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The current version of the Declaration of Helsinki states that ‘the benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention(s) … ’. This wording implies that it is acceptable for patients to be assigned to receive an unproven new intervention and to be denied a best current proven intervention. We assert that patients being invited to participate in controlled trials cannot, ethically, be expected to forego proven beneficial forms of care. Patients being treated in controlled trials should not knowingly be disadvantaged compared with similar patients being treated in usual clinical care, where they have access to beneficial care. In this article, we have tried to separate for discussion ‘the withholding of effective care from trial participants’, ‘informed consent to treatment’, ‘blinding’ and ‘use of placebos’.

To assess the prevalence of abortion among population groups and changes in rates between 2008 and 2014.We used secondary data from the Abortion Patient Survey, the American Community Survey, and the National Survey of Family Growth to estimate abortion rates. We used information from the Abortion Patient Survey to estimate the lifetime incidence of abortion.Between 2008 and 2014, the abortion rate declined 25%, from 19.4 to 14.6 per 1000 women aged 15 to 44 years. The abortion rate for adolescents aged 15 to 19 years declined 46%, the largest of any group. Abortion rates declined for all racial and ethnic groups but were larger for non-White women than for non-Hispanic White women. Although the abortion rate decreased 26% for women with incomes less than 100% of the federal poverty level, this population had the highest abortion rate of all the groups examined: 36.6. If the 2014 age-specific abortion rates prevail, 24% of women aged 15 to 44 years in that year will have an abortion by age 45 years.The decline in abortion was not uniform across all population groups.

Recent years have seen a paradigm shift in the management of patients with diabetes mellitus. Rather than good glycaemic control being the sole primary aim, the therapeutic focus has broadened to consider potential additional cardiovascular and renal benefits. Sodium-glucose co-transporter 2 inhibitors, such as empagliflozin, canagliflozin and dapagliflozin, have gained increasing prominence, with evidence suggesting significant improvement in outcomes in patients with established cardiovascular and renal disease. Here, we discuss the benefits and relative risks of these novel agents and highlight important clinical issues of relevance to general physicians.

Objective: To study the relationship between consumption of milk and milk products, calcium, lactose and vitamin D and occurrence of colorectal cancers. Design: Prospective cohort study. Subjects: A total of 9959 men and women aged 15 y or older without history of cancer at baseline. During a 24 y follow-up, 72 new cancers of the large bowel (38 in the colon and 34 in the rectum) were detected. Results: Consumption of milk and total milk products was suggested to be inversely related to colon cancer incidence, whereas no similar association was seen for rectal cancer. The relative risk between the highest and lowest quartiles of intake adjusted for potential confounding factors was 0.46 (95% confidence interval 0.14–1.46, P for trend 0.09) for milk and 0.37 (95% CI=0.12–1.39, P for trend 0.06) for total milk products. Lactose intake showed a similar inverse relationship with colon cancer: the relative risk was 0.31 (95% CI=0.08–1.15, P for trend 0.03). Intake of vitamin D or total dietary calcium was not significantly related to colorectal cancer risk, whereas calcium provided by fermented milk products was associated with increased colorectal cancer incidence; in the highest quartile the multivariate adjusted relative risk for colorectal cancer was 2.07 (95% CI=1.00–4.28). Conclusions: Our results indicate that individuals showing high consumption of milk have a potentially reduced risk of colon cancer; however, the association does not appear to be due to intake of calcium, vitamin D, or to specific effects of fermented milk. Sponsorship: This study was supported by a grant from the Swedish Cancer Foundation. European Journal of Clinical Nutrition (2001) 55, 1000–1007

Objective: To demonstrate sexual dimorphism in serum leptin levels not only during puberty, but also in childhood in Japan. Design: Cross-sectional study. Setting: Hamamatsu-Hokuen study in Japan. Subjects: Body weight and height were measured in normal-weight Japanese children and adolescents (143 boys, 178 girls), and 161 boys and 129 girls whose percentage of overweight for the standard (%Wt) was more than+25%. Serum leptin levels were compared with %Wt. Subjects were divided into group 1 (6–10 y of age) and group 2 (11–15 y of age) according to their age. Results: In overweight subjects, leptin was more highly correlated with %Wt in boys of group 2 (r=0.67, P

