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Describes variations in the isocenter of a Philips SL-20 linear accelerator used for stereotactic radiosurgery and radiotherapy. Measurement of variations for the gantry and couch rotations; Accuracy in the isocenter required by stereotactic radiation; Isocenter stability.

Abstract: The assumption of an instrument response that is linear with carbon number is frequently used to quantify atmospheric non-methane hydrocarbons (NMHCs) when using gas chromatography (GC) and detection by flame ionisation detector (FID). In order to assess the validity of this widely used method the results of intercomparison measurements by 14 laboratories across Europe were evaluated. The intercomparison measurements were made on synthetic, gravimetrically-prepared, gas mixtures containing 30 hydrocarbons (C2–C9) in the low ppbv range, using various different GC–FID systems. The response per carbon atom of GC–FID systems to individual NMHCs, relative to that of butane, were found to differ by more than 25% across different systems. The differences were mostly caused by analytical errors within particular GC–FID systems and to a more minor degree by systematic deviations related to the molecular structure. (Correction factors due to the molecular structure would lessen the differences, e.g. by about 5% for olefin compounds.) The differences were larger than 10% even after elimination of obvious outliers. Thus, calibration of GC–FID systems with multicomponent NMHC mixtures is found to be essential whenever the accuracy of NMHC measurements is required to be better than about 10%. If calibration by multicomponent gas mixtures is not possible and effective carbon atom response factors are used to quantify the individual NMHC compounds then the particular analytical system should be carefully characterised and its responses to individual compounds be verified. [Copyright &y& Elsevier]

Aesthetic procedures should be avoided in patients with body dysmorphic disorder (BDD) since they can negatively impact mental health and lead to further aesthetic dissatisfaction. There are no evidence-based patient pathways for BDD in facial aesthetics which can result in the failure to identify patients with BDD, leading to unsuitable treatments and suboptimal patient care. We aim to construct the first evidence-based patient pathway for BDD in surgical and nonsurgical facial aesthetics. A systematic review was performed and articles that discussed screening or patient pathways for BDD in field of facial aesthetics were included. We extracted relevant information from each article on screening tools and pathways for BDD. Data were synthesized by summarizing the data under column headings into a structured narrative and into new tables. Based on this synthesis, a practical pathway for BDD was constructed. Forty articles fulfilled the criteria for inclusion. Twenty-eight BDD screening tools were discussed in the included articles, and we provide an overview of these tools. Thirty-one articles discussed patient pathways for BDD, and we synthesized this information into a structured narrative. Combining these findings, we present an evidence-based patient pathway for BDD for patients presenting for facial aesthetic treatments. This systematic review has resulted in the first, evidence-based, patient pathway for BDD in surgical and nonsurgical facial aesthetics. This practical pathway can be used by aesthetic clinicians to identify patients with potential BDD and provide clear guidance for managing cases where BDD is suspected. It will help reduce the number of facial aesthetic procedures performed on patients with BDD, safeguard patient mental well-being, and prevent further aesthetic dissatisfaction., Competing Interests: None declared., (Thieme. All rights reserved.)

Nature is dynamic and interdependent. Yet we typically study and understand it as a hierarchy of independent static things (objects, factors, capacities, traits, attributes) with well-defined boundaries. Hence, since Plato, the dominant research practice has been to 'carve Nature at its joints' (Phaedrus 265e), rooted in the view that the world comes to us pre-divided - into static forms or essences - and that the goal of science is to simply discover (identify and classify) them. This things-based approach dominates developmental science, and especially the study of neurodevelopmental conditions. The goal of this paper is to amplify the marginalised process-based approach: that Nature has no joints. It is a hierarchy of interacting processes from which emerging functions (with fuzzy boundaries) softly assemble, become actively maintained, and dissipate over various timescales. We further argue (with a specific focus on children with Down syndrome) that the prevailing focus on identifying, isolating, and analysing things rather than understanding dynamic interdependent processes is obstructing progress in developmental science and particularly our understanding of neurodiversity. We explain how re-examining the very foundation of traditional Western thought is necessary to progress our research on neurodiversity, and we provide specific recommendations on how to steer developmental science towards the process-based approach., (Copyright © 2024. Published by Elsevier Inc.)

