-adjusted probability of undergoing each procedure between socioeconomic categories measured by the patient's area median income.</p> <p>Results</p> <p>Our findings indicate that income-related inequality exists in the use of high-technology treatment and diagnosis techniques that is not justified by differences in patients' health characteristics. Those inequalities are largely explained, in the US and Quebec, by inequalities in distances to hospitals with on-site cardiac facilities. However, in both Belgium and the US, inequalities persist among patients admitted to hospitals with on-site cardiac facilities, rejecting the hospital location effect as the single explanation for inequalities. Meanwhile, inequality levels diverge across countries (higher in the US and in Belgium, extremely low in Quebec).</p> <p>Conclusion</p> <p>The findings support the hypothesis that income-related inequality in treatment for AMI exists and is likely to be affected by a country's system of health care.</p

Immediate effect of the COVID-19 pandemic on patient health, health-care use, and behaviours : results from an international survey of people with rheumatic diseases

Funding Information: We would like to thank all the clinicians, health-care providers, and patient organisations who helped to develop and disseminate this survey. A full list of all the contributors can be found in the appendix (pp 44?45). Preliminary results were presented at the American College of Rheumatology 2020 conference. The views expressed here are those of the authors and participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology, the European League Against Rheumatism, the UK National Health Service, the National Institute for Health Research, the UK Department of Health, or any other organisation. Funding Information: JSH reports grants from Childhood Arthritis and Rheumatology Research Alliance and Rheumatology Research Alliance; and personal fees from Novartis, Pfizer, and Biogen, outside of the submitted work. JWL reports grants from Pfizer, outside of the submitted work. JAS reports grants and personal fees from Bristol-Myers Squibb; and personal fees from Gilead, Inova Diagnostics, Optum, and Pfizer, outside of the submitted work. CH reports personal fees from AstraZeneca and Aurinia Pharmaceuticals, outside of the submitted work. MJL reports grants from American College of Rheumatology during the conduct of the study and consulting fees from AbbVie, Amgen, Actelion, Boehringer Ingelheim, BMS, Celgene, Gilead, Johnson & Johnson, Mallinckrodt, Novartis, Pfizer, Roche, Sandoz, Sanofi, Sobi, and UCB, outside of the submitted work. SES is supported by the Vasculitis Clinical Research Consortium and Vasculitis Foundation outside of the submitted work. KLD reports grants from Novartis, Sobi, National Institutes of Health, and Horizon Bio, outside of the submitted work. EFM reports that the Liga Portuguesa Contra as Doenças Reumaticas received support for specific activities: grants from Abbvie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal SA, MSD, Celgene, Medac, Pharmakern, GAfPA, AMGEN, A Menarini Portugal; grants and non-financial support from Pfizer; and non-financial support from Grünenthal GmbH and Tilray, outside of the submitted work. DPR is the volunteer Vice President of the Canadian Arthritis Patient Alliance, which is primarily supported by independent grants from pharmaceutical companies. DPR reports consulting fees from NovoNordisk Canada and speaking fees and an honoraria from Eli Lilly Canada, outside of the submitted work. DPR also lives with rheumatoid arthritis. SB reports personal fees from Novartis, AbbVie, Pfizer, and Horizon Pharma, outside of the submitted work. RG reports personal fees from AbbVie New Zealand, Cornerstones, Janssen New Zealand; and personal fees and non-financial support from Pfizer New Zealand, (all <$10 000) outside of the submitted work. PMM reports personal fees from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; and grants and personal fees from Orphazyme, outside of the submitted work. PCR reports personal fees from Abbvie, Gilead, Lilly, and Roche; grants and personal fees from Novartis, UCB Pharma, Janssen, and Pfizer; and non-financial support from BMS, outside of the submitted work. PS reports honoraria from being a social media editor for @ACR_Journals, outside of the submitted work. ZSW reports grants from National Institutes of Health, BMS, and Sanofi; and personal fees from Viela Bio and MedPace, outside of the submitted work. JY reports personal fees from Pfizer and Eli Lilly, and grants and personal fees from Astra Zeneca, outside of the submitted work. ES is a Board Member of the Canadian Arthritis Patient Alliance, which is a patient-run, volunteer-based organisation whose activities are primarily supported by independent grants from pharmaceutical companies. All other authors declare no competing interests. Publisher Copyright: © 2021 Elsevier LtdBackground: The impact and consequences of the COVID-19 pandemic on people with rheumatic disease are unclear. We developed the COVID-19 Global Rheumatology Alliance Patient Experience Survey to assess the effects of the COVID-19 pandemic on people with rheumatic disease worldwide. Methods: Survey questions were developed by key stakeholder groups and disseminated worldwide through social media, websites, and patient support organisations. Questions included demographics, rheumatic disease diagnosis, COVID-19 diagnosis, adoption of protective behaviours to mitigate COVID-19 exposure, medication access and changes, health-care access and communication with rheumatologists, and changes in employment or schooling. Adults age 18 years and older with inflammatory or autoimmune rheumatic diseases were eligible for inclusion. We included participants with and without a COVID-19 diagnosis. We excluded participants reporting only non-inflammatory rheumatic diseases such as fibromyalgia or osteoarthritis. Findings: 12 117 responses to the survey were received between April 3 and May 8, 2020, and of these, 10 407 respondents had included appropriate age data. We included complete responses from 9300 adults with rheumatic disease (mean age 46·1 years; 8375 [90·1%] women, 893 [9·6%] men, and 32 [0·3%] participants who identified as non-binary). 6273 (67·5%) of respondents identified as White, 1565 (16·8%) as Latin American, 198 (2·1%) as Black, 190 (2·0%) as Asian, and 42 (0·5%) as Native American or Aboriginal or First Nation. The most common rheumatic disease diagnoses included rheumatoid arthritis (3636 [39·1%] of 9300), systemic lupus erythematosus (2882 [31·0%]), and Sjögren's syndrome (1290 [13·9%]). Most respondents (6921 [82·0%] of 8441) continued their antirheumatic medications as prescribed. Almost all (9266 [99·7%] of 9297) respondents adopted protective behaviours to limit SARS-CoV-2 exposure. A change in employment status occurred in 2524 (27·1%) of 9300) of respondents, with a 13·6% decrease in the number in full-time employment (from 4066 to 3514). Interpretation: People with rheumatic disease maintained therapy and followed public health advice to mitigate the risks of COVID-19. Substantial employment status changes occurred, with potential implications for health-care access, medication affordability, mental health, and rheumatic disease activity. Funding: American College of Rheumatology.publishersversionPeer reviewe