AI-augmented clinical decision in paediatric appendicitis: can an AI-generated model improve trainees' diagnostic capability?

Accurate diagnosis of paediatric appendicitis remains a challenge due to its diverse clinical presentations and reliance on subjective assessments. The integration of artificial intelligence (AI) with an expert's ''clinical sense'' has the potential to improve diagnostic accuracy. In this study, we aimed to evaluate the effectiveness of the Artificial Intelligence Pediatric Appendicitis Decision-tree (AiPAD) model in enhancing the diagnostic capabilities of trainees and compare their performance with that of an expert supervisor. Between March 2019 and October 2022, we included paediatric patients aged 0-12 years who were referred for suspected appendicitis. Trainees collected clinical findings using five predefined parameters before ordering any imaging studies. The AiPAD model, which was blinded to the surgical team, made predictions from the supervisor's and trainees' findings independently. The diagnosis verdicts of the supervisor and the trainees were statistically evaluated in comparison to the prediction of the AI model, taking into account the revealed correct diagnosis. A total of 136 cases were included, comprising 58 cases of acute appendicitis (AA) and 78 cases of non-appendicitis (NA). The supervisor's correct verdict showed 91% accuracy compared to an average of 70% for trainees. However, if trainees were enabled with AiPAD, their accuracy would improve significantly to an average of 97%. Significantly, a strong association was observed between the expert's clinical sense and the predictions generated by AiPAD. CONCLUSION:  The utilisation of the AiPAD model in diagnosing paediatric appendicitis has significant potential to improve trainees' diagnostic accuracy, approaching the level of an expert supervisor. This hybrid approach combining AI and expert knowledge holds promise for enhancing diagnostic capabilities, reducing medical errors and improving patient outcomes. WHAT IS KNOWN: • Sharpening clinical judgement for pediatric appendicitis takes time and seasoned exposure. Traditional training leaves junior doctors yearning for a faster path to diagnostic mastery. WHAT IS NEW: • AI-generated models unlock the secrets of expert intuition, crafting an explicit guide for juniors to rapidly elevate their diagnostic skills. This leapfrog advancement empowers young doctors, democratizing medical expertise and paving the way for brighter outcomes in clinical training.

Ethnic differences in the characteristics of patients with newly diagnosed lung cancer in the Te Manawa Taki region of New Zealand.

BACKGROUND: Maori have three times the mortality from lung cancer compared with non-Maori. The Te Manawa Taki region has a population of 900 000, of whom 30% are Maori. We have little understanding of the factors associated with developing and diagnosing lung cancer and ethnic differences in these characteristics. AIMS: To explore the differences in the incidence and characteristics of patients with newly diagnosed lung cancer between Maori and non-Maori. METHODS: Patients were identified from the regional register. Incidence rates were calculated based on population data from the 2013 and 2018 censuses. The patient and tumour characteristics of Maori and non-Maori were compared. The analysis used Χ2 tests and logistic models for categorical variables and Student t tests for continuous variables. RESULTS: A total of 4933 patients were included, with 1575 Maori and 3358 non-Maori. The age-standardised incidence of Maori (236 per 100 000) was 3.3 times higher than that of non-Maori. Maori were 1.3 times more likely to have an advanced stage of disease and 1.97 times more likely to have small cell lung cancer. Maori were more likely to have comorbidities, chronic obstructive pulmonary disease, cardiovascular disease and diabetes. They also had higher levels of social deprivation and tended to be younger, female and current smokers. CONCLUSIONS: The findings point to the need to address barriers to early diagnosis and the need for system change including the need to introduce a lung cancer screening focussing on Maori. There is also the need for preventive programmes to address comorbidities that impact lung cancer outcomes as well as a continued emphasis on creating a smoke-free New Zealand.

Ha Ora: secondary care barriers and enablers to early diagnosis of lung cancer for Maori communities.