Background: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down., Methods: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids., Findings: Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage., Interpretation: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies., Funding: Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements"., Competing Interests: Declaration of interests GL is the founder and owner of Genos Ltd., a private research organisation that specialises in high-throughput glycomic analyses and has several patents in this field and is also a shareholder in GlycanAge Ltd., a company that sells the GlycanAge test of biological age. AC, FV, JJ, MPB, ASla, HD, AF, DP and JK are employees of Genos Ltd. AStr has served on the Advisory Boards of AC Immune and ProMIS Neuroscience, and is a past president of the Trisomy21 Research Society. TS is the scientific co-founder and a shareholder of Zoe Ltd., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Early in life, infants exhibit motor overflow, which can be defined as the generation of involuntary movements accompanying purposeful actions. We present the results of a quantitative study exploring motor overflow in 4-month-old infants. This is the first study quantifying motor overflow with high accuracy and precision provided by Inertial Motion Units. The study aimed to investigate the motor activity across the non-acting limbs during goal-directed action. To this end, we used wearable motion trackers to measure infant motor activity during a baby-gym task designed to capture overflow during reaching movements. The analysis was conducted on the subsample of participants (n = 20), who performed at least four reaches during the task. A series of Granger causality tests revealed that the activity differed depending on the non-acting limb and the type of the reaching movement. Importantly, on average, the non-acting arm preceded the activation of the acting arm. In contrast, the activity of the acting arm was followed by the activation of the legs. This may be caused by their distinct purposes in supporting postural stability and efficiency of movement execution. Finally, our findings demonstrate the utility of wearable motion trackers for precise measurement of infant movement dynamics.

