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Differently from the adult patients, in paediatric age it is more difficult to assess and treat efficaciously the pain and often this symptom is undertreated or not treated. In children, a selection of appropriate pain assessment tools should consider the age, the cognitive level, the presence of eventual disability, the type of pain and the situation in which it is occurring. Improved understanding of developmental neurobiology and paediatric analgesic drug pharmacokinetics should facilitate a better management of childhood pain. The objective of this update is to discuss the current practice and the recent advances in pediatric pain management.  Using PubMed and the Cochrane Library we conducted an extensive literature analysis on pediatric pain assessment and commonly used analgesic agents in this kind of patients. According to our results, a multimodal analgesic regimen provides a better pain control and a functional outcome in children. Cooperation and communication among the anaesthesiologist, the surgeon and the paediatrician remains essential for successful anaesthesia and pain management in childhood.

Background: Suspending ordinary care activities during the COVID-19 pandemic made it necessary to find alternative routes to comply with care recommendations not only for acute health needs but also for patients requiring follow-up and multidisciplinary visits. We present the 'Contactless' model, a comprehensive operational tool including a plurality of services delivered remotely, structured according to a complexity gradient, aimed to cover diagnostic procedures and monitor disease progression in chronic pediatric patients., Methods: A multidisciplinary and multiprofessional project team was recruited, in collaboration with patients' associations, to map a panel of available Evidence-Based solutions and address individual needs in full respect of the concept of personalized medicine. The solutions include a number of services from videoconsultations to more structure videotraining sessions., Results: A modular framework made up of four three Macro-levels of complexity - Contactless Basic, Intermediate and Advanced - was displayed as an incremental set of services and operational planning establishing each phase, from factors influencing eligibility to the delivery of the most accurate and complex levels of care., Conclusion: The multimodal, multidisciplinary 'Contactless' model allowed the inclusion of all Units of our Pediatric Department and families with children with disability or complex chronic conditions. The strengths of this project rely on its replicability outside of pediatrics and in the limited resources needed to practically impact patients, caregivers and professionals involved in the process of care. Its implementation in the future may contribute to reduce the duration of hospital admissions, money and parental absence from work.

Several forensic sciences, especially of the pattern-matching kind, are increasingly seen to lack the scientific foundation needed to justify continuing admission as trial evidence. Indeed, several have been abolished in the recent past. A likely next candidate for elimination is bitemark identification. A number of DNA exonerations have occurred in recent years for individuals convicted based on erroneous bitemark identifications. Intense scientific and legal scrutiny has resulted. An important National Academies review found little scientific support for the field. The Texas Forensic Science Commission recently recommended a moratorium on the admission of bitemark expert testimony. The California Supreme Court has a case before it that could start a national dismantling of forensic odontology. This article describes the (legal) basis for the rise of bitemark identification and the (scientific) basis for its impending fall. The article explains the general logic of forensic identification, the claims of bitemark identification, and reviews relevant empirical research on bitemark identification-highlighting both the lack of research and the lack of support provided by what research does exist. The rise and possible fall of bitemark identification evidence has broader implications-highlighting the weak scientific culture of forensic science and the law's difficulty in evaluating and responding to unreliable and unscientific evidence.