BACKGROUND: Lung Cancer is the leading cause of cancer deaths in Aotearoa New Zealand. Maori communities in particular have higher incidence and mortality rates from Lung Cancer. Diagnosis of lung cancer at an early stage can allow for curative treatment. This project aimed to document the barriers to early diagnosis and treatment of lung cancer in secondary care for Maori communities. METHODS: This project used a kaupapa Maori approach. Nine community hui (focus groups) and nine primary healthcare provider hui were carried out in five rural localities in the Midland region. Community hui included cancer patients, whanau (families), and other community members. Healthcare provider hui comprised staff members at the local primary healthcare centre, including General Practitioners and nurses. Hui data were thematically analysed. RESULTS: Barriers and enablers to early diagnosis of lung cancer were categorised into two broad themes: Specialist services and treatment, and whanau journey. The barriers and enablers that participants experienced in specialist services and treatment related to access to care, engagement with specialists, communication with specialist services and cultural values and respect, whereas barriers and enablers relating to the whanau journey focused on agency and the impact on whanau. CONCLUSIONS: The study highlighted the need to improve communication within and across healthcare services, the importance of understanding the cultural needs of patients and whanau and a health system strategy that meets these needs. Findings also demonstrated the resilience of Maori and the active efforts of whanau as carers to foster health literacy in future generations.

Universal screening for Lynch syndrome in uterine cancer patients: A quality improvement initiative.

OBJECTIVE: To determine the feasibility and effectiveness of a quality improvement initiative (QI) to adopt universal screening for Lynch syndrome in uterine cancer patients at an institution that previously employed age-based screening. METHODS: Prior to the initiative, tumors of patients with uterine cancer diagnosed at age ≤ 60 years were screened for mismatch repair deficiency (MMR) and microsatellite instability (MSI). The QI process change model adopted universal testing of all uterine cancer specimens and implemented provider training, standardized documentation, and enhanced use of the electronic medical record (EMR). We compared screening rates, results of screening, follow up of abnormal results, and final diagnoses from the pre- and post-implementation periods. RESULTS: Pre- and post-implementation screening rates for women age ≤ 60 years at the time of diagnosis were 45/78 (57.7%) and 64/68 (94.5%), respectively. The screening rate for all patients with uterine cancer increased from 73/190 (38.4%) to 172/182 (94.5%). The rate of abnormal screening results increased from 15/190 (7.9%) to 44/182 (24.0%) cases. Genetics referral rates among screen positives increased from 3/15 (20.0%) to 16/44 (36.4%). Germline diagnoses increased from 2/190 (1.1%) with two Lynch syndrome diagnoses to 4/182 (2.2%) including three Lynch syndrome diagnoses and one BRCA1 germline diagnosis. The number of patients errantly not screened decreased from at least 32 patients to 3 patients after the intervention. CONCLUSIONS: Adherence to screening guidelines significantly improved after interventions involving provider education, optimal use of the EMR, and simplification of screening indications. These interventions are feasible at other institutions and translatable to other screening indications.

Endometrial Adenocarcinomas With No Specific Molecular Profile: Morphologic Features and Molecular Alterations of "Copy-number Low" Tumors.

The study evaluated morphologic patterns, mutational profiles, and ß-catenin immunohistochemistry (IHC) in copy-number low (CNL) endometrial adenocarcinomas (EAs). CNL EAs (n=19) with next-generation or whole genome sequencing results and available tissue for IHC were identified from our institutional database. Clinical data and histologic slides were reviewed. IHC for ß-catenin was performed and correlated with mutation status. Images of digital slides of CNL EAs from The Cancer Genome Atlas (TCGA) database (n=90) were blindly reviewed by 4 pathologists, and morphology was correlated with mutation status. Categorical variables were analyzed using the Fisher exact test, and agreement was assessed using Fleiss κ. CTNNB1 mutations were present in 63% (12/19) of CNL EAs. ß-catenin nuclear localization was present in 83% of CTNNB1-mutated tumors (10/12) and in 0% (0/7) of CTNNB1-wildtype tumors (sensitivity 0.83, specificity 1.00). Squamous differentiation (SD) was present in 47% (9/19) and was more often observed in CTNNB1-mutated tumors (P=0.02). Mucinous differentiation (MD) was associated with KRAS mutations (P<0.01). Digital image review of TCGA CNL EAs revealed that pathologist agreement on SD was strong (κ=0.82), whereas agreement on MD was weak (κ=0.48). Pathologists identified SD in 22% (20/90), which was significantly associated with the presence of CTNNB1 mutations (P<0.01). CNL EAs demonstrate several morphologies with divergent molecular profiles. SD was significantly associated with CTNNB1 mutations and nuclear localization of ß-catenin in these tumors. Nuclear expression of ß-catenin is a sensitive and specific IHC marker for CTNNB1 mutations in CNL EAs. CNL EAs with KRAS mutations often displayed MD.