Background: An infodemic is excess information, including false or misleading information, that spreads in digital and physical environments during a public health emergency. The COVID-19 pandemic has been accompanied by an unprecedented global infodemic that has led to confusion about the benefits of medical and public health interventions, with substantial impact on risk-taking and health-seeking behaviors, eroding trust in health authorities and compromising the effectiveness of public health responses and policies. Standardized measures are needed to quantify the harmful impacts of the infodemic in a systematic and methodologically robust manner, as well as harmonizing highly divergent approaches currently explored for this purpose. This can serve as a foundation for a systematic, evidence-based approach to monitoring, identifying, and mitigating future infodemic harms in emergency preparedness and prevention., Objective: In this paper, we summarize the Fifth World Health Organization (WHO) Infodemic Management Conference structure, proceedings, outcomes, and proposed actions seeking to identify the interdisciplinary approaches and frameworks needed to enable the measurement of the burden of infodemics., Methods: An iterative human-centered design (HCD) approach and concept mapping were used to facilitate focused discussions and allow for the generation of actionable outcomes and recommendations. The discussions included 86 participants representing diverse scientific disciplines and health authorities from 28 countries across all WHO regions, along with observers from civil society and global public health-implementing partners. A thematic map capturing the concepts matching the key contributing factors to the public health burden of infodemics was used throughout the conference to frame and contextualize discussions. Five key areas for immediate action were identified., Results: The 5 key areas for the development of metrics to assess the burden of infodemics and associated interventions included (1) developing standardized definitions and ensuring the adoption thereof; (2) improving the map of concepts influencing the burden of infodemics; (3) conducting a review of evidence, tools, and data sources; (4) setting up a technical working group; and (5) addressing immediate priorities for postpandemic recovery and resilience building. The summary report consolidated group input toward a common vocabulary with standardized terms, concepts, study designs, measures, and tools to estimate the burden of infodemics and the effectiveness of infodemic management interventions., Conclusions: Standardizing measurement is the basis for documenting the burden of infodemics on health systems and population health during emergencies. Investment is needed into the development of practical, affordable, evidence-based, and systematic methods that are legally and ethically balanced for monitoring infodemics; generating diagnostics, infodemic insights, and recommendations; and developing interventions, action-oriented guidance, policies, support options, mechanisms, and tools for infodemic managers and emergency program managers., Competing Interests: Conflicts of Interest: SB, SBr, NG, SH, AI, MK, RL, TN, TDP, and BY are staff of the World Health Organization (WHO); CBF and BKW are consultants with WHO; SK and CV are staff of the US Centers for Disease Control and Prevention (US CDC). These authors alone are responsible for the views expressed in this paper, and they do not represent the views of their organizations. The conflicts of interest were reviewed and managed as per WHO procedures. AD declared that his university received research support on information diet measurement by WHO for the product owned by WHO. He was not part of the consensus driving during the closing session of the meeting. TM is the current Editor-in-Chief of JMIR Infodemiology and declared ownership interest in a company for work not related to the deliberation in this publication. LMB works for Immunize Canada/the Canadian Public Health Association, which has received educational grants/funding from Merck Canada, Pfizer Canada, Pfizer Global, Moderna Canada, Seqirus, Sanofi Canada, GSK Canada, and the Public Health Agency of Canada (PHAC). These funds are not related to the paper. CW was executive director of the nonprofit organization First Draft, which received funds for research and advocacy work from Google, and research project support on the effectiveness of SMS-based social inoculation from WHO. She chaired the first 3 days of the conference but was not part of the consensus driving during the closing session of the meeting. EP declared receiving conference stipends, training fees, and publication fees from the Medical Research Council. He was not part of the consensus driving during the closing session of the meeting. IB is director of the WHO Collaborating Center on information systems for health, which supports WHO with broader digital health analytics and policy analysis. The center has supported the Pan American Health Organization (PAHO)/WHO with infodemic analytics during COVID-19. SMR declared receiving consultancy fees from the EURO Health Group research consortium and is currently a consultant in infodemic management for WHO. JR and SVDL declared that their university received research funding from NATO Strategic Communications Centre of Excellence, Google Jigsaw, WhatsApp, British Academy, the Economic and Social Research Council (ESRC), the UK Cabinet Office, and EU Horizon 2020. They were not part of the consensus driving during the closing session of the meeting. AG declared that his university received research funds from the Canadian Institutes of Health Research (CIHR). AS declared receiving consultancy fees from Euro Health Group A/S – Denmark for services unrelated to the topic of the conference. PB is founder and CEO of HealthEnabled, which received past funding from Gavi, the Vaccine Alliance, to conduct digital social listening. JN declared employment with Harvard University, working in the field of medical misinformation. MG and MEB declared no conflicts of interest for this paper., (©Elisabeth Wilhelm, Isabella Ballalai, Marie-Eve Belanger, Peter Benjamin, Catherine Bertrand-Ferrandis, Supriya Bezbaruah, Sylvie Briand, Ian Brooks, Richard Bruns, Lucie M Bucci, Neville Calleja, Howard Chiou, Abhinav Devaria, Lorena Dini, Hyjel D'Souza, Adam G Dunn, Johannes C Eichstaedt, Silvia M A A Evers, Nina Gobat, Mika Gissler, Ian Christian Gonzales, Anatoliy Gruzd, Sarah Hess, Atsuyoshi Ishizumi, Oommen John, Ashish Joshi, Benjamin Kaluza, Nagwa Khamis, Monika Kosinska, Shibani Kulkarni, Dimitra Lingri, Ramona Ludolph, Tim Mackey, Stefan Mandić-Rajčević, Filippo Menczer, Vijaybabu Mudaliar, Shruti Murthy, Syed Nazakat, Tim Nguyen, Jennifer Nilsen, Elena Pallari, Natalia Pasternak Taschner, Elena Petelos, Mitchell J Prinstein, Jon Roozenbeek, Anton Schneider, Varadharajan Srinivasan, Aleksandar Stevanović, Brigitte Strahwald, Shabbir Syed Abdul, Sandra Varaidzo Machiri, Sander van der Linden, Christopher Voegeli, Claire Wardle, Odette Wegwarth, Becky K White, Estelle Willie, Brian Yau, Tina D Purnat. Originally published in JMIR Infodemiology (https://infodemiology.jmir.org), 20.02.2023.)

Low inhibitory control (IC) is sometimes associated with enhanced problem-solving amongst adults, yet for young children high IC is primarily framed as inherently better than low IC. Here, we explore associations between IC and performance on a novel problem-solving task, amongst 102 English 2- and 3-year-olds (Study 1) and 84 Swedish children, seen at 18-months and 4-years (Study 2). Generativity during problem-solving was negatively associated with IC, as measured by prohibition-compliance (Study 1, both ages, Study 2 longitudinally from 18-months). High parent-reported IC was associated with poorer overall problem-solving success, and greater perseveration (Study 1, 3-year-olds only). Benefits of high parent-reported IC on persistence could be accounted for by developmental level. No concurrent association was observed between problem-solving performance and IC as measured with a Delay-of-Gratification task (Study 2, concurrent associations at 4-years). We suggest that, for young children, high IC may confer burden on insight- and analytic-aspects of problem-solving., (© 2022 The Authors. Infant and Child Development published by John Wiley & Sons Ltd.)

