Ibrutinib combination therapy for advanced gastrointestinal and genitourinary tumours: results from a phase 1b/2 study.

BACKGROUND: Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated. METHODS: Ibrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival [PFS] for CRC) in phase 2. RESULTS: A total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9-7.5) months in RCC, 4.0 (2.7-4.2) months in GC, and 5.4 (4.1-5.8) months in CRC. CONCLUSIONS: Clinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02599324.

A summary of the Malaysian Clinical Practice Guidelines on the management of postmenopausal osteoporosis, 2022.

Objectives: The aim of these Clinical Practice Guidelines is to provide evidence-based recommendations to assist healthcare providers in the screening, diagnosis and management of patients with postmenopausal osteoporosis (OP). Methods: A list of key clinical questions on the assessment, diagnosis and treatment of OP was formulated. A literature search using the PubMed, Medline, Cochrane Databases of Systematic Reviews, and OVID electronic databases identified all relevant articles on OP based on the key clinical questions, from 2014 onwards, to update from the 2015 edition. The articles were graded using the SIGN50 format. For each statement, studies with the highest level of evidence were used to frame the recommendation. Results: This article summarizes the diagnostic and treatment pathways for postmenopausal OP. Risk stratification of patients with OP encompasses clinical risk factors, bone mineral density measurements and FRAX risk estimates. Non-pharmacological measures including adequate calcium and vitamin D, regular exercise and falls prevention are recommended. Pharmacological measures depend on patients' fracture risk status. Very high-risk individuals are recommended for treatment with an anabolic agent, if available, followed by an anti-resorptive agent. Alternatively, parenteral anti-resorptive agents can be used. High-risk individuals should be treated with anti-resorptive agents. In low-risk individuals, menopausal hormone replacement or selective estrogen receptor modulators can be used, if indicated. Patients should be assessed regularly to monitor treatment response and treatment adjusted, as appropriate. Conclusions: The pathways for the management of postmenopausal OP in Malaysia have been updated. Incorporation of fracture risk stratification can guide appropriate treatment.

B-cell Receptor Pathway Mutations Are Infrequent in Patients with Chronic Lymphocytic Leukemia on Continuous Ibrutinib Therapy.

PURPOSE: Acquired mutations in Bruton's tyrosine kinase (BTK) or phospholipase C-γ2 (PLCG2) genes are associated with clinical progressive disease (PD) in patients with chronic lymphocytic leukemia (CLL) treated with BTK inhibitors. Data on mutation rates in patients without PD on ibrutinib treatment are limited. EXPERIMENTAL DESIGN: We evaluated frequency and time to detection of BTK and PLCG2 mutations in peripheral blood samples from 388 patients with previously untreated (n = 238) or relapsed/refractory (n = 150) CLL across five clinical trials. RESULTS: With median follow-up of 35 months (range, 0-72) without PD at last sampling, mutations in BTK (3%), PLCG2 (2%), or both genes (1%) were rare in previously untreated patients. With median follow-up of 35 months (range, 1-70) without PD at last sample, mutations in BTK (30%), PLCG2 (7%), or both genes (5%) were more common in patients with relapsed/refractory CLL. Median time to first detection of BTK C481S mutation was not reached in previously untreated patients and was >5 years in patients with relapsed/refractory CLL. Among patients evaluable at PD, previously untreated patients (n = 12) had lower rates than those with relapsed/refractory disease (n = 45) of BTK (25% vs. 49%) and PLCG2 mutations (8% vs. 13%). Time from first detection of BTK C481S mutation to PD was 11.3 months in 1 previously untreated patient and median 8.5 months (range, 0-35.7) among 23 patients with relapsed/refractory CLL. CONCLUSIONS: This systematic investigation describes development of mutations over time in patients without PD and informs the potential clinical opportunity to optimize ongoing benefits for such patients.

Results from a Phase 1b/2 Study of Ibrutinib Combination Therapy in Advanced Urothelial Carcinoma.

Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0-37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC.

Engaging Stigmatised Communities in Australia with Digital Health Systems: Towards Data Justice in Public Health.

Introduction: In 2018, following government policy changes to Australia's national electronic health record system, 'My Health Record', consumer advocates-including organisations representing people living with HIV, people who use drugs and sex workers-raised concerns about privacy and data security. Responding to these controversies, this study explores the practical, ethical and political complexities of engaging stigmatised communities with digital health systems. Methods: We conducted 16 qualitative semi-structured interviews in 2020 with key informants representing communities who experience stigma, discrimination and marginalisation in Australia. These communities included people living with HIV, sex workers, people who inject drugs, gay and bisexual men and transgender and gender diverse people. We conducted a reflexive thematic analysis. Results: Key informants were sceptical of proposed benefits of electronic health records for their communities, and concerned about privacy risks and the potential for discrimination. Meaningful consultation, consent mechanisms and tackling structural stigma were raised as solutions for engaging communities. Conclusions: Although communities could benefit from being included in digital health systems, significant cultural, legal and social reforms from government were believed to be necessary to build trust in digital health systems. We argue that these forms of data justice are necessary for effective future systems. Policy Implications: Engaging stigmatised communities-including in relation to gender, sexuality, sex work, drug use, HIV-requires a commitment to data justice. The design and implementation of digital health systems requires investment in ongoing and meaningful consultation with communities and representative organisations.