Objective: To evaluate clinical trial registration, reporting and publication rates for new drugs by: (1) legal requirements and (2) the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge., Design: Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration (FDA) for drugs approved in 2012, sponsored by large biopharmaceutical companies., Data Sources: Information from Drugs@FDA, ClinicalTrials.gov, MEDLINE-indexed journals and drug company communications., Main Outcome Measures: Clinical trial registration and results reporting in ClinicalTrials.gov, publication in the medical literature, and compliance with the 2007 FDA Amendments Acts (FDAAA), analysed on the drug level., Results: The FDA approved 15 drugs sponsored by 10 large companies in 2012. We identified 318 relevant trials involving 99 599 research participants. Per drug, a median of 57% (IQR 32-83%) of trials were registered, 20% (IQR 12-28%) reported results in ClinicalTrials.gov, 56% (IQR 41-83%) were published, and 65% (IQR 41-83%) were either published or reported results. Almost half of all reviewed drugs had at least one undisclosed phase II or III trial. Per drug, a median of 17% (IQR 8-20%) of trials supporting FDA approvals were subject to FDAAA mandated public disclosure; of these, a median of 67% (IQR 0-100%) were FDAAA-compliant. 68% of research participants (67,629 of 99,599) participated in FDAAA-subject trials, with 51% (33,405 of 67,629) enrolled in non-compliant trials. Transparency varied widely among companies., Conclusions: Trial disclosures for new drugs remain below legal and ethics standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve compliance with legal and ethics standards and the quality of medical knowledge., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: The 22q11.2 deletion syndrome (22q11.2DS) is a congenital multisystem anomaly characterized by typical facial features, palatal anomalies, congenital heart defects, hypocalcemia, immunodeficiency, and cognitive and neuropsychiatric symptoms. The aim of our study was to investigate T- and B-lymphocyte characteristics associated with 22q11.2DS., Methods: Seventy-five individuals with 22q11.2DS were tested for T and B lymphocytes by examination of T-cell receptor rearrangement excision circles (TRECs) and B-cell κ-deleting recombination excision circles (KRECs), respectively., Results: The 22q11.2DS individuals displayed low levels of TRECs, while exhibiting normal levels of KRECs. There was a significant positive correlation between TREC and KREC in the 22q11.2DS group, but not in controls. Both TREC and KREC levels showed a significant decrease with age and only TREC was low in 22q11.2DS individuals with recurrent infections. No difference in TREC levels was found between 22q11.2DS individuals who underwent heart surgery (with or without thymectomy) and those who did not., Conclusion: T-cell immunodeficiency in 22q11.2DS includes low TREC levels, which may contribute to recurrent infections in individuals with this syndrome. A correlation between T- and B-cell abnormalities in 22q11.2DS was identified. The B-cell abnormalities could account for part of the immunological deficiency seen in 22q11.2DS.

Purpose: Chromosomal instability syndromes include a group of rare diseases characterized by defective DNA-damage-response and increased risk of chromosomal breakage. Patients display defects in the recognition and/or repair of DNA damage, with a subsequent high rate of malignancies and abnormal gene rearrangements. Other clinical manifestations, such as immunodeficiency, neurodevelopmental delay and skeletal abnormalities, are present in some of these syndromes. We studied a patient with profound T-lymphocyte defect, neurodevelopmental delay, facial dysmorphism, nephrotic syndrome and spondyloepiphyseal bone dysplasia typical of SIOD., Methods: Karyotype and chromosome fragility assays on patients' peripheral blood mononuclear cells showed an abnormal rate of spontaneous breaks. Cell cycle analysis of patient's fibroblasts following replication stress induced by hydroxyhurea revealed a delay in their release from S-phase to G2. When using higher concentrations of hydroxyhurea no patient fibroblast colonies could survive, compared with control fibroblasts. Whole-exome sequencing revealed novel compound heterozygote mutations in SMARCAL1 gene, resulting in putative frame shifts of encoded SMARCAL1 from each allele and no detected protein in patient's cells. The patient's youngest brother was found to have similar manifestations of SIOD but of less severity, including short stature, facial dysmorphism and typical osseous dysplasia, but no clinical findings suggestive of immunodeficiency and no chromosomal fragility. Similar to his sister, the brother carries both bi-allelic mutations in SMARCAL1 gene., Conclusions: We present here the first evidence of intrinsic chromosomal instability in a severe SMARCAL1-deficient patient with a clinical picture of SIOD. Our results are consistent with the recently outlined role of SMARCAL1 protein in DNA damage response.