Indigenous perspectives on breaking bad news: ethical considerations for healthcare providers.

Most healthcare providers (HCPs) work from ethical principles based on a Western model of practice that may not adhere to the cultural values intrinsic to Indigenous peoples. Breaking bad news (BBN) is an important topic of ethical concern in health research. While much has been documented on BBN globally, the ethical implications of receiving bad news, from an Indigenous patient perspective in particular, is an area that requires further inquiry. This article discusses the experiences of Maori (Indigenous peoples of New Zealand) lung cancer patients and their families, in order to investigate the ethical implications of receiving bad news. Data collection occurred through 23 semistructured interviews and nine focus groups with Maori lung cancer patients and their families in four districts in the Midland Region of New Zealand: Waikato, Bay of Plenty, Lakes and Tairawhiti. The findings of this study were categorised into two key themes: communication and context. Avenues for best practice include understanding the centrality of the HCP-patient relationship and family ties in the healthcare journey, and providing patients with the full range of viable treatment options including hope, clear advice and guidance when the situation calls for it. Overall, the findings of this study hold implications for providing culturally safe and humanistic cancer care when BBN to Maori and Indigenous patients.

Ha Ora: Barriers and enablers to early diagnosis of lung cancer in primary healthcare for Maori communities.

OBJECTIVE: The objective of this research was to document the barriers to early presentation and diagnosis of lung cancer within primary healthcare, identified by Maori whanau (families) and primary healthcare providers in the Midland region of Aotearoa New Zealand. METHODS: This project used a kaupapa Maori approach. Nine community hui (focus groups) and nine primary healthcare provider hui were carried out in five rural localities in the Midland region. Each community hui included cancer patients, whanau, and other community members. Each healthcare provider hui comprised staff members at the local primary healthcare centre, including General Practitioners and nurses. Hui data were thematically analysed. RESULTS: Barriers and enablers to early diagnosis of lung cancer were categorised into three key themes: GP relationship and position in the community, health literacy and pathways to diagnosis. CONCLUSION: This study demonstrates that culturally responsive, patient-centred healthcare, and positive GP-patient relationships are significant factors for Maori patients and whanau serving as barriers and enablers to early diagnosis of lung cancer.

Nanolipoprotein Particles as a Delivery Platform for Fab Based Therapeutics.

Nanolipoprotein particles (NLPs), a lipid bilayer-based nanoparticle platform, have recently been developed for in vivo delivery of a variety of molecules of therapeutic interest, but their potential to deliver Fabs with valencies that exceed those of current multivalent formats has not yet been evaluated. Here we describe the development, optimization, and characterization of Fab-NLP conjugates. NLPs were generated with maleimide reactive lipids for conjugation to a Fab with a C-terminal cysteine. Of note, maleimide reactive lipids were shown to conjugate to the apolipoprotein when the NLPs were assembled at pH 7.4. However, this undesirable reaction was not observed when assembled at pH 6. Site-specific Fab conjugation conditions were then optimized, and conjugation of up to 30 Fab per NLP was demonstrated. Interestingly, although conjugation of higher numbers of Fabs had a significant impact on NLP molecular weight, only a minimal impact on NLP hydrodynamic radius was observed, indicating that particle size is largely dictated by the discoidal shape of the NLP. Fab-NLP viscosity and its stability upon lyophilization were also evaluated as an assessment of the manufacturability of the Fab-NLP. Significantly higher Fab concentrations were achieved with the Fab-NLP conjugates relative to another multivalent format (Fab-PEG conjugates). Fab conjugation to the NLP was also not found to have an impact on Fab activity in both an inhibitory and agonist setting. Finally, the stability of the Fab-NLP conjugates was evaluated in 50% serum and Fab-NLPs demonstrated increased stability, with >63% of Fab-NLP remaining intact after 24 h at Fab per particle ratios of 7 or greater. Our findings suggest Fab-NLPs are a promising platform for the targeted delivery of Fabs in a multivalent format and are compatible with established manufacturing processes.

Management of patients with early stage lung cancer - why do some patients not receive treatment with curative intent?

