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Competing Interests: Competing interests statement:The authors declare no competing interest.

Policy action for sustainability transformation faces inherent and ever-present sources of conflict, pushback, and resistance (i.e., discord). However, conceptual frameworks and policy prescriptions for sustainability transformations often reflect an undue image of accord. This involves simplified assumptions about consensus, steering, friction, discreteness, and additiveness of policy action, conferring an unrealistic view of the potential to deliberately realize transformation. Instead, negotiating discord through continuously finding partial political settlements among divided actors needs to become a key focus of policy action for sustainability transformations. Doing so can help to navigate deeply political settings through imperfect but workable steps that loosen deadlock, generate momentum for further policy action, and avoid complete derailment of transformation agendas when discord arises., Competing Interests: Competing interests statement:The authors declare no competing interest.

Community-supported agriculture (CSA) initiatives are spaces where diverse work relations are performed. From a postcapitalist perspective, these initiatives attempt to create alternative-capitalist and non-capitalist work relations next to capitalist ones. While analyses of work relations in CSA abound, it remains uncertain how such diversification is made possible and how it is shaped by the micro-politics of and power relations in these initiatives. This paper addresses this gap by analysing how power shapes transformations to postcapitalist work relations in CSA. It provides substantial empirical evidence of multiple manifestations of power enabling or constraining postcapitalist work relations through a comparative case study of three CSA initiatives in Portugal. Results show that while CSA creates postcapitalist work relations that are non-alienated, non-monetised and full of care, they insufficiently unmake unbalanced power relations established in capitalist work relations. This paper argues that, when establishing postcapitalist work relations, the selected CSA initiatives could benefit from actively deconstructing internal hierarchies, de-centralising decision-making power from farm owners and addressing oppressive power relations that are ossified in their local and cultural context., Competing Interests: Conflict of ineterstThe authors have no conflict of interest to declare., (© The Author(s) 2023.)

Objectives: There is a scarcity of data on the outcomes and predictors of therapeutic failure of monoclonal antibodies (mAbs) in frail patients with COVID-19., Methods: Prospective study including consecutive COVID-19 outpatients referred by primary care physicians for mAb treatment. The outcomes evaluated were 60-day mortality, time to SARS-CoV-2 clearance, need for hospitalization, and O 2 therapy., Results: Among 1026 COVID-19 patients enrolled, 60.2% received casirivamab/imdevimab and 39.8% sotrivimab. Median age was 63 years, 52.4% were males and median time from positive nasopharyngeal swab to mAbs administration was 3 days (interquartile range, 2-5). 78.1% were vaccinated. Overall, the 60-day mortality was 2.14%. No differences in outcomes were observed between the two mAbs used. No difference was observed in mortality between vaccinated and unvaccinated patients (P = 0.925); although, lower rate of hospitalization (P <0.005), less need for O 2 therapy (P <0.0001) and reduced nasopharyngeal swab negativity time (P <0.0001) were observed in vaccinated patients. Early administration of mAbs was associated with lower mortality (P <0.007), whereas corticosteroid use worsened prognosis (P <0.004). The independent predictors associated with higher mortality were older age (P <0.0001), presence of active hematologic malignancies (P <0.0001), renal failure (P <0.041), and need for O 2 therapy (P <0.001)., Conclusion: This study shows similar effectiveness among mAbs used, regardless of vaccination status and identifies patients with COVID-19 in whom mAbs have poor activity., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