Sex differences are commonly observed in behaviors that are closely linked to adaptive function, but sex differences can also be observed in behavioral "building blocks" such as locomotor activity and reward processing. Modern neuroscientific inquiry, in pursuit of generalizable principles of functioning across sexes, has often ignored these more subtle sex differences in behavioral building blocks that may result from differences in these behavioral building blocks. A frequent assumption is that there is a default (often male) way to perform a behavior. This approach misses fundamental drivers of individual variability within and between sexes. Incomplete behavioral descriptions of both sexes can lead to an overreliance on reduced "single-variable" readouts of complex behaviors, the design of which may be based on male-biased samples. Here, we advocate that the incorporation of new machine-learning tools for collecting and analyzing multimodal "big behavior" data allows for a more holistic and richer approach to the quantification of behavior in both sexes. These new tools make behavioral description more robust and replicable across laboratories and species, and may open up new lines of neuroscientific inquiry by facilitating the discovery of novel behavioral states. Having more accurate measures of behavioral diversity in males and females could serve as a hypothesis generator for where and when we should look in the brain for meaningful neural differences.

OBJECTIVES: Following the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and the subsequent global spread of the 2019 novel coronavirus disease (COVID-19), health systems and the populations who use them have faced unprecedented challenges. We aimed to measure the impact of COVID-19 on the uptake of hospital-based care at a national level. DESIGN: The study period (weeks ending 5 January to 28 June 2020) encompassed the pandemic announcement by the World Health Organization and the initiation of the UK lockdown. We undertook an interrupted time-series analysis to evaluate the impact of these events on hospital services at a national level and across demographics, clinical specialties and National Health Service Health Boards. SETTING: Scotland, UK. PARTICIPANTS: Patients receiving hospital care from National Health Service Scotland. MAIN OUTCOME MEASURES: Accident and emergency (A&E) attendances, and emergency and planned hospital admissions measured using the relative change of weekly counts in 2020 to the averaged counts for equivalent weeks in 2018 and 2019. RESULTS: Before the pandemic announcement, the uptake of hospital care was largely consistent with historical levels. This was followed by sharp drops in all outcomes until UK lockdown, where activity began to steadily increase. This time-period saw an average reduction of −40.7% (95% confidence interval [CI]: −47.7 to −33.7) in A&E attendances, −25.8% (95% CI: −31.1 to −20.4) in emergency hospital admissions and −60.9% (95% CI: −66.1 to −55.7) in planned hospital admissions, in comparison to the 2018–2019 averages. All subgroup trends were broadly consistent within outcomes, but with notable variations across age groups, specialties and geography. CONCLUSIONS: COVID-19 has had a profoundly disruptive impact on hospital-based care across National Health Service Scotland. This has likely led to an adverse effect on non-COVID-19-related illnesses, increasing the possibility of potentially avoidable morbidity and mortality. Further research is required to elucidate these impacts.

Aims: To determine the efficacy of XPro1595 to improve pathophysiological and functional outcomes in a mouse model of traumatic brain injury (TBI). Background: Symptoms associated with TBI can be debilitating, and treatment without off-target side effects remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of TBI. Objectives: Use XPro1595 to determine whether injury-induced solTNF promotes hippocampal inflammation and dendritic plasticity and associated functional impairments. Methods: Mild-to-moderate traumatic brain injury (CCI model) was induced in adult male C57Bl/6J WT and Thy1-YFPH mice, with XPro1595 (10 mg/kg, S.C.) or vehicle being administered in a clinically relevant window (60 minutes post-injury). The animals were assessed for differences in neurological function, and hippocampal tissue was analyzed for inflammation and glial reactivity, as well as neuronal degeneration and plasticity. Results: We report that unilateral CCI over the right parietal cortex in mice promoted deficits in learning and memory, depressive-like behavior, and neuropathic pain. Using immunohistochemical and Western blotting techniques, we observed the cortical injury promoted a set of expected pathophysiology’s within the hippocampus consistent with the observed neurological outcomes, including glial reactivity, enhanced neuronal dendritic degeneration (dendritic beading), and reduced synaptic plasticity (spine density and PSD-95 expression) within the DG and CA1 region of the hippocampus, that were prevented in mice treated with XPro1595. Conclusion: Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of brain-injured mice, which provides support for its use in patients with TBI.

China is the most productive seaweed farming country in the world and her seaweed imports and exports have a significant impact on global seaweed trade commodities and food security. Nevertheless, few studies had delved into the main characteristics and development of China's seaweed farming industry. This paper aims to narrow this research gap by analyzing trade patterns in China's seaweed products and the international competitiveness of seaweed product by using the international market share index (IMS), the trade competitiveness index (TC), and revealed comparative advantage index (RCA) from 2002 to 2017. The results showed that Japan, the Association of Southeast Asian Nations (ASEAN), Chile, Peru, and the Republic of Korea are China's main trade partners, the total trade value of China's seaweed products has grown rapidly, its imports have gradually exceeded exports, the trade deficit continues to expand, and its competitiveness keeps decreasing. The reasons for this trend may include the changing seaweed trade commodity structure, product differentiation, increased government support in competing countries, and trade barriers among the trade partners. We propose actively expanding international trade markets, establishing a strong seaweed product processing industry to develop high value-added seaweed products, optimizing the trade commodity structure, and differentiating of seaweed products to improve the competitiveness of China's seaweed products.

