Brain Tumor Imaging in Adolescents and Young Adults: 2021 WHO Updates for Molecular-based Tumor Types.

Published in 2021, the fifth edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) introduced new molecular criteria for tumor types that commonly occur in either pediatric or adult age groups. Adolescents and young adults (AYAs) are at the intersection of adult and pediatric care, and both pediatric-type and adult-type CNS tumors occur at that age. Mortality rates for AYAs with CNS tumors have increased by 0.6% per year for males and 1% per year for females from 2007 to 2016. To best serve patients, it is crucial that both pediatric and adult radiologists who interpret neuroimages are familiar with the various pediatric- and adult-type brain tumors and their typical imaging morphologic characteristics. Gliomas account for approximately 80% of all malignant CNS tumors in the AYA age group, with the most common types observed being diffuse astrocytic and glioneuronal tumors. Ependymomas and medulloblastomas also occur in the AYA population but are seen less frequently. Importantly, biologic behavior and progression of distinct molecular subgroups of brain tumors differ across ages. This review discusses newly added or revised gliomas in the fifth edition of the CNS WHO classification, as well as other CNS tumor types common in the AYA population.

Development and characterization of a hemolysis inhibition assay to determine functionality of anti-Streptolysin O antibodies in human sera.

The high burden of disease and the long-lasting sequelae following Streptococcus pyogenes (Strep A) infections make the development of an effective vaccine a global health priority. Streptolysin O (SLO), is a key toxin in the complex pathogenesis of Strep A infection. Antibodies are elicited against SLO after natural exposure and represent a key target for vaccine-induced immunity. Here we present the setup and characterization of a hemolysis assay to measure functionality of anti-SLO antibodies in human sera. Assay specificity, precision, linearity, reproducibility, and repeatability were determined. The assay was demonstrated to be highly sensitive, specific, reproducible, linear and performed well in assessing functionality of anti-SLO antibodies induced by exposed individuals. Moreover, different sources of critical reagents, in particular red- blood cells, have been compared and had minimal impact on assay performance. The assay presented here has throughput suitable for evaluating sera in vaccine clinical trials and sero-epidemiological studies to gain further insights into the functionality of infection- and vaccine-induced antibodies.

Proton Therapy Mediates Dose Reductions to Brain Structures Associated With Cognition in Children With Medulloblastoma.

PURPOSE: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy. METHODS AND MATERIALS: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores. RESULTS: The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P = .03 and .007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P < .001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P < .001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores. CONCLUSIONS: Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma.

Brain Tumors in Adolescents and Young Adults: A Review.

Brain tumors account for the majority of cancer-related deaths in adolescents and young adults (AYAs), defined as individuals aged 15 to 39. AYAs constitute a distinct population in which both pediatric- and adult-type central nervous system (CNS) tumors can be observed. Clinical manifestations vary depending on tumor location and often include headaches, seizures, focal neurological deficits, and signs of increased intracranial pressure. With the publication of the updated World Health Organization CNS tumor classification in 2021, diagnoses have been redefined to emphasize key molecular alterations. Gliomas represent the majority of malignant brain tumors in this age group. Glioneuronal and neuronal tumors are associated with longstanding refractory epilepsy. The classification of ependymomas and medulloblastomas has been refined, enabling better identification of low-risk tumors that could benefit from treatment de-escalation strategies. Owing to their midline location, germ cell tumors often present with oculomotor and visual alterations as well as endocrinopathies. The management of CNS tumors in AYA is often extrapolated from pediatric and adult guidelines, and generally consists of a combination of surgical resection, radiation therapy, and systemic therapy. Ongoing research is investigating multiple agents targeting molecular alterations, including isocitrate dehydrogenase inhibitors, SHH pathway inhibitors, and BRAF inhibitors. AYA patients with CNS tumors should be managed by multidisciplinary teams and counselled regarding fertility preservation, psychosocial comorbidities, and risks of long-term comorbidities. There is a need for further efforts to design clinical trials targeting CNS tumors in the AYA population.

Subcutaneous infusion of high-dose benzathine penicillin G is safe, tolerable, and suitable for less-frequent dosing for rheumatic heart disease secondary prophylaxis: a phase 1 open-label population pharmacokinetic study.

Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order (t1/2 = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng/mL (0.02 µg/mL) was 57 days for 10.8 MU delivered by subcutaneous infusion every 13 weeks compared with 9 days of every 4-weekly dosing interval for the standard 1.2 MU intramuscular dose (i.e., 63% and 32% of the dosing interval, respectively). High-dose SCIP (BPG) is safe, has acceptable tolerability, and may be suitable for up to 3 monthly dosing intervals for secondary prophylaxis of RHD.