rVIII-SingleChain is indicated for treatment and prophylaxis of bleeding in patients with haemophilia A (HA). The safety and efficacy of rVIII-SingleChain have previously been shown in the AFFINITY clinical trial programme. This survey evaluated clinical experience following a switch to rVIII-SingleChain from the perspective of both physicians and patients. A web-based survey (July-September 2019) involving 14 Haemophilia Treatment Centres (HTCs) collected data about HA patients who were under treatment with rVIII-SingleChain for ≥ 12 months, as reported by their physicians. In addition, about half of these patients were separately interviewed. Out of 91 patients receiving rVIII-SingleChain in the 14 participating HTCs, 48 had been treated for ≥ 12 months; among those 48, 38% were ≤ 18 years, 37% 19-40 years and 25 % ≥ 41 years; 73% of them had severe HA and 85% were being treated with prophylactic therapy. Twenty-six patients accepted to be separately interviewed: mean age was 30 years; 62% had severe HA and 85% were receiving prophylaxis. Focusing on those patients who were already in prophylaxis with prior FVIII (all but one with recombinant factors), infusion frequency was significantly reduced from 3-2 per week following the switch to rVIII-SingleChain (mean, 2.74 vs. 2.44, respectively; p=0.013), as reported by physicians; the rate of patients needing 3 infusions per week dropped from 74% with previous products to 44% with rFVIII-SingleChain. The annual mean factor consumption was 4740 IU/Kg (median, 4500 IU/Kg; min, 2.215 IU/Kg; max, 7.200 IU/Kg) with prior product and 4320 IU/Kg (median, 4320 IU/Kg; min, 2.215 IU/Kg; max, 6.646 IU/Kg) with rVIII-SingleChain. Both physicians and patients reported a significant reduction in annual total bleeding rates with rVIII-SingleChain compared with prior product (mean 2.15-0.96 and 2.46-0.71 events/year, p = 0.031 and p = 0.018, respectively). Mean satisfaction ratings (from 1; dissatisfied, to 5; very satisfied) for rVIII-SingleChain were quite high for both physicians (4.14, 86% satisfied/very satisfied) and patients (4.18, 86% satisfied/very satisfied). This survey suggested that switching to rVIII-SingleChain allowed patients to reduce their injection frequency without increasing factor consumption or compromising clinical results. Both physicians and patients reported a positive experience with rVIII-SingleChain after 1 year of treatment., (© 2021. The Author(s).)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The convergence of climate change and post-Soviet socio-economic and institutional transformations has been underexplored so far, as have the consequences of such convergence on crop agriculture in Central Asia. This paper provides a place-based analysis of constraints and opportunities for adaptation to climate change, with a specific focus on water use, in two districts in southeast Kazakhstan. Data were collected by 2 multi-stakeholder participatory workshops, 21 semi-structured in-depth interviews, and secondary statistical data. The present-day agricultural system is characterised by enduring Soviet-era management structures, but without state inputs that previously sustained agricultural productivity. Low margins of profitability on many privatised farms mean that attempts to implement integrated water management have produced water users associations unable to maintain and upgrade a deteriorating irrigation infrastructure. Although actors engage in tactical adaptation measures, necessary structural adaptation of the irrigation system remains difficult without significant public or private investments. Market-based water management models have been translated ambiguously to this region, which fails to encourage efficient water use and hinders adaptation to water stress. In addition, a mutual interdependence of informal networks and formal institutions characterises both state governance and everyday life in Kazakhstan. Such interdependence simultaneously facilitates operational and tactical adaptation, but hinders structural adaptation, as informal networks exist as a parallel system that achieves substantive outcomes while perpetuating the inertia and incapacity of the state bureaucracy. This article has relevance for critical understanding of integrated water management in practice and adaptation to climate change in post-Soviet institutional settings more broadly.

This paper presents an integrative and spatially explicit modeling approach for analyzing human and environmental exposure from pesticide application of smallholders in the potato-producing Andean region in Colombia. The modeling approach fulfills the following criteria: (i) it includes environmental and human compartments; (ii) it contains a behavioral decision-making model for estimating the effect of policies on pesticide flows to humans and the environment; (iii) it is spatially explicit; and (iv) it is modular and easily expandable to include additional modules, crops, or technologies. The model was calibrated and validated for the Vereda La Hoya and was used to explore the effect of different policy measures in the region. The model has moderate data requirements and can be adapted relatively easily to other regions in developing countries with similar conditions.