Using a continuous-time model of litigation, we show that the increasingly popular practice of third-party litigation financing has ambiguous welfare implications. A defendant and a plaintiff bargain over a settlement payment. The defendant takes costly actions to avoid deadweight losses associated with large transfers to the plaintiff. Litigation financing bolsters the plaintiff, leading to larger deadweight losses. However, by endogenously deterring the defendant from taking costly actions, litigation financing can nonetheless improve the joint surplus of the plaintiff and the defendant. In contrast to popular opinion, litigation financing does not necessarily encourage high-risk frivolous lawsuits.

Given the alleged uniqueness of Islamic stocks, it is expected that they should provide insurance when faced with adverse market conditions. This expectation is tested by assessing contagion, using 25 Islamic indexes during the period 2007–2017, by employing contemporary econometric techniques. The results reveal robust contagion effects of the financial crisis on Islamic stock indexes. Furthermore, we find Baker and Wurgler’s investor sentiment can predict Islamic stock returns during the crisis period. Our findings indicate that Islamic stocks cannot be used as a haven asset during financial turmoil.

Shariah screening discards the firms that belong to impermissible business sectors (or sin industries) and follow capital structure with high debt and current assets. This study tests whether the firms passing Shariah screening have better (or worse) governance quality as compared to firms not subjected to Islamic screening. The screened firms may have lesser governance quality as they cannot use debt to discipline managers or achieve optimal capital structure. On the contrary, they may be better governed as these firms get higher presence of institutional investors and better analyst coverage. This paper provides comparison of governance quality of Shariah compliant (SC) firms in United States by using proprietary dataset of Dow Jones US Indices. The screened firms offer ground for a natural experiment as they pass negative ethical screening and meet financial criteria for the inclusion in the index. The findings suggest that the SC firms have lesser governance quality than Shariah Non-Compliant firms. The lower level of governance can be attributed to lower Size, lower Profitability, higher Dividend Payout, higher Total Risk and lower Free Cash Flow. Various robustness tests are performed to validate the findings and the results remained robust. These findings provide useful insights about the governance mechanism of SC firms that are emerging as an important alternative investment class in the last two decades.

Mediterranean mussel farming in Greece developed considerably during the last 40 years reaching a gross commodity product up to the limits of the country's production capacity (35–40,000 tonnes/year). Despite the achievements in the sector's growth, little or no effort has been attributed yet to risk assessment and moreover to risk management of the activity. The present effort aims at developing a working framework for the shellfish aquaculture of Greece to be used as a tool by the sector's decision makers to advance strategies for risk elimination or avoidance. The work was based on a generic risk management standard tool, the Joint Australian and New Zealand Risk Management Standard AS/NZS ISO 31000:2009 that has been adapted to the specific national characteristics of all levels of the mussel farming business -activities and the industry function. The framework supported by data sets regarding development, production, profits and losses, retrieved by surveys through distributed questionnaires or interviews during site-visits, as well as by collecting data from national and international authorities. Data input covered technology, farm size, farmer risk-attitude, risk-management strategies, risk-perceptions and socioeconomic profiles. Major risks and risk management options were identified providing aid for remediation risk policies to the stakeholders.

To overcome the cost of competition resulting from close social proximity while foraging in a group, individuals may balance their use of private (i.e. acquired from personal sampling) and social (i.e. acquired by watching other individuals) information in order to adjust their foraging strategy accordingly. Reliability of private information about environmental characteristics, such as the spatial distribution of prey, is thus likely to affect individual movement and social interactions during foraging. Our aim was to investigate how movement characteristics of foraging individuals changed as they acquired reliable private information about the spatial occurrence of prey in a foraging context. We allowed guppies (Poecilia reticulata) to develop the reliability of their private knowledge about prey spatial occurrence by repeatedly testing shoals in a foraging task under three experimental distributions of prey: 1) aggregated prey forming three patches located in fixed locations, 2) scattered distribution of prey with random locations, or 3) no prey (used as control). We then applied tracking methods to obtain individual time series of spatial coordinates from which we computed a suite of movement variables reflecting search effort, social proximity and locomotion characteristics during foraging, in order to examine changes occurring over repeated trials and to investigate which best explained foraging success. We show that foraging shoals became more efficient at finding and consuming food over the first three days by increasing their time spent active. Over time, individuals foraging on either scattered or aggregated prey travelled greater distances, showed an increasing distance to their closest neighbour and became slightly more stochastic in their acceleration profile, compared to control individuals. We found that behaviour changed as private information increased over time. Social proximity was the major predictor of foraging success in the absence of prior foraging information, while stochasticity in acceleration and search effort became the most important predictors of foraging success as information increased. In conclusion, we show that individual movement patterns changed as they acquire private information. Contrary to our predictions, the spatial distribution of prey did not affect any of the movement variables of interest. Our results emphasise the importance of information, both private and social, in shaping movement behaviour in animals. Keywords: social foraging, movement, private information, prey spatial distribution, fish.