Trends in penicillin dispensing during an acute rheumatic fever prevention programme.

AIM: Acute rheumatic fever (ARF), a serious inflammatory condition, often leads to rheumatic heart disease (RHD). Between 2011 and 2016, Aotearoa New Zealand implemented a rheumatic fever prevention programme (RFPP) to reduce high rates of ARF through improved community access to timely diagnosis and early treatment of group A streptococcal (GAS) pharyngitis, which has been shown to prevent subsequent ARF. This study aimed to quantify the change in penicillin antibiotic dispensing rates among children aged 18 years or younger during the RFPP. METHOD: This retrospective analysis utilised administrative data from the National Pharmaceutical Collection. Using a controlled, interrupted time series analysis, the effect of the RFPP on antibiotic dispensing rates was explored. Poisson regression models were used to assess the change in dispensing rates during the RFPP among control regions (those not in the RFPP) and regions participating in the RFPP. The primary measure was rate ratio (RR) for the difference between the observed versus counterfactual rates of penicillin dispensing. RESULT: A total of 12,154,872 dispensing records between 2005 and 2018 were included. Amoxicillin was the most frequently dispensed penicillin (57.7%), followed by amoxicillin-clavulanate (23.4%). Amoxicillin dispensing increased by 4.3% in regions operating the RFPP compared to the increase in control regions (p<0.001). The overall rate of penicillin dispensing decreased, driven by a rapid decline in amoxicillin-clavulanate dispensing. CONCLUSION: During the RFPP an increase in amoxicillin dispensing was seen in regions participating in the programme and regions outside of the programme, indicating the programmatic approach led to improved adherence to recommended first-line antibiotics.

Bridging the age gap: a review of molecularly informed treatments for glioma in adolescents and young adults.

Gliomas are the most common primary central nervous system (CNS) tumors and a major cause of cancer-related mortality in children (age <15 years), adolescents and young adults (AYA, ages 15-39 years), and adults (age >39 years). Molecular pathology has helped enhance the characterization of these tumors, revealing a heterogeneous and ever more complex group of malignancies. Recent molecular analyses have led to an increased appreciation of common genomic alterations prevalent across all ages. The 2021 World Health Organization (WHO) CNS tumor classification, 5th edition (WHO CNS5) brings forward a nomenclature distinguishing "pediatric-type" and "adult-type" gliomas. The spectrum of gliomas in AYA comprises both "pediatric-like" and "adult-like" tumor entities but remains ill-defined. With fragmentation of clinical management between pediatric and adult centers, AYAs face challenges related to gaps in medical care, lower rates of enrollment in clinical trials and additional psychosocial and economic challenges. This calls for a rethinking of diagnostic and therapeutic approaches, to improve access to appropriate testing and potentially beneficial treatments to patients of all ages.

Continued mitigation needed to minimise the high health burden from COVID-19 in Aotearoa New Zealand.

In this article we review the COVID-19 pandemic experience in Aotearoa New Zealand and consider the optimal ongoing response strategy. We note that this pandemic virus looks likely to result in future waves of infection that diminish in size over time, depending on such factors as viral evolution and population immunity. However, the burden of disease remains high with thousands of infections, hundreds of hospitalisations and tens of deaths each week, and an unknown burden of long-term illness (long COVID). Alongside this there is a considerable burden from other important respiratory illnesses, including influenza and RSV, that needs more attention. Given this impact and the associated health inequities, particularly for Maori and Pacific Peoples, we consider that an ongoing respiratory disease mitigation strategy is appropriate for New Zealand. As such, the previously described "vaccines plus" approach (involving vaccination and public health and social measures), should now be integrated with the surveillance and control of other important respiratory infections. Now is also a time for New Zealand to build on the lessons from the COVID-19 pandemic to enhance preparedness nationally and internationally. New Zealand's experience suggests elimination (or ideally exclusion) should be the default first choice for future pandemics of sufficient severity.

Shouldn't We Know This Already? UK Women's Views About Communicating the Link Between Alcohol Consumption and Risk of Breast Cancer.