Web-based health information plays an increasingly vital role in spreading health information. Many patients interested in aesthetic surgery study the procedure on the Internet. This study aims to evaluate the quality of online health information on injectable fillers using the modified "Ensuring Quality Information for Patients" (EQIP) tool. Nine different search terms, including "fillers," "fuller cheeks," "wrinkle removal," and "antiwrinkle treatment" were identified and queried on Google. Unique links from the first three pages of each search term were identified and evaluated if the contents were in English language and were for general non-medical public use. A total of 172 websites were analyzed, with a median EQIP score of 20. In total 129 websites belonged to aesthetic practitioners, of which 81 were operated by medical doctors. Eighty-three percent of websites disclosed some forms of postoperative complications, most commonly edema (74%) and bruising (73%). Blindness and tissue necrosis were only mentioned by 12 and 10% of the websites, respectively. The current health information available on injectable fillers is of poor quality. While many do provide some information on risks, the majority of websites fail to disclose severe complications and quantifying risks. This poses a barrier against informed decision-making and may lead to unrealistic expectations. Patient satisfaction and expectations may be improved by developing better online education resources on fillers., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Fractures of the distal radius represent the most common fracture of the upper limb, and can be managed surgically with volar locking plate osteosynthesis (VLPO). Uncertainty remains regarding the optimal length of the distal locking screws. The aim of this study was to determine the optimal VLPO screw length which provided adequate stability while minimizing complications., Methods: A systematic review of relevant literature published within Cochrane, PubMed, MEDLINE and Embase, including studies up to April 2020, was performed using the Preferred Reporting Items for Systemic Reviews and Meta-analysis (PRISMA) guidelines. Studies were included if they investigated distal radius fracture fixation with VLPO, screw lengths, complications, and associated imaging., Results: Search results identified 664 relevant studies, of which 14 studies examining 926 radii were included for review. Synthesis revealed that unicortical locking fixation with screws ~75% the depth of the radius, or 2 mm short of the dorsal cortex, provided equivalent stability to bicortical fixation. The lunate may be used as a proxy to determine radial depth at each quartile column. Inadvertent screw protrusion can be assessed by taking four images intra-operatively; anteroposterior (AP), lateral, 45° supinated and dorsal tangential views (DTVs). Radial shaft screws can have up to 2 mm prominence with no clinical significance., Conclusion: Unicortical locking fixation at least 75% the depth of the distal radius provides equivalent stability to bicortical fixation in extra-articular fractures with lower complication rates. Imaging should be used to confirm that penetration of the dorsal cortex has not occurred., (© 2021 Royal Australasian College of Surgeons.)

During the past 10 years, the "Prevention of Violence Against Medicare Persons and Institutions Act" has failed to achieve its object. With the advent of the pandemic, stricter measures were taken and on 22 April 2020, all acts of violence against healthcare personnel confronting the Covid-19 pandemic became "cognizable and non-bailable offences" by means of the Epidemic Diseases (Amendment) Ordinance, a direct statement from the Government of India that there would be zero tolerance for violence against its health care workers. The Amendment aims to fill gaps in the previous law which did not protect healthcare workers against occupational violence at the workplace and at home. The amendment of the Ordinance will have a positive impact on the medical community which is much needed, particularly during the pandemic.