BACKGROUNDS: This study aims to understand the factors that influence whether patients receive potentially curative treatment for early stage lung cancer. A key question was whether indigenous Maori patients were less likely to receive treatment. METHODS: Patients included those diagnosed with early stage lung cancer in 2011-2018 and resident in the New Zealand Midland Cancer Network region. Logistic regression model was used to estimate the odds ratios of having curative surgery/ treatment. The Kaplan Meier method was used to examine the all-cause survival and Cox proportional hazard model was used to estimate the hazard ratio of death. RESULTS: In total 419/583 (71.9%) of patients with Stage I and II disease were treated with curative intent - 272 (46.7%) patients had curative surgery. Patients not receiving potentially curative treatment were older, were less likely to have non-small cell lung cancer (NSCLC), had poorer lung function and were more likely to have an ECOG performance status of 2+. Current smokers were less likely to be treated with surgery and more likely to receive treatment with radiotherapy and chemotherapy. Those who were treated with surgery had a 2-year survival of 87.8% (95% CI: 83.8-91.8%) and 5-year survival of 69.6% (95% CI: 63.2-76.0%). Stereotactic ablative body radiotherapy (SABR) has equivalent effect on survival compared to curative surgery (hazard ratio: 0.77, 95% CI: 0.37-1.61). After adjustment we could find no difference in treatment and survival between Maori and non-Maori. CONCLUSIONS: The majority of patients with stage I and II lung cancer are managed with potentially curative treatment - mainly surgery and increasingly with SABR. The outcomes of those being diagnosed with stage I and II disease and receiving treatment is positive with 70% surviving 5 years.

Engineering mammalian cells to seek senescence-associated secretory phenotypes.

Since the removal of senescent cells in model organisms has been linked to rejuvenation and increased lifespan, senotherapies have emerged to target senescent cells for death. In particular, interleukin-6 (IL6) is a prominent senescence-associated secretory phenotype (SASP) and, thus, seeking IL6 could potentially localize engineered cells to senescent cells for therapeutic intervention. Here, we engineered a chimeric IL6 receptor (IL6Rchi) that generates a Ca2+ signal in response to IL6 stimulation. When IL6Rchi was co-expressed with an engineered Ca2+-activated RhoA (CaRQ), it enabled directed migration to IL6 in cells that have no such natural ability. Next, the removal of target cells was accomplished by the mechanism of membrane fusion and subsequent death. This work represents a first step towards engineering a cell to target senescent cells that secrete high levels of IL6. For increased specificity to senescent cells, it will likely be necessary for an engineered cell to recognize multiple SASPs simultaneously.

Elevated bone morphogenic protein 4 expression implicated in site-specific adipogenesis in thyroid associated orbitopathy.

Periorbital adipose tissue expansion is a key pathological change in thyroid associated orbitopathy (TAO). Bone morphogenic protein 4 (BMP4) is instrumental in adipogenesis. We compared site-specific BMP4 expression and its effect on adipogenesis using donor-matched adipose tissue-derived stromal cells (ADSC) from TAO patients. In this study, ADSC were generated from periorbital (eyelid, orbital) and subcutaneous (abdominal) adipose tissue. BMP4 expression was characterized by RT-PCR and immunofluorescent staining and compared among ADSC from the three anatomic depots. Effects on adipogenesis after knocking down endogenous BMP4 were quantified by adipogenic markers PPARγ and perilipin. Exogenous BMP4 protein was added after BMP4 knockdown to study the role of BMP4 in adipogenesis. Our results showed that BMP4 staining in periorbital adipose tissue was stronger than those in subcutaneous. BMP4 mRNA expression was higher in eyelid (4.4-2489.4-fold) and orbital (6.9-1811-fold) than that of subcutaneous ADSC, whereas expression fell during induced adipogenesis. After BMP4 knockdown, both adipogenic markers PPARγ (eyelid: 1.7-fold, p = 0.038; orbital: 1.4-fold, p = 0.126) and perilipin (eyelid:1.7-fold, p = 0.001; orbital:2.6-fold, p = 0.066) increased in periorbital ADSC upon induction. These increased expression fell after adding exogenous BMP4 protein. Our findings demonstrated higher BMP4 expression was found in periorbital ADSC and adipose tissue compared to donor-matched subcutaneous counterparts, which fell during adipogenic induction. Knocking down BMP4 expression further enhanced adipogenesis in periorbital ADSC. This effect was reversed by adding exogenous BMP4 protein. We suggested a novel role of BMP4 in modulating site-specific adipogenesis in TAO patients.

A sclerocornea-associated RAD21 variant induces corneal stroma disorganization.