Offsite pesticide losses in tropical mountainous regions have been little studied. One example is measuring pesticide drift soil deposition, which can support pesticide risk assessment for surface water, soil, bystanders, and off-target plants and fauna. This is considered a serious gap, given the evidence of pesticide-related poisoning in those regions. Empirical data of drift deposition of a pesticide surrogate, Uranine tracer, within one of the highest potato-producing regions in Colombia, characterized by small plots and mountain orography, is presented. High drift values encountered in this study reflect the actual spray conditions using hand-held knapsack sprayers. Comparison between measured and predicted drift values using three existing empirical equations showed important underestimation. However, after their optimization based on measured drift information, the equations showed a strong predictive power for this study area and the study conditions. The most suitable curve to assess mean relative drift was the IMAG calculator after optimization.

Background: Primitive electronic waste (e-waste) recycling creates exposures to several hazardous substances including lead. In Uruguay, primitive recycling procedures are a significant source of lead exposure., Objectives: The aim of this study was to examine lead exposure in blood lead levels (BLLs) in low-income children exposed to lead through burning cables., Methods: A sample of children and adolescents exposed to lead through burning cable activities were assessed at the Department of Toxicology in Montevideo, Uruguay, between 2010 and 2014. Soil lead levels of residences were taken shortly after their assessment., Findings: The final sample included 69 children and adolescents (mean age 7.89 years). More than 66% of participants had an additional source of lead exposure-manual gathering of metals-and <5% were exposed to lead through landfills or paint. Average BLLs at first consultation were 9.19 ug/dL and lower at the second measurement (5.86 μg/dL). Data from soil lead levels ranged from 650 to 19,000 mg of lead/kg of soil. The interventions conducted after the assessment included family education in the clinic and at home, indoor and outdoor remediation. We found a decrease in BLLs of 6.96 μg/dL. Older children had lower BLLs (r = -0.24; P = 0.05). Statistical analyses also showed that children living in areas with higher soil lead levels had significantly higher BLLs (r = 0.50; P < 0.01). Additionally, we found greater BLLs from burning cable activities when children had been exposed to lead-based paint (r = 0.23; P < 0.1)., Conclusion: Among children exposed to e-waste recycling, the most common additional source of lead exposure was the manual gathering of metals. The average BLL among children and adolescents in this study is higher than the BLLs currently suggested in medical intervention. Future research should focus on exploring effective interventions to reduce lead exposure among this vulnerable group., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The study of societal transformation in response to environmental change has become established, yet little consensus exists regarding the conceptual basis of transformation. This paper aims to provide structure to the dialog on transformation, and to reflect on the challenges of social research in this area. Concepts of transformation are identified through a literature review, and examined using four analytical criteria. It is found that the term 'transformation' is frequently used merely as a metaphor. When transformation is not used as a metaphor, eight concepts are most frequently employed. They differ with respect to (i) system conceptualization, (ii) notions of social consciousness (deliberate/emergent), and (iii) outcome (prescriptive/descriptive). Problem-based research tends to adopt concepts of deliberate transformation with prescriptive outcome, while concepts of emergent transformation with no prescriptive outcome tend to inform descriptive-analytical research. Dialog around the complementarities of different concepts and their empirical testing are priorities for future research.

Rigorous evidence is lacking on long-term outcomes of factor VIII (FVIII) prophylaxis initiated in adolescent or adult patients with severe haemophilia A. The prospective, open-label Prophylaxis versus On-demand Therapy Through Economic Report (POTTER) study (ClinicalTrials.gov NCT01159587) compared long-term late secondary prophylaxis (recombinant FVIII-FS 20-30 IU/kg thrice weekly) with on-demand treatment in patients aged 12 to 55 years with severe haemophilia A. The annual number of joint bleeding episodes (primary endpoint), total bleeding episodes, orthopaedic and radiologic (Pettersson) scores, health-related quality of life (HRQoL), pharmacoeconomic impact, and safety were evaluated over a > 5-year period (2004-2010). Fifty-eight patients were enrolled at 11 centres in Italy; 53 (27 prophylaxis, 26 on demand) were evaluated and stratified into 2 age subgroups (12-25 and 26-55 years). Patients receiving prophylaxis experienced a significantly lower number of joint bleeding episodes vs the on-demand group (annualised bleeding rate, 1.97 vs 16.80 and 2.46 vs 16.71 in younger and older patients, respectively; p=0.0043). Results were similar for total bleeding episodes. Prophylaxis was associated with significantly fewer target joints (p< 0.001), better orthopaedic (p=0.0019) and Pettersson (p=0.0177) scores, better HRQoL, and fewer days of everyday activities lost (p< 0.0001) but required significantly higher FVIII product consumption. The POTTER study is the first prospective, controlled trial documenting long-term benefits of late secondary prophylaxis in adolescents and adults with severe haemophilia A. The benefits of reduced bleeding frequency, improved joint status, and HRQoL may offset the higher FVIII consumption and costs.