Background: Enumeration of T cell receptor excision circles (TREC) was recently adopted as a neonatal screening assay for severe combined immunodeficiency (SCID). Enumeration of kappa-deleting recombination excision circle (KREC) copy numbers can be similarly used for early assessment of B cell lymphopenia., Objective: To assess the ability of TREC and KREC counts to identify patients with combined T and B cell immunodeficiency in a pilot study in Israel., Methods: We studied seven children born in Israel during the years 2010-2011 and later diagnosed with SCID, and an additional patient with pure B cell immunodeficiency. TREC and KREC in peripheral blood upon diagnosis and in their neonatal Guthrie cards were analyzed using real-time quantitative polymerase chain reaction, as were Guthrie cards with dried blood spots from healthy newborns and from normal and SCID-like controls., Results: The first features suggestive of SCID presented at age 3.1 +/- 2.4 months in all patients. Yet, the diagnosis was made 4.1 +/- 2.9 months later. Their TREC were undetectable or significantly low at their clinical diagnosis and in their originally stored Guthrie cards, irrespective of the amount of their circulating T cells. KREC were undetectable in six SCID patients who displayed B cell lymphopenia in addition to T cell lymphopenia. KREC were also undetectable in one patient with pure B cell immunodeficiency., Conclusions: TREC and KREC quantification are useful screening tests for severe T and B cell immunodeficiency. Implementation of these tests is highly important especially in countries such as Israel where a high frequency of consanguinity is known to exist.

David Korn speaks to Tarryn Greenberg, Managing Commissioning Editor David Korn (BA, scl, MD, cl; Harvard University, MA, USA) stepped down from his position as Harvard University's inaugural Vice-Provost for Research on June 30, 2011. He is presently Consultant in Pathology and member of the medical staff at the Massachusetts General Hospital, Boston, MA, USA and Professor of Pathology at Harvard Medical School. Dr Korn has been a member of the editorial boards of the American Journal of Pathology, The Journal of Biological Chemistry, and Human Pathology, and for many years was an Associate Editor of the latter. He has sat on many societies, councils and boards. He has written many scientific articles, ranging from bacteriophage biochemistry and genetics to the biochemistry and molecular biology of DNA replication in human cells. During the past two decades his work, writings and lectures have focused on issues of academic values and integrity, research integrity, and health and science policy, and he is presently regarded as a national authority on matters of financial conflicts of interest in academic research.

This review represents my best effort to recreate and memorialize events that occurred 44 years ago, when I was invited to join the Stanford University faculty to create, essentially de novo, what rapidly became and remains today one of the very best and most admired departments of pathology in the world. That I was able to accomplish this challenging task I attribute to my holding fast to a somewhat inchoate vision of where the science and practice of pathology would go in future decades, a little bit to my gut instincts and innate ability to spot up-and-coming talent, but a lot to circumstances and good fortune in leading me to a small nucleus of wonderful young professionals of outstanding promise who were willing to join me in "betting the house" that, working together, we could pull off this once-in-a-lifetime opportunity--and we did.

This report is the first empirical study to compare pathological gambling (PG), posttraumatic stress disorder (PTSD), and their co-occurrence. The sample was 106 adults recruited from the community (35 with current PG; 36 with current PTSD, and 35 with BOTH). Using a cross-sectional design, the three groups were rigorously diagnosed and compared on various measures including sociodemographics, psychopathology (e.g., dissociation, suicidality, comorbid Axis I and II disorders), functioning, cognition, life history, and severity of gambling and PTSD. Overall, the PG group reported better psychological health and higher functioning than PTSD or BOTH; and there were virtually no differences between PTSD and BOTH. This suggests that it is the impact of PTSD, rather than comorbidity per se, that appears to drive a substantial increase in symptoms. We also found high rates of additional co-occurring disorders and suicidality in PTSD and BOTH, which warrants further clinical attention. Across the total sample, many reported a family history of substance use disorder (59%) and gambling problems (34%), highlighting the intergenerational impact of these. We also found notable subthreshold PTSD and gambling symptoms even among those not diagnosed with the disorders, suggesting a need for preventive care. Dissociation measures had mixed results. Discussion includes methodology considerations and future research areas.

We documented the extent of point-of-sale (POS) lottery promotions in Ontario, Canada and the relationship between lottery promotions and store and city characteristics. This is the first quantitative study of POS lottery promotions. A total of 366 stores-independent and chain convenience stores, gas stations and grocery stores-were visited across 20 cities in Ontario. Data collectors unobtrusively observed the type of lottery promotions in each store and completed a data collection checklist. A lottery promotion index was created and hierarchical linear modeling (HLM) was conducted to examine the relationship between extent of lottery promotions and independent variables such as neighbourhood socioeconomic status and city prevalence of lottery ticket purchasing. POS lottery promotions were widespread across Ontario, with the highest level of promotion found in independent convenience stores. In the multivariable HLM model, none of the remaining independent variables remained statistically significant, except for store type. Lottery promotions are extensive at the POS in Ontario. These findings can help initiate discussions around the appropriateness and possible future regulation of this form of advertising.