Sclerocornea is a cornea opacification disorder. Disorganized corneal stroma fibrils are observed in patients' cornea. Previously we identified a RAD21C1348T variant that is associated with a peripheral sclerocornea pedigree. To explore whether this RAD21 variant can induce sclerocornea-related phenotype, and to investigate the possible mechanisms of such phenotype, the orthologous rad21 wild-type and variant mRNAs were injected into Xenopus laevis embryos and the developed eyes were subjected for histological examination. Transmission electron microscopy was applied for corneal stroma organization check. rad21 is highly expressed in the eye region during X. laevis development. Disrupted eye development was observed in the rad21 variant injected embryos. Disorganized corneal stroma and decreased diameters of collagen fibrils were observed in the rad21 variant injected X. laevis eyes. These eye defects can be rescued by overexpression of the wild-type rad21. Histological examination found stroma attracting center, a key structure in X. laevis corneal development, was impaired in rad21 variant injected embryos. Our results suggest a key role of RAD21 during corneal development. Our data indicates the RAD21R450C variant contributes to peripheral sclerocornea by disturbing collagen fibril organization in the corneal stroma.

Functional connectivity of the vigilant-attention network in children and adolescents with attention-deficit/hyperactivity disorder.

The ability to maintain attention to simple tasks (i.e., vigilant attention, VA) is often impaired in attention-deficit/hyperactivity disorder (ADHD), but the underlying pathophysiological mechanisms at the brain network level are not clear yet. We therefore investigated ADHD-related differences in resting-state functional connectivity within a meta-analytically defined brain network of 14 distinct regions subserving VA (comprising 91 connections in total), as well as the association of connectivity with markers of behavioural dysfunction in 17 children (age range: 9-14 years) with a diagnosis of ADHD and 21 age-matched neurotypical controls. Our analyses revealed selective, rather than global, differences in the intrinsic coupling between nodes of the VA-related brain network in children with ADHD, relative to controls. In particular, ADHD patients showed substantially diminished intrinsic coupling for 7 connections and increased coupling for 4 connections, with many differences involving connectivity with the anterior insula. Moreover, connectivity strength of several aberrant connections was found to be associated with core aspects of ADHD symptomatology, such as poor attention, difficulties with social functioning, and impaired cognitive control, attesting to the behavioural relevance of specific connectivity differences observed in the resting state.

Natural history of neurological abnormalities in cerebrotendinous xanthomatosis.

OBJECTIVES: Cerebrotendinous xanthomatosis (CTX) is a rare inherited neurodegenerative disorder in bile acid synthesis. The natural history of neurological abnormalities in CTX is not well understood. The object of this study was to determine neurological progression in CTX. METHODS: A literature search on PubMed for "cerebrotendinous xanthomatosis" yielded 91 publications that reported cases of CTX patients. Two independent reviewers abstracted information about the presence and age of onset of neurological abnormalities in published CTX cases. For each neurological abnormality, we estimated the probability of its onset at any given age using cumulative incidence function analysis. We also present our own case series, in which five CTX patients were evaluated. RESULTS: The literature search yielded 194 CTX cases (ages ranging from newborn to 67 years old). The most common neurological abnormalities were corticospinal tract abnormalities including weakness, hyperreflexia, spasticity, Babinski sign (59.8%), ataxia (58.8%), cognitive decline (46.4%), and gait difficulty (38.1%); 68 (35.0%) had baseline cognitive problems. Cumulative incidence function analysis revealed that ataxia, gait difficulties, and corticospinal tract abnormalities developed throughout life, while cognitive decline tended to develop later in life. Of the less common neurological abnormalities, seizures, psychiatric changes and speech changes developed throughout life, while parkinsonism and sensory changes tended to develop later in life. Our case series corroborated this temporal pattern of neurological abnormalities. CONCLUSION: We provide estimates for the neurological progression of CTX, categorizing neurological abnormalities according to time and probability of development. Our approach may be applicable to other rare disorders.

Food Insecurity Is Associated with Subsequent Cognitive Decline in the Boston Puerto Rican Health Study.

