Capturing Collaborative Challenges: Designing Complexity-Sensitive Theories of Change for Cross-Sector Partnerships

Systems change requires complex interventions. Cross-sector partnerships (CSPs) face the daunting task of addressing complex societal problems by aligning different backgrounds, values, ideas and resources. A major challenge for CSPs is how to link the type of partnership to the intervention needed to drive change. Intervention strategies are thereby increasingly based on Theories of Change (ToCs). Applying ToCs is often a donor requirement, but it also reflects the ambition of a partnership to enhance its transformative potential. The current use of ToCs in partnering efforts varies greatly. There is a tendency for a linear and relatively simple use of ToCs that does limited justice to the complexity of the problems partnerships aim to address. Since partnership dynamics are already complex and challenging themselves, confusion and disagreement over the appropriate application of ToCs is likely to hamper rather than enhance the transformative potential of partnerships. We develop a complexity alignment framework and a diagnostic tool that enables partnerships to better appreciate the complexity of the context in which they operate, allowing them to adjust their learning strategy. This paper applies recent insights into how to deal with complexity from both the evaluation and theory of change fields to studies investigating the transformative capacity of partnerships. This can (1) serve as a check to define the challenges of partnering projects and (2) can help delineate the societal sources and layers of complexity that cross-sector partnerships deal with such as failure, insufficient responsibility taking and collective action problems at four phases of partnering

The Neutrophil:The Underdog That Packs a Punch in the Fight against Cancer

The advent of immunotherapy has had a major impact on the outcome and overall survival in many types of cancer. Current immunotherapeutic strategies typically aim to (re)activate anticancer T cell immunity, although the targeting of macrophage-mediated anticancer innate immunity has also emerged in recent years. Neutrophils, although comprising approximate to 60% of all white blood cells in the circulation, are still largely overlooked in this respect. Nevertheless, neutrophils have evident anticancer activity and can induce phagocytosis, trogocytosis, as well as the direct cytotoxic elimination of cancer cells. Furthermore, therapeutic tumor-targeting monoclonal antibodies trigger anticancer immune responses through all innate Fc-receptor expressing cells, including neutrophils. Indeed, the depletion of neutrophils strongly reduced the efficacy of monoclonal antibody treatment and increased tumor progression in various preclinical studies. In addition, the infusion of neutrophils in murine cancer models reduced tumor progression. However, evidence on the anticancer effects of neutrophils is fragmentary and mostly obtained in in vitro assays or murine models with reports on anticancer neutrophil activity in humans lagging behind. In this review, we aim to give an overview of the available knowledge of anticancer activity by neutrophils. Furthermore, we will describe strategies being explored for the therapeutic activation of anticancer neutrophil activity

APEX-CHAMP+ high-J CO observations of low-mass young stellar objects: III. NGC 1333 IRAS 4A/4B envelope, outflow and UV heating

NGC 1333 IRAS 4A and IRAS 4B sources are among the best studied Stage 0 low-mass protostars which are driving prominent bipolar outflows. Most studies have so far concentrated on the colder parts (T<30K) of these regions. The aim is to characterize the warmer parts of the protostellar envelope in order to quantify the feedback of the protostars on their surroundings in terms of shocks, UV heating, photodissociation and outflow dispersal. Fully sampled large scale maps of the region were obtained; APEX-CHAMP+ was used for 12CO 6-5, 13CO 6-5 and [CI] 2-1, and JCMT-HARP-B for 12CO 3-2 emissions. Complementary Herschel-HIFI and ground-based lines of CO and its isotopologs, from 1-0 upto 10-9 (Eu/k 300K), are collected at the source positions. Radiative-transfer models of the dust and lines are used to determine temperatures and masses of the outflowing and UV-heated gas and infer the CO abundance structure. Broad CO emission line profiles trace entrained shocked gas along the outflow walls, with typical temperatures of ~100K. At other positions surrounding the outflow and the protostar, the 6-5 line profiles are narrow indicating UV excitation. The narrow 13CO 6-5 data directly reveal the UV heated gas distribution for the first time. The amount of UV-heated and outflowing gas are found to be comparable from the 12CO and 13CO 6-5 maps, implying that UV photons can affect the gas as much as the outflows. Weak [CI] emission throughout the region indicates a lack of CO dissociating photons. Modeling of the C18O lines indicates the necessity of a "drop" abundance profile throughout the envelope where the CO freezes out and is reloaded back into the gas phase, thus providing quantitative evidence for the CO ice evaporation zone around the protostars. The inner abundances are less than the canonical value of CO/H_2=2.7x10^-4, indicating some processing of CO into other species on the grains.Comment: 20 pages, 22 figures, Accepted by A&

Therapeutic options in the management of acromegaly: focus on lanreotide Autogel®