This overview of the molecular pathology of lung cancer includes a review of the most salient molecular alterations of the genome, transcriptome, and the epigenome. The insights provided by the growing use of next-generation sequencing (NGS) in lung cancer will be discussed, and interrelated concepts such as intertumor heterogeneity, intratumor heterogeneity, tumor mutational burden, and the advent of liquid biopsy will be explored. Moreover, this work describes how the evolving field of molecular pathology refines the understanding of different histologic phenotypes of non-small-cell lung cancer (NSCLC) and the underlying biology of small-cell lung cancer. This review will provide an appreciation for how ongoing scientific findings and technologic advances in molecular pathology are crucial for development of biomarkers, therapeutic agents, clinical trials, and ultimately improved patient care.

The last 30 years have seen a revolution in the provision of minimal access surgery for many conditions, and technological advances are increasing exponentially. Many instruments are superseded by improved versions before the NHS and publicly funded health services can offer widespread coverage. Although we tend to think of minimal access surgery as a modern concept, Parts I and II of this series have shown that there is a 5000-year history to this specialty and our predecessors laid down many principles which still apply today. During the 19th and early 20th centuries, minimal access surgery was driven forward by visionary individuals, often in the face of opposition from colleagues and the medical establishment. However, in the last 30 years, innovation has been driven more in partnerships between healthcare, scientific, financial, educational and charitable organisations. There are far too many individuals involved to detail every contribution here, but this third part of the series will concentrate on some of the important themes in the development of minimal access surgery to its current status.

Despite the best efforts of clinicians, traditional healthcare models often struggle to meet the increasingly complex needs of children and young people under the age of 18 years, as well as 21st century challenges such as obesity and mental health problems. Policy makers and clinical leaders have argued that greater integration of primary and secondary care has the potential to meet the ‘Quadruple aim’ of better population health outcomes, patient and family satisfaction, provider satisfaction and reduced costs.1 More integrated services and improved data sharing across organisations are key enablers of child health improvement. However, there is sparse literature on how more integrated care for children and young people might work in practice or contribute to achieving these goals. We present the experience of developing a new model for integrated care delivery for children and young people in North West London, based on a common system of clinical records or dashboards across all providers. It includes case studies that illustrate the development of strong relationships and shared learning experiences between primary and secondary care.

The airways are frequently involved in nonneoplastic lung diseases, and sometimes their involvement dominates the clinical picture. In these situations, the combination of clinical and radiologic findings is sometimes sufficient to reach a firm diagnosis; however, in a significant proportion of cases a biopsy is obtained, frequently representing a challenge for the practicing pathologists. In the present chapter, beside the description of some well defined entities, we present the most relevant morphologic features that can be encountered on small endoscopic biopsies and on surgical samples, trying to identify the elementary lesions and to correlate them with the complexity of the different clinical settings where they can be found. It is a rare case in which the morphological features are diagnostic per se of a specific disease. Conversely, the identification of a few key elementary lesions can be of help to narrow the differential diagnoses that can be offered to clinicians to complete the difficult puzzle of interstitial lung diseases.

Project finance is a complex network of contracts. This explains why legal aspects are of paramount importance in deal structuring. The intricacies that lawyers must solve when advising on project finance legal design are complicated by the fact that the legal framework of project finance originated in common law systems. Their task becomes a meticulous search of the available legal instruments in civil law countries that can fit for the purpose.

This review will detail the embryology and morphology of the heart. We will begin with the heart's origin in the lateral plate mesoderm of the early embryo, review its fusion into a linear heart tube, followed by looping and remodeling to create a four-chambered organ with pulmonary and systemic venous inflow and pulmonary and systemic arterial outflow. We will discuss important concepts in heart development at genetic, cellular, and physiologic levels and review some key experimental models and methods important to the study of cardiac development. This review will also serve to introduce some of the congenital heart defects that can result from abnormalities in development and some of the genetic syndromes that are linked to congenital heart defects.