Purpose: To determine the positive predictive value (PPV) of four photoscreening devices in detecting amblyogenic risk factors (ARFs)., Methods: This is a retrospective cohort study of 1,200 failed vision screenings (FVS) referred to a pediatric eye care practice from general pediatric practices over a 5-year period. Comprehensive eye examinations and cycloplegic refractions were performed. Examination findings and FVS parameters were collected through chart review after completion of visits. Inclusion criteria were age 1-8 years, eye examination within 3 months of initial FVS, and availability of FVS and visit documentation., Results: A total of 689 patients met inclusion criteria and were included in final analysis. The PPVs were 64.3% (95% CI, 62.73-65.81) for iScreen (n = 455), 26.8% (95% CI, 26.32-27.25) for Spot (n = 113), 18.9% (95% CI, 17.95-19.92) for Plusoptix (n = 38), and 18.5% (95% CI, 17.86-19.19) for GoCheck Kids (n = 55). For comparison, patients referred for failed Titmus tests were also analyzed. The PPV for Titmus testing was 39.3% (95% CI, 36.65-41.99; n = 28)., Conclusions: The only screening device with a PPV >50% was the iScreen. PPV is a useful metric, because it enables referring providers to guide patients on a post-screening plan and to choose devices that minimize over-referral. Device PPV in the general pediatric population can be markedly different from device PPV in already existing pediatric eye care populations due to inherently different prevalence of ARFs. The iScreen also detected conditions such as cataracts, anisocoria, eyelid abnormalities, esotropia, exotropia, hypertropia, and amblyogenic astigmatism., (Copyright © 2021 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Infants raised in bilingual homes redirect attention faster than infants raised in monolingual homes. How can mere exposure to a bilingual environment affect an infant's cognitive development? The more complex language environment may drive infants to explore (gather more information from) their visual environment to facilitate learning., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose/background: Olecranon fractures are common, particularly in the elderly osteoporotic population. Although various techniques of fixation are available, the gold standard-tension band wiring (TBW)-has high complication and reoperation rates. We sought to identify current evidence for the use of high-strength suture tension banding methods to determine whether they reduce complications and reoperation rates while maintaining fixation., Methods: A systematic review of several databases was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases included Cochrane, PubMed, MEDLINE and Embase. We searched for evidence of at least Level I to IV (according to NHMRC) of the use of tension band suturing or anchors in the surgical treatment of displaced olecranon fractures. We also analyzed the cost of fixation in our institute., Results: Four hundred and forty articles were identified. Of these, 9 met the inclusion criteria. One hundred thirty-one subjects had an average age of 66 years. All the studies showed that high-strength suture tension banding/anchoring maintained fixation with displaced olecranon fractures, reducing the complication rates and showed minimal reoperation rates. There was also a significant cost advantage of the suture tape construct mainly due to avoiding subsequent removal of metal., Conclusion: Tension band suturing or anchoring displaced olecranon fractures may be an alternative cost effective method to TBW in maintaining fixation, reducing metalware complications and reducing re-operation rates., Level of Evidence: IV., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

To adapt to their more varied and unpredictable (language) environments, infants from bilingual homes may gather more information (sample more of their environment) by shifting their visual attention more frequently. However, it is not known whether this early adaptation is age-specific or lasts into adulthood. If the latter, we would expect to observe it in adults who acquired their second language early, not late, in life. Here we show that early bilingual adults are faster at disengaging attention to shift attention, and at noticing changes between visual stimuli, than late bilingual adults. In one experiment, participants were presented with the same two visual stimuli; one changed (almost imperceptibly), the other remained the same. Initially, participants looked at both stimuli equally; eventually, they fixated more on the changing stimulus. This shift in looking occurred in the early but not late bilinguals. It suggests that cognitive processes adapt to early bilingual experiences.

Typically developing (TD) infants adapt to the social world in part by shifting the focus of their processing resources to the relevant aspects of a visual scene. Any impairment in visual orienting may therefore constrain learning and development in domains such as language. However, although something is known about visual orienting in infants at risk of autism, very little is known about it in infants/toddlers with other neurodevelopmental disorders. This is partly because previous studies focused on older children and rarely compared the children to both chronological age (CA)- and mental age (MA)-matched TD controls. Yet, if visual orienting is important for learning and development, then it is imperative to investigate it early in development and ascertain whether it relates to higher level cognitive functions such as language. We used eye-tracking technology to directly compare visual orienting in infants/toddlers with one of three neurodevelopmental disorders-Down syndrome (DS), fragile X syndrome (FXS) and Williams syndrome (WS)-matched on CA or MA to TD controls (~15 months). We also measured language ability using the Mullen Scales of Early Learning (MSEL). We found that the ability to disengage attention from a visual stimulus in order to shift it to another visual stimulus is related to language ability in infants/toddlers irrespective of group affiliation. We also found that, contrary to the literature, infants and toddlers with DS (but not WS) are slow at disengaging attention. Our data suggest that orienting attention constrains language development and is impaired in DS., (© 2020 John Wiley & Sons Ltd.)