Alcohol is a causal factor in about 10% of breast cancer (BCa) cases, but awareness of this link is low. This study explored how to raise awareness and inform the development of an intervention using the COM-B model (capability, opportunity, motivation, behavior) framework. Eight online focus groups were conducted with 36 participants (6 expert stakeholders,and 30 women aged 40-65). Participants reflected on a package of information about alcohol and BCa and discussed how to impart this information and encourage women to reduce drinking. Thematic analysis of focus group transcripts was undertaken. Three themes were identified: understanding ineffective messaging; transitions and challenges; and message acceptability. Current health information about alcohol was perceived as judgmental and BCa was put down to chance. Mid-life consisted of many challenges that could lead to increased consumption, but menopause transition may be a key moment for alcohol reduction. Barriers and enablers to communicating risk information and encouraging alcohol reduction were mapped onto the COM-B model. Psychological capability (relating to knowledge), social opportunity (in the form of social pressure) and automatic motivation (relating to drinking to cope) were barriers to behavior change.  These will be targeted in an alcohol reduction intervention. It is important to tailor information to women's experiences, taking into account the social benefits of drinking, and encourage the development of healthy coping strategies. Acceptable intervention messages may include personal stories, clear statistics, and suggest healthy alternatives to drinking. It is vital that messaging does not appear judgmental or patronizing.

Invasive group A streptococcal disease in Hawke's Bay, New Zealand: epidemiology, manifestations and impact.

AIMS: To describe the epidemiology, clinical features and healthcare impact of invasive group A streptococcal (iGAS) disease in Hawke's Bay from 2016 to 2021, to inform public health efforts. METHODS: The case definition of iGAS for this study was isolation of group A streptococcus (GAS) from blood culture. "Severe iGAS" included cases that required intensive care admission or died within 60 days. Cases were identified retrospectively from the Te Whatu Ora Te Matau a Maui Hawke's Bay laboratory database. Clinical data were obtained from inpatient electronic health records. RESULTS: A total of 93 cases of iGAS were identified in Hawke's Bay during the 6-year study period. The overall age-standardised incidence of iGAS was 5.6 per 100,000 (95%CI 4.1-7.4). The incidence was significantly higher among people of Pacific, Maori and Asian ethnicities than European/Other ethnicities, and higher in areas of socio-economic disadvantage. Skin infections were the most common source (70% of cases). Thirty-seven cases (41%) were classified as severe, including 11 deaths (12% case fatality rate). CONCLUSIONS: Further action is required to address inequities in social determinants of skin health in Hawke's Bay. Mandatory national notification of iGAS would provide opportunity for improved surveillance of GAS-related disease, and consideration of a public health response to iGAS disease in New Zealand.

Qualitative assessment of healthy volunteer experience receiving subcutaneous infusions of high-dose benzathine penicillin G (SCIP) provides insights into design of late phase clinical studies.

INTRODUCTION: Secondary prophylaxis to prevent rheumatic heart disease (RHD) progression, in the form of four-weekly intramuscular benzathine benzylpenicillin G (BPG) injections, has remained unchanged since 1955. Qualitative investigations into patient preference have highlighted the need for long-acting penicillins to be delivered less frequently, ideally with reduced pain. We describe the experience of healthy volunteers participating in a phase-I safety, tolerability and pharmacokinetic trial of subcutaneous infusions of high-dose benzathine penicillin G (BPG)-the SCIP study (Australian New Zealand Clinical Trials Registry ACTRN12622000916741). METHODS: Participants (n = 24) received between 6.9 mL to 20.7 mL (3-9 times the standard dose) of BPG as a single infusion into the abdominal subcutaneous tissues via a spring-driven syringe pump over approximately 20 minutes. Semi-structured interviews at four time points were recorded, transcribed verbatim and thematically analysed. Tolerability and specific descriptors of the experience were explored, alongside thoughts on how the intervention could be improved for future trials in children and young adults receiving monthly BPG intramuscular injections for RHD. RESULTS: Participants tolerated the infusion well and were able describe their experiences throughout. Most reported minimal pain, substantiated via quantitative pain scores. Abdominal bruising at the infusion site did not concern participants nor impair normal activities. Insight into how SCIP could be improved for children included the use of topical analgesia, distractions via television or personal devices, a drawn-out infusion time with reduced delivery speed, and alternative infusion sites. Trust in the trial team was high. CONCLUSION: Qualitative research is an important adjunct for early-phase clinical trials, particularly when adherence to the planned intervention is a key driver of success. These results will inform later-phase SCIP trials in people living with RHD and other indications.

Protecting school communities from COVID-19 and other infectious disease outbreaks: the urgent need for healthy schools in Aotearoa New Zealand.

Nil.

Review of the Impact of Housing Quality on Inequalities in Health and Well-Being.