Congress created 180-day exclusivity for generic drug applicants in the 1984 Hatch-Waxman amendments to the Federal Food, Drug, and Cosmetic Act (FDCA) and amended the provision substantially in the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA). The fundamental goal behind 180-day exclusivity was to provide an incentive for generic drug applicants to challenge innovator patents, and the core of the concept--as it has been applied by the Food and Drug Administration (FDA) and the courts--is that the first generic drug applicant to challenge an innovator's patent is entitled to six months of exclusivity against subsequent patent challengers for the same innovator drug. 180-day exclusivity is governed by sections 505(j)(5)(B)(iv) and 505(j)(5)(D) of the FDCA. In this article, the authors provide a comprehensive resource on 180-day exclusivity for old abbreviated new drug applications (ANDAs) (but less detail in some places where the 2007 article may be referenced) but focus more discussion on the new provisions as well as some policy and legal issues related to 180-day exclusivity that have not previously addressed.

International medical graduates (IMGs) constitute an appreciable fraction of full-time faculty at US medical schools and of principal investigators (PIs) on National Institutes of Health (NIH) research project grants. Information from the Faculty Roster of the Association of American Medical Colleges (AAMC) and from the NIH Consolidated Grant Applicant File (CGAF) was examined to assess IMGs' contribution to US medical school faculty and research. The study found that the number of IMG full-time faculty more than doubled over two decades-from 7,866 individuals in 1984 to 17,085 individuals in 2004, but that IMGs remained relatively stable as a share of physician full-time faculty (from 18.8 to 19.4%); the share is somewhat higher (20.0% of full-time physician faculty in 1984 to 23.7% in 2004) if faculty with degrees of unknown provenance are included. From 1984 to 2004, IMGs increased as a share of full-time physician faculty who are principal investigators on NIH research grants from 16.5% (540) to 21.3% (1,143). Including faculty with incomplete data on degree provenance, the corresponding IMG share increases to 18.0 and 24.0% respectively. Thus, IMGs comprise at least one-fifth and more likely one-fourth of all full-time faculty physicians who are PIs on NIH research project grants. The proportion of IMG full-time physician faculty who are in basic science departments is about twice that of their US/Canadian counterparts, as is the proportion of IMG physician PIs. Slightly fewer than half (48%) of full-time IMG faculty PIs pursue human subjects research (as coded by the NIH), while the majority of US/Canadian counterparts pursue human subjects research.

Context: Although concerns have persisted for decades about the production of new physician clinical scientists and their success in receiving and sustaining research supported by the National Institutes of Health (NIH), no comprehensive analysis documents the experiences of first-time investigators with an MD over a long period., Objective: To ascertain the perseverance and comparative success of physician-scientists competing for NIH research (R01) grants awarded over 40 years., Design, Setting, and Participants: A longitudinal, comparative study of all first-time applicants and recipients of NIH R01 grants between 1964 and 2004 stratified by the principal investigators' major degrees (MD, PhD, or MD and PhD) and their proposed involvement in research of humans or human tissues., Main Outcome Measures: Number of first- and second-time NIH R01 grant applicants and recipients by academic degree and by research type (clinical vs nonclinical)., Results: The annual number of first-time investigators with an MD only as NIH R01 grant applicants remained remarkably stable over 4 decades (41-year mean of 707 [range, 537-983] applicants). Among first-time applicants, those with an MD consistently had less success in obtaining funding (mean annual percentage [MAP], 28%) than either investigators with a PhD (MAP, 31%; P = .03 vs MD only) or both an MD and a PhD (MAP, 34%; P<.001 vs MD only and P = .002 vs PhD only). Among investigators who obtained a first R01 grant, those with an MD were consistently less likely (MAP, 70%) than those with a PhD (MAP, 73%; P = .04 vs MD only) or those with an MD and a PhD (MAP, 78%; P<.001 vs MD only and P = .007 vs PhD only) to obtain a subsequent R01 grant. First-time applicants with an MD were much more likely to propose clinical research (MAP, 67%) than applicants with an MD and a PhD (MAP, 43%) and applicants with a PhD only (39%). First-time applicants with an MD only who proposed clinical research were funded at lower rates than their MD-only counterparts proposing nonclinical research (23% vs 29%, respectively; P<.001)., Conclusions: From 1964-2004, the number of physician-investigators applying for first R01 grants showed little net change. Physician-investigators consistently experienced higher rates of attrition and failure, even after receiving a first R01 grant, and those proposing clinical research were less successful in obtaining funding than physicians proposing nonclinical research.