Purpose of Review: The aim of this article is to summarize up-to-date research on the effects of obstructive sleep apnea (OSA) on retinal vascular conditions., Recent Findings: OSA is associated with the development of diabetic retinopathy, retinal vein occlusion, and central serous chorioretinopathy. The severity of OSA and biomarkers such as the apnea-hypopnea index (AHI) correlate with the severity of retinal disease. Dysregulation of circadian locomotor output cycles kaput (CLOCK) genes that govern circadian rhythm is associated with development of proliferative retinal disease., Summary: OSA and retinal vascular disease have a high cost burden on the healthcare system. OSA creates systemic changes and hypoxic conditions that may incite or exacerbate retinal vascular diseases. Retinal changes may be the first clinical manifestation of otherwise undiagnosed OSA, so it is important to refer patients with new-onset retinal vascular disease for appropriate sleep testing.

Background: Regimens for palliation in patients with head and neck cancer recommended by the US National Comprehensive Cancer Network (NCCN) have low applicability (less than 1-3%) in low-income and middle-income countries (LMICs) because of their cost. In a previous phase 2 study, patients with head and neck cancer who received metronomic chemotherapy had better outcomes when compared with those who received intravenous cisplatin, which is commonly used as the standard of care in LMICs. We aimed to do a phase 3 study to substantiate these findings., Methods: We did an open-label, parallel-group, non-inferiority, randomised, phase 3 trial at the Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India. We enrolled adult patients (aged 18-70 years) who planned to receive palliative systemic treatment for relapsed, recurrent, or newly diagnosed squamous cell carcinoma of the head and neck, and who had an Eastern Cooperative Oncology Group performance status score of 0-1 and measurable disease, as defined by the Response Evaluation Criteria In Solid Tumors. We randomly assigned (1:1) participants to receive either oral metronomic chemotherapy, consisting of 15 mg/m 2 methotrexate once per week plus 200 mg celecoxib twice per day until disease progression or until the development of intolerable side-effects, or 75 mg/m 2 intravenous cisplatin once every 3 weeks for six cycles. Randomisation was done by use of a computer-generated randomisation sequence, with a block size of four, and patients were stratified by primary tumour site and previous cancer-directed treatment. The primary endpoint was median overall survival. Assuming that 6-month overall survival in the intravenous cisplatin group would be 40%, a non-inferiority margin of 13% was defined. Both intention-to-treat and per-protocol analyses were done. All patients who completed at least one cycle of the assigned treatment were included in the safety analysis. This trial is registered with the Clinical Trials Registry-India, CTRI/2015/11/006388, and is completed., Findings: Between May 16, 2016, and Jan 17, 2020, 422 patients were randomly assigned: 213 to the oral metronomic chemotherapy group and 209 to the intravenous cisplatin group. All 422 patients were included in the intention-to-treat analysis, and 418 patients (211 in the oral metronomic chemotherapy group and 207 in the intravenous cisplatin group) were included in the per-protocol analysis. At a median follow-up of 15·73 months, median overall survival in the intention-to-treat analysis population was 7·5 months (IQR 4·6-12·6) in the oral metronomic chemotherapy group compared with 6·1 months (3·2-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·773 [95% CI 0·615-0·97, p=0·026]). In the per-protocol analysis population, median overall survival was 7·5 months (4·7-12·8) in the oral metronomic chemotherapy group and 6·1 months (3·4-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·775 [95% CI 0·616-0·974, p=0·029]). Grade 3 or higher adverse events were observed in 37 (19%) of 196 patients in the oral metronomic chemotherapy group versus 61 (30%) of 202 patients in the intravenous cisplatin group (p=0·01)., Interpretation: Oral metronomic chemotherapy is non-inferior to intravenous cisplatin with respect to overall survival in head and neck cancer in the palliative setting, and is associated with fewer adverse events. It therefore represents a new alternative standard of care if current NCCN-approved options for palliative therapy are not feasible., Funding: Tata Memorial Center Research Administration Council., Translations: For the Hindi, Marathi, Gujarati, Kannada, Malayalam, Telugu, Oriya, Bengali, and Punjabi translations of the abstract see Supplementary Materials section., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In this article, we focus on the causes of individual