Housing quality is essential for population health and broader well-being. The World Health Organization Housing and health guidelines highlight interventions that protect occupants from cold and hot temperatures, injuries, and other hazards. The COVID-19 pandemic has emphasized the importance of ventilation standards. Housing standards are unevenly developed, implemented, and monitored globally, despite robust research demonstrating that retrofitting existing houses and constructing high-quality new ones can reduce respiratory, cardiovascular, and infectious diseases. Indigenous peoples, ethnic minorities, and people with low incomes face cumulative disadvantages that are exacerbated by poor-quality housing. These can be partially ameliorated by community-based programs to improve housing quality, particularly for children and older people, who are hospitalized more often for housing-related illnesses. There is renewed interest among policy makers and researchers in the health and well-being of people in public and subsidized housing, who are disproportionately disadvantaged by avoidable housing-related diseases and injuries. Improving the overall quality of new and existing housing and neighborhoods has multiple cobenefits, including reducing carbon emissions.

Adolescent and young adult glioma: systematic review of demographic, disease, and treatment influences on survival.

Background: Prognostic factors in adolescent and young adult (AYA) glioma are not well understood. Though clinical and molecular differences between pediatric and adult glioma have been characterized, their application to AYA populations is less clear. There is a major need to develop more robust evidence-based practices for managing AYA glioma patients. Methods: A systematic review using PRISMA methodology was conducted using multiple databases with the objective of identifying demographic, clinical, molecular and treatment factors influencing AYA glioma outcomes. Results: 40 Studies met inclusion criteria. Overall survival was highly variable across studies depending on glioma grade, anatomic compartment and cohort characteristics. Thirty-five studies suffered from high risk of bias in at least one domain. Several studies included older adults within their cohorts; few captured purely AYA groups. Despite study heterogeneity, identified favorable prognosticators included younger age, higher functional status at diagnosis, low-grade pathology, oligodendroglioma histology and increased extent of surgical resection. Though isocitrate dehydrogenase (IDH) mutant status was associated with favorable prognosis, validity of this finding within AYA was compromised though may studies including older adults. The prognostic influence of chemotherapy and radiotherapy on overall survival varied across studies with conflicting evidence. Conclusion: Existing literature is heterogenous, at high risk of bias, and rarely focused solely on AYA patients. Many included studies did not reflect updated pathological and molecular AYA glioma classification. The optimal role of chemotherapy, radiotherapy, and targeted agents cannot be determined from existing literature and should be the focus of future studies.

Clinical and molecular features of disseminated pediatric low-grade glioma and glioneuronal tumors: a systematic review and survival analysis.

Background: Disseminated pediatric low-grade gliomas and glioneuronal tumors (dpLGG/GNTs) are associated with a poorer prognosis than nondisseminated pLGG/GNTs. To date there is no comprehensive report characterizing the genome profile of dpLGG/GNTs and their relative survival. This systematic review aims to identify the pattern of genetic alterations and long-term outcomes described for dpLGG/GNT. Methods: A systematic review of the literature was performed to identify relevant articles. A quality and risk of bias assessment of articles was done using the GRADE framework and ROBINS-I tool, respectively. Results: Fifty studies published from 1994 to 2020 were included in this review with 366 cases reported. There was sporadic reporting of genetic alterations. The most common molecular alterations observed among subjects were 1p deletion (75%) and BRAF-KIAA1549 fusion (55%). BRAF p.V600E mutation was found in 7% of subjects. A higher proportion of subjects demonstrated primary dissemination compared to secondary dissemination (65% vs 25%). First-line chemotherapy consisted of an alkylation-based regimen and vinca alkaloids. Surgical intervention ranged from biopsy alone (59%) to surgical resection (41%) and CSF diversion (28%). Overall, 73% of cases were alive at last follow-up. Survival did not vary by tumor type or timing of dissemination. All studies reviewed either ranked low or moderate for both quality and risk of bias assessments. Conclusions: Chromosome 1p deletion and BRAF-KIAA1549 fusion were the most common alterations identified in dpLGG/GNT cases reviewed. The relative molecular heterogeneity between DLGG and DLGNT, however, deserves further exploration and ultimately correlation with their biologic behavior to better understand the pathogenesis of dpLGG/GNT.

Risk factors for acute rheumatic fever: A case-control study.