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by the quantitative or qualitative deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived VWF/factor VIII (FVIII) concentrates is required in patients unresponsive to desmopressin. To assess the efficacy, safety and ease of use of a new, volume-reduced (VR) formulation of VWF/FVIII concentrate Haemate(®) P in patients requiring treatment for bleeding or prophylaxis for recurrent bleeding or for invasive procedures. Pharmacoeconomic variables were also recorded. Data were analysed using descriptive statistics. This was a multicentre, prospective, observational study. Consecutively enrolled patients received Haemate(®) P VR according to their needs, and were followed for 24 months. Of the 121 patients enrolled, 25.6% had type 3 VWD and more than 40% had severe disease. All patients were followed for 2 years, for a total of 521 visits. On-demand treatment was given to 61.9% of patients, secondary long-term prophylaxis to 25.6% and prophylaxis for surgery, dental or invasive procedures to 45.5%. The response to treatment was rated as good to excellent in >93-99% of interventions. The new formulation was well tolerated by all patients with no report of drug-related adverse events. The switch to volume-reduced Haemate(®) P was easy to perform and infusion duration was decreased twofold compared with the previous formulation. Volume-reduced Haemate(®) P was at least as effective and well-tolerated as the previous formulation., (© 2012 Blackwell Publishing Ltd.)

The misuse of personal protective equipment (PPE) during pesticide application was investigated among smallholders in Colombia. The integrative agent-centered (IAC) framework and a logistic regression approach were adopted. The results suggest that the descriptive social norm was significantly influencing PPE use. The following were also important: (1) having experienced pesticide-related health problems; (2) age; (3) the share of pesticide application carried out; and (4) the perception of PPE hindering work. Interestingly, the influence of these factors differed for different pieces of PPE. Since conformity to the social norm is a source of rigidity in the system, behavioral change may take the form of a discontinuous transition. In conclusion, five suggestions for triggering a transition towards more sustainable PPE use are formulated: (1) diversifying targets/tools; (2) addressing structural aspects; (3) sustaining interventions in the long-term; (4) targeting farmers' learning-by-experience; and (5) targeting PPE use on a collective level.