Objective: YouthBet.net's (www.youthbet.net) goal is to prevent gambling problems among youth through an interactive, multimedia website based on a public health approach., Participants: YouthBet.net was designed by youth for youth. A youth working group spent several months designing the look and feel of the site to ensure that it would appeal to youth aged 10-19. In total, 34 youth from the Greater Toronto Area participated in the first 3 phases of the usability testing of the site using Video Capture of User Site Interaction methodology., Setting: Urban Toronto., Intervention: Utilizing public health strategies such as health promotion, harm reduction and problem prevention, YouthBet.net features games, information and help resources to protect youth from gambling-related harm., Outcomes: Youth participants indicated that they liked the interactive way gambling information was presented via realistic games and quizzes, often citing that YouthBet.net would be a fun and educational tool to be used by teachers in the classroom. Participants had no difficulties navigating the site, finding content and playing games. Additionally, all youth said that they would return to the site and would recommend it to a friend if they were having a problem with gambling., Conclusion: YouthBet.net is one of the first comprehensive websites designed for youth gambling. Findings from this research will inform future health promotion, harm reduction and problem prevention efforts for youth gambling using Internet technology.

Background to the Debate: In the United States, the passage of the Bayh-Dole Act in 1980 encouraged universities to license inventions for commercial development. Although this financial incentive can stimulate academic researchers to discover new drugs and devices, there is concern that the possibility of monetary reward could distort investigators' objectivity.

Academic and industrial scientists have sharply increased their demand for properly prepared and clinically annotated tissue samples that yield valuable insights into the origins and expressions of human disease. Historically, research on human tissue samples has been relatively unencumbered by federal regulations and occurred without delineation of ownership rights to the specimens, patient data, or research products. As regulations have become increasingly restrictive, and because clear ownership interests have never been established, the presumed right of researchers and institutions to collect, use, and dispose of specimens and their associated patient data has remained undefined and occasionally contentious. Recent examination of these issues by a US federal court resulted in a ruling that individuals do not retain rights of ownership or control of biological materials contributed for research, regardless of whether commercial benefit accrues. This article examines the legal, regulatory, and ethical framework within which human tissue research is currently conducted. We contend that because the benefits of medical knowledge derived from tissue research potentially accrue to all individuals and future generations (rather than a single recipient), society may justify an expansive use of these valuable resources for future studies.

Background: Over the past decade, there has been a rapid growth of gambling in Canada and internationally. Although youth are a potentially vulnerable group, little is known about what they understand and if they are being affected by the recent increase in gambling., Methods: This study examined how youth view gambling using an inductive qualitative research design and analysis based on grounded theory principles. Twelve focus groups were conducted comprising 103 participants (median age = 15 years) with diverse representation of Ontario youth. Focus-group questions were designed to capture youth's experiences and opinions about gambling., Results: Youth participants defined a spectrum of gambling from a dare and friendly betting to legalized forms of gambling (lotteries, casinos) and addiction. Their opinions varied according to age and gambling type. For example, daring and friendly betting were identified as positive activities used by younger adolescents to relieve boredom and establish social relationships. Gambling was separate from daring because of its association with money. Many participants had minimal awareness of the potential negative impact of gambling. Information technology (Internet) was seen as an attractive medium for playing games and gambling where no money was involved., Conclusion: Lack of awareness of gambling among youth and its consequences underscores the need for public education. The diverse range of gambling behaviour and age-dependent access to money need careful consideration in defining youth gambling "problems" and in designing public health interventions.