BACKGROUND: Living with hunger and fear of not having enough food is a growing worldwide concern. In our previous cross-sectional study, we found that food insecurity was associated with poor cognitive function, but the direction of this relation remains unclear. OBJECTIVE: We investigated whether food insecurity is associated with subsequent cognitive decline. METHODS: This was a longitudinal study of 597 participants aged 40-75 y from the Boston Puerto Rican Health Study cohort, with a Mini-Mental State Examination score of ≥24 at baseline. Food security was assessed at baseline with the US Household Food Security Scale. Participants completed cognitive batteries, which included 7 cognitive tests, twice-at baseline and again at a 2-y follow-up. The primary outcome was the change in global cognitive function over 2 y. Multiple linear regression was used to obtain adjusted mean differences and 95% CIs in cognitive decline across baseline food security status. RESULTS: Food insecurity at baseline was associated with a 2-y decline in global cognitive function (P-trend = 0.03) after adjusting for relevant potential confounders, including age, sex, baseline cognitive score, body mass index, education, poverty, acculturation score, depression score, smoking status, use of alcohol, physical activity score, presence of diabetes and hypertension, apolipoprotein E status, plasma homocysteine, healthy eating index, and time between baseline and follow-up measures. Compared with the food-secure group, the decline in the very low food security group was greater [mean difference: -0.26 (95% CI: -0.41, -0.10)]. Baseline food insecurity was significantly associated with a faster decline in executive function (P-trend = 0.02) but not memory function (P-trend = 0.66). CONCLUSIONS: Food insecurity was associated with faster cognitive decline in this cohort of Puerto Rican adults. Our study emphasizes the importance of developing interventions for food insecurity that take into account the impact of food insecurity on cognition.

Distancing, self-esteem, and subjective well-being in head and neck cancer.

BACKGROUND: Distancing (i.e. construing oneself as dissimilar to a negatively-stereotyped group) preserves self-esteem and may benefit other domains of subjective well-being. Head and neck cancer (HNC) is stigmatized because major risk factors include avoidable lifestyle variables (smoking, alcohol consumption, and human papilloma virus). Because the benefits of coping efforts, such as distancing, are most evident when people are under stress, we hypothesize that the psychosocial benefits of distancing will be most pronounced when cancer and its treatment interfere substantially with participation in valued activities and interests (i.e. high illness intrusiveness). OBJECTIVE: To test whether distancing preserves self-esteem and other domains of subjective well-being (SWB) in HNC, especially when illness intrusiveness is high. METHODS: Five hundred and twenty-two HNC outpatients completed a semantic-differential measure of perceived similarity to the 'cancer patient' and measures of illness intrusiveness, self-esteem, depressive symptoms, and psychological well-being in structured interviews. Evaluations of the 'cancer patient' reflected cancer stereotypes. RESULTS: A statistically significant interaction supported the central hypothesis: When people held negative stereotypes, those who construed themselves as similar to the 'cancer patient' reported lower self-esteem than those who construed themselves as dissimilar. Distancing did not benefit other SWB variables. Some results were counter-intuitive: e.g. Emotional distress increased with increasing illness intrusiveness when people did not hold negative cancer stereotypes, but when they held highly negative stereotypes, distress decreased with increasing illness intrusiveness. CONCLUSIONS: Overall, distancing preserved self-esteem in people with HNC and was associated with benefits in other SWB domains.

Involvement of low- and middle-income countries in randomized controlled trial publications in oncology.

BACKGROUND: We describe trends in participation by investigators from low- and middle-income countries (LMCs) in publications describing oncology randomized control trials (RCTs) over a decade. METHODS: We used Medline to identify RCTs published in English from 1998 to 2008 evaluating treatment in lung, breast, colorectal, stomach and liver cancers. Data on author affiliations, authorship roles, trial characteristics, funding and interventions were extracted from each article. Countries were stratified as low-, middle- or high-income using World Bank data. Interventions were categorized as requiring basic, limited, enhanced or maximal resources as per the Breast Health Global Initiative classification. Logistic regression was used to identify factors associated with authorship by investigators from LMCs. RESULTS: 454 publications were identified. Proportion of articles with at least one LMC author increased over time from 20% in 1998 to 29% in 2008 (p = 0.01), but almost all LMC authors were from middle-income countries. Proportion of articles with at least one LMC author was higher among articles that explicitly reported recruitment in at least one LMC vs those that did not (76% vs 13%). Among 87 articles (19%) that involved authors from LMCs, 17% had LMC authors as first or corresponding authors, and 67% evaluated interventions requiring enhanced or maximal resources. Factors associated with LMC authorship included industry funding (OR = 3.54, p = 0.0001), placebo comparator arm (OR = 2.57, p = 0.02) and palliative intent treatment (OR = 4.00, p = 0.0003). CONCLUSION: An increasing number of publications describing oncology RCTs involve authors from LMC countries but primarily in non-leadership roles in industry-funded trials.