Background: Injection of long-acting insulin at bedtime is a common therapeutic approach for patients with type 2 diabetes that is poorly controlled with oral regimens. Neutral protamine lispro (NPL) insulin has demonstrated better glycemic control and similar incidence of hypoglycemic events than that of neutral protamine Hagedorn insulin., Objective: To compare the clinical efficacy and safety of bedtime NPL insulin or insulin glargine in patients with type 2 diabetes who had suboptimal glycemic control while receiving stable doses of metformin and sulfonylurea., Design: Open-label, randomized trial., Setting: Teaching hospital (Azienda Ospedaliera Universitaria, Second University of Naples), Naples, Italy., Patients: 116 adults receiving stable doses of metformin plus sulfonylurea for longer than 90 days with hemoglobin A(1c) (HbA(1c)) levels of 7.5% to 10% and fasting plasma glucose levels of 6.7 mmol/L or greater (> or =120 mg/dL)., Intervention: 10 IU of NPL insulin or insulin glargine injected subcutaneously at bedtime with weekly dose titrations to target fasting glucose levels less than 5.6 mmol/L (<100 mg/dL) in addition to stable oral regimens. Patients receiving nighttime sulfonylurea before the study were switched to metformin., Measurements: The primary outcome was change in HbA(1c) levels from baseline to week 36. Secondary outcomes were HbA(1c) levels less than 7%, self-reported hypoglycemic episodes, insulin dose, self-monitored glucose level, and body weight. Twenty patients in each group had continuous glucose monitoring for 3 consecutive days before adding insulin and at week 36., Results: Improvement in HbA(1c) levels was similar in both groups (1.83% and 1.89% for NPL and glargine, respectively). The difference between the groups was 0.06 percentage point (95% CI, -0.1 to 0.15 percentage points). Secondary outcomes did not differ between groups. Hemoglobin A(1c) levels less than 7% occurred in 62% of patients receiving NPL and 64% of patients receiving glargine (difference, 2.0 percentage points [CI, -1.1 to 5.0 percentage points]). Fasting plasma glucose levels less than 5.6 mmol/L (<100 mg/dL) occurred in 40% of patients receiving NPL and 41% of patients receiving glargine (difference, 1.0 percentage point [CI, -0.9 to 3.0 percentage points]). Any hypoglycemic event occurred in 74% of patients receiving NPL and 67% of patients receiving glargine (difference, 7 percentage points [CI, -5 to 13 percentage points]). Continuous glucose level monitoring in the patients who had this measurement did not differ statistically., Limitation: The study was not blinded, had limited power to detect differences in hypoglycemic events, and did not obtain continuous glucose level monitoring for all patients., Conclusion: Similar glycemic control occurred with the addition of NPL or glargine insulin to oral regimens in patients with poorly controlled type 2 diabetes. Hypoglycemia was similar in the 2 groups, but sample size limited the ability to make a definite safety assessment.

While primary prophylaxis is a well-established and recommended method of care delivery for children with severe haemophilia, fewer studies have documented the benefits of secondary prophylaxis started in adolescence or adulthood. To evaluate the role of secondary prophylaxis started in adolescent and adult severe haemophiliacs, a retrospective observational cohort study was conducted in 10 Italian Centres that investigated 84 haemophiliacs who had bled frequently and had thus switched from on-demand to prophylactic treatment during adolescence (n = 30) or adulthood (n = 54). The consumption of clotting factor concentrates, the orthopaedic and radiological scores, quality of life and disease-related morbidity were compared before and after starting secondary prophylaxis. Prophylaxis reduced the mean annual number of total and joint bleeds (35.8 vs. 4.2 and 32.4 vs. 3.3; P < 0.01) and of days lost from work/school (34.6 vs. 3.0, P < 0.01). A statistically significant reduction in the orthopaedic score was observed during prophylaxis in adolescents, but not in the whole cohort. Patients used more factor concentrates with corresponding higher costs on prophylaxis, but experienced a better quality of life. With respect to on-demand treatment, higher factor consumption and cost of secondary prophylaxis were balanced by marked clinical benefits and greater well-being in this cohort of adolescent/adult haemophiliacs.

Autosomal dominant high myopia, a genetic disorder already mapped to region 18p11.31, is common in Carloforte (Sardinia, Italy), an isolated village of 8,000 inhabitants descending from a founder group of 300 in the early 1700s. Fifteen myopic propositi and 36 normal controls were selected for not having ancestors in common at least up to the grandparental generation, although still descendants of the original founders. All subjects were genotyped for 14 markers located on autosome 18 at a resolution of about 10 cM. Allelic distributions were found to be similar at all tested loci in propositi and controls, except for the candidate marker D18S63 known to segregate in close linkage association with high myopia. In particular, the frequency of allele 85 among the propositi was almost double that of the controls (Fisher's exact test, p = 0.037). The association is more striking when the frequency of the genotype 85/85 in the two groups is compared (Fisher's exact test, p = 0.005). This conclusion was further evaluated through a bootstrap analysis by computing the overall probability of the observed data under the null hypothesis (i.e. no difference between the two groups in frequency distributions for the chromosome 18 markers). Again, marker D18S63 was found to have a sample probability lower than 0.004, which is significant at the 0.05 level after correcting for simultaneous testing of multiple loci. The study demonstrates the efficiency of our novel strategy to detect identity by descent (IBD) in small numbers of patients and controls when they are both part of well-defined Mendelian breeding units (MBUs). The iterative application of our strategy in separate MBUs is expected to become the method of choice to evaluate the ever-growing number of reported associations between candidate genes and multifactorial traits and diseases., (Copyright 2002 S. Karger AG, Basel)