This paper examines the public policy value of looking at gambling from a public health perspective. The manner in which social issues are framed will either expand or curtail public policy debates. The existing and traditional frames for gambling (e.g. gambling as a matter of individual freedom, gambling as a form of recreation) fail to consider research on the social and economic impacts of gambling. Because a public health frame offers a broad viewpoint of society, it encompasses a number of social and economic impacts not considered in traditional frames. However, the existing gambling frames enjoy varying degrees of cultural, economic, and political support and, as a result, creating a higher profile for a public health framework will encounter a number of barriers. Research can play a decisive role in overcoming these barriers, as it has in a number of related fields (e.g., tobacco use, addiction and product liability, the epidemiology of AIDS). The paper concludes that research that identifies and quantifies the public health factors of gambling will substantially contribute to a public shift toward a public health frame.

Financial self-interests in medical research are again the subject of increasing public and government concern. Proposed new statutes and regulations would prescribe research conduct and oversight, as well as faculty behavior, in ways that would represent an unprecedented interposition of federal authority into areas of traditional university autonomy. Overly zealous regulation could also interdict a fruitful product development pathway of enormous benefit to public health. Yet, the universities and their academic medical centers have failed to respond sufficiently or credibly to the profound transformation of their research culture in the past two decades, which has witnessed a dramatic increase in the privatization of historically public biomedical research, and in the financial self-interests of investigators and institutions in the research they conduct. The author reviews the history of federal regulation of individual conflicts of interest in biomedical research, and examines the always-complex relationships and expectations of research universities with industry and society. While university oversight of individual conflicts of interest demands strengthening, the issues are long debated and well understood. In contrast, the financial interest of institutions in the medical research they conduct is recent, more complicated, poorly understood, and highly sensitive, involving investment decisions that lie at the heart of university autonomy. The author argues that institutions and professional societies must promulgate and enforce transparent standards of conduct, and strengthen oversight and management of financial self-interests, to avoid burdensome federal intervention and corrosive public skepticism. He concludes by reporting three promising responses from academia and major medical journals.

This article reviews the prevalence of gambling and related mental disorders from a public health perspective. It traces the expansion of gambling in North America and the psychological, economic, and social consequences for the public's health, and then considers both the costs and benefits of gambling and the history of gambling prevalence research. A public health approach is applied to understanding the epidemiology of gambling-related problems. International prevalence rates are provided and the prevalence of mental disorders that often are comorbid with gambling problems is reviewed. Analysis includes an examination of groups vulnerable to gambling-related disorders and the methodological and conceptual matters that might influence epidemiological research and prevalence rates related to gambling. The major public health problems associated with gambling are considered and recommendations made for public health policy, practice, and research. The enduring value of a public health perspective is that it applies different 'lenses' for understanding gambling behaviour, analysing its benefits and costs, as well as identifying strategies for action. Harvey A. Skinner (160, p. 286)

During the last decade there has been an unprecedented expansion of legalized gambling throughout North America. Three primary forces appear to be motivating this growth: (1) the desire of governments to identify new sources of revenue without invoking new or higher taxes; (2) tourism entrepreneurs developing new destinations for entertainment and leisure; and (3) the rise of new technologies and forms of gambling (e.g., video lottery terminals, powerball mega-lotteries, and computer offshore gambling). Associated with this phenomenon, there has been an increase in the prevalence of problem and pathological gambling among the general adult population, as well as a sustained high level of gambling-related problems among youth. To date there has been little dialogue within the public health sector in particular, or among health care practitioners in general, about the potential health impact of gambling or gambling-related problems. This article encourages the adoption of a public health perspective towards gambling. More specifically, this discussion has four primary objectives:1. Create awareness among health professionals about gambling, its rapid expansion and its relationship with the health care system;2. Place gambling within a public health framework by examining it from several perspectives, including population health, human ecology and addictive behaviors;3. Outline the major public health issues about how gambling can affect individuals, families and communities;4. Propose an agenda for strengthening policy, prevention and treatment practices through greater public health involvement, using the framework of The Ottawa Charter for Health Promotion as a guide.By understanding gambling and its potential impacts on the public's health, policy makers and health practitioners can minimize gambling's negative impacts and appreciate its potential benefits.