In acromegaly, expert surgery is curative in only about 60% of patients. Postoperative radiation therapy is associated with a high incidence of hypopituitarism and its effect on growth hormone (GH) production is slow, so that adjuvant medical treatment becomes of importance in the management of many patients. To delineate the role of lanreotide in the treatment of acromegaly. Search of Medline, Embase, and Web of Science databases for clinical studies of lanreotide in acromegaly. Treatment with lanreotide slow release and lanreotide Autogel((R)) normalized GH and insulin-like growth factor-I (IGF-I) concentrations in about 50% of patients. The efficacy of 120 mg lanreotide Autogel((R)) on GH and IGF-I levels was comparable with that of 20 mg octreotide LAR. There were no differences in improvement of cardiac function, decrease in pancreatic beta-cell function, or occurrence of side effects, including cholelithiasis, between octreotide LAR and lanreotide Autogel(R). When postoperative treatment with somatostatin analogs does not result in normalization of serum IGF-I and GH levels after noncurative surgery, pegvisomant alone or in combination with somatostatin analogs can control these levels in a substantial number of patient

Exploring sibling relationships and experiences in adolescent non-fatal self-harm: a systematic review and grounded theory study

BACKGROUND: Non-fatal self-harm is associated with negative health outcomes and common among adolescents. Family factors have been implicated as contributing to the onset and maintenance of adolescent self-harm but can also have protective effects as well. Self-harm has also been found to be distressing for family members. Most research has focussed on understanding the role and experiences of parents or the family in general. Siblings have largely been overlooked, despite most young people having at least one sibling and the unique characteristics of sibling relationships. OBJECTIVES: A systematic review was conducted to identify, summarise and evaluate studies that investigated any possible associations between sibling relationship dimensions and nonfatal self-injurious thoughts and behaviours (SITBs) in adolescence. An empirical study was conducted to develop a theoretical understanding of the sibling experience of adolescent self-harm and explore if there were any unmet needs in knowledge or support for siblings. METHODS: Systematic review: A comprehensive literature search identified eligible studies that reported on associations between sibling warmth, conflict, and/or differential treatment with adolescent self-injurious thoughts or behaviours. Study quality was appraised with the shortened Research Triangle Institute Item Bank (RTI-IB) and findings were collated in a narrative synthesis. Empirical study: Eight participants (ages 16 to 23 years) took part in online interviews about their experience growing up with an adolescent sister who engaged in self-harm. This study was informed by constructivist grounded theory methods. RESULTS: Systematic review: Thirteen studies were identified that presented mixed results. Due to poor study quality, no conclusions could be drawn about associations with warmth or differential treatment. There was some indication that sibling conflict was positively associated with certain SITBs, but these associations were often no longer significant when mental health problems were considered. Inconsistency in construct definitions, varied populations, poor psychometric quality of measures, and issues with confounding were among identified problems that made it hard to compare studies and have confidence in their results. Empirical study: Siblings varied in what they knew and understood about their sister’s self-harm, but all were impacted on an intrapersonal and interpersonal level. They were mostly overlooked by health services. Siblings adapted through self-sacrifice, minimising personal distress, disengagement, and seeking social support outside of their sister and parents. Most siblings also tried self-harm themselves. Over time, siblings found ways that helped with coming to terms with their experience. Interactions with others shaped individual experiences. Siblings also provided suggestions on support for others. CONCLUSIONS: Systematic review: No conclusive associations between sibling relationship dimensions and adolescent self-injurious thoughts or behaviours were evidenced. Methodological limitations of the evidence base were identified to inform future research. Empirical study: Adolescent self-harm is often difficult for siblings. It is important that families and professionals consider and address siblings’ needs. Further research into sibling experiences of adolescent self-harm is also indicated

Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease

Suspected survivor bias in case–control studies: stratify on survival time and use a negative control

AbstractObjectivesSelection bias in case–control studies occurs when control selection is inappropriate. However, selection bias due to improper case sampling is less well recognized. We describe how to recognize survivor bias (i.e., selection on exposed cases) and illustrate this with an example study.Study Design and SettingA case–control study was used to analyze the effect of statins on major bleedings during treatment with vitamin K antagonists. A total of 110 patients who experienced such bleedings were included 18–1,018 days after the bleeding complication and matched to 220 controls.ResultsA protective association of major bleeding for exposure to statins (odds ratio [OR]: 0.56; 95% confidence interval: 0.29–1.08) was found, which did not become stronger after adjustment for confounding factors. These observations lead us to suspect survivor bias. To identify this bias, results were stratified on time between bleeding event and inclusion, and repeated for a negative control (an exposure not related to survival): blood group non-O. The ORs for exposure to statins increased gradually to 1.37 with shorter time between outcome and inclusion, whereas ORs for the negative control remained constant, confirming our hypothesis.ConclusionWe recommend the presented method to check for overoptimistic results, that is, survivor bias in case–control studies