Atypical Antipsychotic Prescribing in Australian Children and Adolescents: A Survey of Medical Practitioners.

OBJECTIVE: Prescriptions for atypical antipsychotics in children and adolescents are increasing globally. However, a precise understanding of the clinical variables and evidence that prescribers consider before using these agents is lacking. While empirical literature on the long-term safety and efficacy of these medications is available, the literature concerning their use in these younger age groups is relatively sparse. In this study, we examined the current prescribing patterns of medical professionals employed by a public health service in Australia. METHODS: A survey examining their current practice when prescribing atypical antipsychotics to children and adolescents was completed by 103 physicians. Questions were asked about commonly prescribed atypical antipsychotics, indications, dose ranges, target symptoms, duration of treatment, and the evidence base(s) used when making treatment decisions. RESULTS: Physicians prescribed atypical antipsychotics for a wide range of indications in this age group, with the most common agents being risperidone, quetiapine, and olanzapine. Adverse effects were reported as the main reason for treatment discontinuation. More than half of the respondents indicated that the most common source of guidance/evidence they referred to when initiating prescriptions were peers or expert opinion. CONCLUSIONS: Children and adolescents were prescribed a number of atypical antipsychotics for a variety of indications, with variable perceived confidence and a relatively heavy reliance on "own or peer experience" as opposed to good quality evidence. Challenges exist for both prescribers and policymakers, and further "head-to-head" studies are needed in this age group to ensure that a balance is maintained between therapeutic benefit and safety.

Parkinson's disease, parkinsonism, and traumatic brain injury.

We review the relationship between traumatic brain injury (TBI) and the development of idiopathic Parkinson's disease (PD) or secondary parkinsonism. Limited by methodological issues such as recall bias and confounding risk factors, epidemiological studies on the association between TBI and idiopathic PD have so far yielded mixed results. While clinical reports describe parkinsonism - often with lesions in the substantia nigra - secondary to traumatic brain injury, these do not represent cases of idiopathic PD. In laboratory studies, animal models of traumatic brain injury demonstrate neuronal loss in the substantia nigra, altered dopaminergic metabolism, or altered synuclein pathology. While parkinsonism does occur secondary to TBI, the relationship between TBI and subsequent idiopathic PD remains controversial.

Pharmacological inhibition of adipocyte fatty acid binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in mice.

BACKGROUND & AIMS: Adipocyte fatty acid binding protein (A-FABP) is a key mediator of inflammatory response in macrophages. Increased hepatic expression and circulating levels of A-FABP have been observed in patients with non-alcoholic fatty liver disease (NAFLD). Here, we investigated the role of A-FABP in both lipopolysaccaride (LPS)-induced acute liver injury and high fat high cholesterol (HFHC) diet-induced NAFLD in mice. METHODS: Mice with LPS-induced acute liver injury and HFHC diet-induced obesity were treated with the A-FABP inhibitor BMS309403. Liver tissues of the mice were analyzed by immunohistochemistry, Western blot or real-time PCR. RESULTS: A-FABP expression in Kupffer cells was significantly elevated in mice with LPS-induced acute liver injury and HFHC diet-induced obesity, as compared to their healthy controls. Pretreatment of mice with BMS309403 led to a diminished LPS-induced elevation in serum levels of alanine transaminase and hepatic production of pro-inflammatory cytokines. Likewise, chronic treatment of HFHC diet-induced obese mice with BMS309403 ameliorated hepatic steatosis, macrophage infiltration, and cellular ballooning of hepatocytes. Such improvements in liver function and morphology were accompanied by significantly decreased activation of both c-Jun and NF-κB. Pretreatment with BMS309403 suppressed both LPS- and palmitate-induced pro-inflammatory responses in isolated rat Kupffer cells. Adenovirus-mediated ectopic expression of A-FABP alone was sufficient to induce liver injury and inflammation in mice. CONCLUSIONS: These findings suggest that A-FABP is an important contributor to both LPS-induced acute liver injury and diet-induced NAFLD by potentiating inflammation in Kupffer cells. Pharmacological inhibition of A-FABP may represent a promising modality for obesity-related non-alcoholic steatohepatitis.