• The presentation of urinary tract infections (UTIs) in neonates differs from that seen in older children. • The type and route of infection also differ in neonates, when compared with older children. • An appropriate urine sample for diagnosis is needed, but treatment should not be delayed. • A neonate in whom a UTI is suspected should be evaluated for sepsis, including invasive cultures. • After a documented neonatal UTI, a radiologic work-up is warranted to detect anatomic anomalies. • Vesicoureteral reflux (VUR) is diagnosed in 30%–50% of neonates with proven UTI. • Voiding cystourethrogram is the gold standard for the diagnosis of VUR and should be performed on high-risk neonates. • Treatment of VUR should be tailored to each patient's individual risk of UTI recurrence, with the goals of preventing future UTIs and renal scar formation.

• Papulopustular lesions on the palms and/or soles in the first month of life likely represent a self-limited inflammatory process such as eosinophilic pustular folliculitis or infantile acropustulosis – but scabies should be ruled out. • Neonatal acne (aka cephalic pustulosis) is typically multifactorial and self-limited. Treatment is not necessary but topical agents aimed at reduction of the commensal yeast Malassezia can be beneficial. • Evidence suggests that early use of emollients in infants at risk of developing atopic dermatitis may prevent later disease. • Subcutaneous fat necrosis of the newborn is generally benign and self-limited but when extensive can cause hypercalcemia.

Thrombocytopenia is, after anemia, the most frequent hematological problem among sick neonates. In this population, thrombocytopenia has traditionally been defined as a platelet count 9 /L, and has been classified as mild (100–150 × 10 9 /L), moderate (50–99 × 10 9 /L), and severe ( 9 /L). However, large population-based studies have shown that platelet counts increase with advancing gestational age, and platelet counts between 100 and 150 × 10 9 /L are more frequent among otherwise healthy extremely preterm infants than among full term neonates or older children. This suggests that different definitions of thrombocytopenia and thrombocytosis should be applied to preterm infants. The diagnostic approach to a thrombocytopenic neonate is facilitated if the thrombocytopenia is categorized as “early onset” (within the first 72 hours of life, usually secondary to congenital or intrauterine abnormalities) or “late onset” (after 72 hours, usually due to acquired conditions). Importantly, infection/sepsis should always be considered near the top of the differential diagnosis, as any delay in diagnosis and treatment can have life-threatening consequences. While in vitro studies have clearly shown that neonatal platelets are hyporesponsive to most agonists, this platelet hyporeactivity is well compensated by factors in neonatal blood that increase clotting (i.e. high hematocrit, high VWF concentrations), resulting in adequate primary hemostasis. The risk of bleeding in thrombocytopenic neonates is poorly predicted by the platelet count; gestational age

Summary This is the second of a three-part series that charts the history of minimal access surgery from antiquity to current times. Although rapid developments in laparoscopic and robotic surgery have transformed surgical care over the last 30 years, our predecessors made significant advances in their time which set the principles for modern practice. Part I of this series described how ancient medical practitioners developed simple instruments, from metal or wood, for viewing body cavities. Improvements in the use of metal, glass and lighting allowed for inspection of deeper parts of the body. This second part of the series will show how advances in electrical technology allowed the development of improved lighting for endoscopy and laparoscopy along with the use of electrocautery for a wide range of therapeutic procedures.

• An understanding of thyroid embryogenesis and the physiology of the thyroid gland in the perinatal period is important for proper interpretation of abnormal laboratory results and initiation of appropriate treatment. • Appropriate thyroid hormone function is essential for normal neurodevelopment in infancy and childhood. Hypothyroidism in the first year of life can result in significant deleterious effects on growth and neurologic injury. • Delay in treatment of congenital hypothyroidism (CH) is the most common preventable cause of mental retardation. • Neonatal screening can provide early diagnosis and can prevent delays in treatment. Newborn screening methods differ and may possibly miss rare forms of congenital hypothyroidism. • Eighty-five percent of cases of permanent CH are associated with abnormal development of the thyroid gland. • In preterm newborns, thyroid hormone levels may fall because of immaturity of the thyroid gland, but these changes may be exacerbated by complications of prematurity. • Thyroid metabolism can be affected by exogenous sources of iodine, dopamine infusions, blood transfusion, and glucocorticoid treatment. • The clinical manifestations of Graves disease in the newborn include irritability, flushing, diarrhea, vomiting, tachycardia, hypertension, poor weight gain, thyroid enlargement, and exophthalmos. • There is concern for neurologic damage in infants with hemangiomas when hypothyroidism is occult and untreated.