differences in Down syndrome (DS), exemplifying the multi-level, multi-method, lifespan developmental approach advocated by Karmiloff-Smith (1998, 2009, 2012, 2016). We evaluate the possibility of linking variations in infant and child development with variations in the (elevated) risk for Alzheimer's disease (AD) in adults with DS. We review the theoretical basis for this argument, considering genetics, epigenetics, brain, behaviour and environment. In studies 1 and 2, we focus on variation in language development. We utilise data from the MacArthur-Bates Communicative Development Inventories (CDI; Fenson et al., 2007), and Mullen Scales of Early Learning (MSEL) receptive and productive language subscales (Mullen, 1995) from 84 infants and children with DS (mean age 2;3, range 0;7 to 5;3). As expected, there was developmental delay in both receptive and expressive vocabulary and wide individual differences. Study 1 examined the influence of an environmental measure (socio-economic status as measured by parental occupation) on the observed variability. SES did not predict a reliable amount of the variation. Study 2 examined the predictive power of a specific genetic measure (apolipoprotein APOE genotype) which modulates risk for AD in adulthood. There was no reliable effect of APOE genotype, though weak evidence that development was faster for the genotype conferring greater AD risk (ε4 carriers), consistent with recent observations in infant attention (D'Souza, Mason et al., 2020). Study 3 considered the concerted effect of the DS genotype on early brain development. We describe new magnetic resonance imaging methods for measuring prenatal and neonatal brain structure in DS (e.g., volumes of supratentorial brain, cortex, cerebellar volume; Patkee et al., 2019). We establish the methodological viability of linking differences in early brain structure to measures of infant cognitive development, measured by the MSEL, as a potential early marker of clinical relevance. Five case studies are presented as proof of concept, but these are as yet too few to discern a pattern., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Risk of Alzheimer disease (AD) is particularly high for individuals with Down syndrome (DS). The ε4 allele of the apolipoprotein E gene (APOE ε4) is associated with an additional risk for AD. In typical development, there is evidence that the APOE ε4 genotype is associated with an early cognitive advantage. Here we investigate associations of APOE ε4 with attention across the life span of individuals with DS., Objective: To investigate associations between APOE ε4 and attentional abilities in young children and in adults with DS., Design, Settings, and Participants: In this cross-sectional study, data were collected from 80 young children with DS (8-62 months of age) and 240 adults with DS (16-71 years of age) during the period from 2013 to 2018 at a research center to examine the association between APOE status (ε4 carrier vs ε4 noncarrier) and attentional abilities., Exposure: APOE status (ε4 carrier vs ε4 noncarrier)., Main Outcomes and Measures: For the children, attentional ability was assessed using an eye-tracking paradigm, the gap-overlap task; the size of the gap effect was the primary outcome. For the adults, attentional ability was assessed using the CANTAB simple reaction time task; the standard deviation of response time latencies was the primary outcome. Cross-sectional developmental trajectories were constructed linking attentional ability with age in ε4 carriers and ε4 noncarriers for children and adults separately., Results: The child sample comprised 23 ε4 carriers and 57 ε4 noncarriers. The adult sample comprised 61 ε4 carriers and 179 ε4 noncarriers. For the children, a significant difference between trajectory intercepts (ηp2 = 0.14) indicated that ε4 carriers (B = 100.24 [95% CI, 18.52-181.96]) exhibited an attentional advantage over ε4 noncarriers (B = 314.78 [95% CI, 252.17-377.39]). There was an interaction between APOE status and age (ηp2 = 0.10); while the gap effect decreased with age for ε4 noncarriers (B = -4.58 [95% CI, -6.67 to -2.48]), reflecting the development of the attention system, there was no change across age in ε4 carriers (B = 0.77 [95% CI, -1.57 to 3.12]). For the adults, there was no main effect of ε4 carrier status, but there was an interaction between APOE status and age (B = 0.02 [95% CI, 0.004-0.07]), so that ε4 carriers had poorer attentional ability than ε4 noncarriers at older ages., Conclusions and Relevance: APOE ε4 is associated with an attentional advantage early in development and a disadvantage later in life for individuals with DS, similar to the pattern reported in typical development. Understanding the differential role of APOE across the life span is an important step toward future interventions.