Background: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain an inequitable cause of avoidable suffering and early death in many countries, including among Indigenous Maori and Pacific populations in New Zealand. There is a lack of robust evidence on interventions to prevent ARF. This study aimed to identify modifiable risk factors, with the goal of producing evidence to support policies and programs to decrease rates of ARF. Methods: A case-control study was undertaken in New Zealand using hospitalised, first episode ARF cases meeting a standard case-definition. Population controls (ratio of 3:1) were matched by age, ethnicity, socioeconomic deprivation, location, sex, and recruitment month. A comprehensive, pre-tested questionnaire was administered face-to-face by trained interviewers. Findings: The study included 124 cases and 372 controls. Multivariable analysis identified strong associations between ARF and household crowding (OR 3·88; 95%CI 1·68-8·98) and barriers to accessing primary health care (OR 2·07; 95% CI 1·08-4·00), as well as a high intake of sugar-sweetened beverages (OR 2·00; 1·13-3·54). There was a marked five-fold higher ARF risk for those with a family history of ARF (OR 4·97; 95% CI 2·53-9·77). ARF risk was elevated following self-reported skin infection (aOR 2·53; 1·44-4·42) and sore throat (aOR 2·33; 1·49-3·62). Interpretation: These globally relevant findings direct attention to the critical importance of household crowding and access to primary health care as strong modifiable causal factors in the development of ARF. They also support a greater focus on the role of managing skin infections in ARF prevention. Funding: This research was funded by the Health Research Council of New Zealand (HRC) Rheumatic Fever Research Partnership (supported by the New Zealand Ministry of Health, Te Puni Kokiri, Cure Kids, Heart Foundation, and HRC) award number 13/959.

Molecular testing for adolescent and young adult central nervous system tumors: A Canadian guideline.

The 2021 World Health Organization (WHO) classification of CNS tumors incorporates molecular signatures with histology and has highlighted differences across pediatric vs adult-type CNS tumors. However, adolescent and young adults (AYA; aged 15-39), can suffer from tumors across this spectrum and is a recognized orphan population that requires multidisciplinary, specialized care, and often through a transition phase. To advocate for a uniform testing strategy in AYAs, pediatric and adult specialists from neuro-oncology, radiation oncology, neuropathology, and neurosurgery helped develop this review and testing framework through the Canadian AYA Neuro-Oncology Consortium. We propose a comprehensive approach to molecular testing in this unique population, based on the recent tumor classification and within the clinical framework of the provincial health care systems in Canada. Contributions to the field: While there are guidelines for testing in adult and pediatric CNS tumor populations, there is no consensus testing for AYA patients whose care occur in both pediatric and adult hospitals. Our review of the literature and guideline adopts a resource-effective and clinically-oriented approach to improve diagnosis and prognostication of brain tumors in the AYA population, as part of a nation-wide initiative to improve care for AYA patients.

The effects of sugar in drinking water on Streptococcus pyogenes colonisation in a murine nasopharyngeal infection model.

The number of sugar-sweetened beverages consumed per day has been associated with an increased risk of acute rheumatic fever, an autoimmune disease triggered by superficial Streptococcus pyogenes infection. To explore if there could be a biological basis for this association, we used a mouse model of S. pyogenes nasopharyngeal colonisation combined with a dietary intervention. We observed an increased bacterial load in the nasopharynx of mice receiving sucrose drinking water post-infection, suggesting that high sucrose intake promotes S. pyogenes growth and/or survival. This provides new insight into the potential biological basis behind the association seen in humans.

Systematic review of diffuse hemispheric glioma, H3 G34-mutant: Outcomes and associated clinical factors.

Background: A comprehensive review and description of the clinical features that impact prognosis for patients with diffuse hemispheric glioma, H3 G34-mutant (G34-DHG) is needed. Understanding survival and prognostic features is paramount for clinical advancements and patient care. Methods: PubMed, Embase, and Google Scholar were searched for English articles published between January 1, 2012 and June 30, 2021. Eligible studies included patient(s) of any age diagnosed with an H3 G34-mutant brain tumor with at least one measure of survival or progression. Patient-level data were pooled for analyses. This study was prospectively registered in PROSPERO (CRD42021267764) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Results: Twenty-seven studies met the criteria with a total of 135 patients included. Median age at diagnosis was 15.8 years (interquartile range [IQR]: 13.3-22.0) with 90% having localized disease. Co-occurring alterations included ATRX mutation in 93%, TP53 mutation in 88%, and MGMT promoter methylation in 70%. Median time-to-progression was 10.0 months (IQR: 6.0-18.0) and median overall survival was 17.3 months (95% CI: 15.0 to 22.9). The median time from progression to death was 5.0 months (IQR: 3.0-11.7). Factors associated with survival duration were age, as patients ≥18 y/o demonstrated longer survival (hazard ratio [HR] =2.05, 95% CI: 1.16 to 3.62), and degree of upfront resection, as near or gross-total resection demonstrated longer survival compared to those with less than near-total resection (HR = 3.75, 95% CI: 2.11 to 6.62). Conclusion: This systematic review highlights available clinical data for G34-DHG demonstrating poor outcomes and important prognostic features, while serving as a baseline for future research and clinical trials.

Indoor air quality, largely neglected and in urgent need of a refresh.

Nil.