In this article we consider the relationship between asthma mortality rates, obtained from the Italian National Institute of Statistics (ISTAT), and the doses of all antiasthmatic drugs except systemic steroids sold in Italy in the years 1974-1988. The total asthma mortality rate showed three different trends: it decreased slowly until 1978 (period A); increased 10-fold from 1979 to 1985, rising from 0.30 to 4.17/100,000 (period B); and remained stable until 1988 (period C). More than half of the deaths in 1988 occurred in people 75 years of age or more. Men died more in the older age groups, while the mortality of women prevailed in the 35- to 54-year age group. In the 5- to 34-year age group the rate rose from 0.01 in 1978 to 0.21 /100,000 in 1986. Coding changes due to the 9th revision of the International Classification of Disease, adopted in Italy in 1979, probably increased the number of deaths being attributed to asthma in case of contemporary mention of bronchitis, a common diagnosis in older men, which showed the greatest increase in mortality. Increased prevalence and awareness of asthma may also have played a role. Although international comparisons strongly suggest undertreatment of asthma in Italy, the doses of anti-asthma drugs sold in Italy grew from 276 to 1,080 million from 1974 to 1985. During period B xanthine sales rose sevenfold and grew from 6.5 to 23.3% of the total doses, along with a twofold increase in beta 2-agonist and cromolyn sales. Period C was characterized by stable total doses (1155 million in 1988), with increases only in antiinflammatory and preventive drug sales. The increase in asthma deaths in Italy has been striking despite the contemporary rise in sales of all antiasthma drugs, particularly of beta 2-agonist metered aerosols and xanthine tablets. The increase in antiinflammatory and preventive drug sales may have contributed to the stabilization of asthma deaths during period C.

A two-part study was undertaken to assess the comparability of the coding of underlying cause of death between ISTAT (Central Statistics Office providing "national" mortality statistics) and RMR (Mortality Registry of Tuscany Region providing "local" mortality statistics). In Part I was compared mortality data of the Province of Florence (years 1985-1986) from the files of ISTAT with those of RMR. The source of the cause of death is the same for both systems (ISTAT certificate), but the data collection and coding of RMR are different from those of ISTAT. In Part II was compared a set of 219 Tuscany death certificates (year 1988) coded by ISTAT and RMR. The results showed an high degree of completeness of RMR (only--0.65% vs. ISTAT) and a satisfactory level of correspondence in the number of deaths for circulatory diseases, for neoplasms and for cancers of most important sites (lung, stomach, intestine, pancreas, breast). Discrepancies were found for some other diseases; for some of these causes of death, also age-adjusted mortality rates showed discrepancies (for example ischaemic heart disease). The cause of these differences have been analyzed.

The second European Atlas of Avoidable deaths, which will be shortly issued, concerns the period 1979-83 for Italy. The causes of deaths included were: tuberculosis, neoplasms of the cervix uteri and those of the uterus with no specified site, Hodgkin's disease, chronic rheumatic heart disease, hypertensive and cerebrovascular disease, childhood respiratory infections, asthma, appendicitis, abdominal hernia, cholecystitis and cholelithiasis, maternal and perinatal deaths. In Italy marked excesses for cholecystitis-cholelithiasis, Hodgkin's disease, hypertensive and cerebrovascular disease and perinatal mortality were observed. A remarkable decrease was observed in comparison with the first Atlas (1974-78); but the European countries generally maintained the differences amongst them and their rank. Proposals to assess the causes of the observed differences are suggested (death certificate quality evaluation studies, case-reference studies, cohort studies) and the role of confidential enquiries is discussed.