Graph Theory Measures and Their Application to Neurosurgical Eloquence.

Improving patient safety and preserving eloquent brain are crucial in neurosurgery. Since there is significant clinical variability in post-operative lesions suffered by patients who undergo surgery in the same areas deemed compensable, there is an unknown degree of inter-individual variability in brain 'eloquence'. Advances in connectomic mapping efforts through diffusion tractography allow for utilization of non-invasive imaging and statistical modeling to graphically represent the brain. Extending the definition of brain eloquence to graph theory measures of hubness and centrality may help to improve our understanding of individual variability in brain eloquence and lesion responses. While functional deficits cannot be immediately determined intra-operatively, there has been potential shown by emerging technologies in mapping of hub nodes as an add-on to existing surgical navigation modalities to improve individual surgical outcomes. This review aims to outline and review current research surrounding novel graph theoretical concepts of hubness, centrality, and eloquence and specifically its relevance to brain mapping for pre-operative planning and intra-operative navigation in neurosurgery.

Functional connectivity in ADHD children doing Go/No-Go tasks: An fMRI systematic review and meta-analysis.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders diagnosed in childhood. Two common features of ADHD are impaired behavioural inhibition and sustained attention. The Go/No-Go experimental paradigm with concurrent functional magnetic resonance imaging (fMRI) scanning has previously revealed important neurobiological correlates of ADHD such as the supplementary motor area and the prefrontal cortex. The coordinate-based meta-analysis combined with quantitative techniques, such as activation likelihood estimate (ALE) generation, provides an unbiased and objective method of summarising these data to understand the brain network architecture and connectivity in ADHD children. Go/No-Go task-based fMRI studies involving children and adolescent subjects were selected. Coordinates indicating foci of activation were collected to generate ALEs using threshold values (voxel-level: p < 0.001; cluster-level: p < 0.05). ALEs were matched to one of seven canonical brain networks based on the cortical parcellation scheme derived from the Human Connectome Project. Fourteen studies involving 457 children met the eligibility criteria. No significant convergence of Go/No-Go related brain activation was found for ADHD groups. Three significant ALE clusters were detected for brain activation relating to controls or ADHD < controls. Significant clusters were related to specific areas of the default mode network (DMN). Network-based analysis revealed less extensive DMN, dorsal attention network, and limbic network activation in ADHD children compared to controls. The presence of significant ALE clusters may be due to reduced homogeneity in the selected sample demographic and experimental paradigm. Further investigations regarding hemispheric asymmetry in ADHD subjects would be beneficial.

Communication methods between physicians and Deaf patients: A scoping review.

OBJECTIVE: Deaf individuals often face communication challenges within healthcare settings. Given the importance of the role played by physicians in shaping patients' health outcomes, it is paramount to explore Deaf patient-physician interactions. This research aims to explore (1) the existing communication support and (2) the factors influencing its usage in medical consultations with Deaf patients. METHODS: A scoping review was carried out and adhered to the Preferred Reporting System for Meta-Analysis. A comprehensive search strategy of four databases; PubMed, Medline, CINAHL Plus and Scopus, from January 2011 to June 2021 was applied. Thematic analysis was used to analyse the data. RESULTS: Ten journal articles were included, and four themes were identified; patient experiences using communication methods, practitioners' cultural competence in Deaf culture, inherent challenges of communication methods, and extrinsic factors. Professional interpreters are often regarded as the preferred modality of communication but writing and lip-reading were commonly used in healthcare settings, with video remote interpreting the least common. CONCLUSION: Healthcare professionals need to appreciate the heterogeneity of Deaf patients and their communication methods and adopt a more person-centred approach. PRACTICE IMPLICATIONS: This review provides up-to-date insight on Deaf patient-physician interactions and provisional recommendations for practice, education and policy.

A qualitative exploration of the healthcare challenges and pharmaceutical care needs of people with Parkinson's and their caregivers.

Background People with Parkinson's are at higher risk of healthcare and pharmaceutical care issues. Objective To determine the healthcare challenges, pharmaceutical care needs, and perceived need of a pharmacist-run clinic by people with Parkinson's and their caregivers. Setting Malaysian Parkinson's Disease Association. Method A focus group discussion adopting a descriptive qualitative approach was conducted involving people with Parkinson's and their caregivers. A semi-structured interview guide was used to determine the challenges they faced with their medications and healthcare system, their pharmaceutical care needs, and their views on a pharmacist-run clinic. Data was thematically analysed. Main outcome measure: Healthcare challenges faced by people with Parkinson's and caregivers along with their pharmaceutical care needs and perceived need of a pharmacist-run clinic. Results Nine people with Parkinson's and four caregivers participated. Six themes were developed: (1) "It's very personalised": the need for self-experimentation, (2) "Managing it is quite difficult": challenges with medication, (3) "The doctor has no time for you": challenges with healthcare providers, (4) "Nobody can do it except me": challenges faced by caregivers, (5) "It becomes a burden": impact on quality of life, and (6) "Lack of consistency could be counterproductive": views on pharmacist-run clinic. Conclusion The provision of pharmaceutical care services by pharmacists could help overcome issues people with Parkinson's face, however there is a need for them to first see pharmacists in their expanded roles and change their limited perception of pharmacists. This can be achieved through integration of pharmacists within multidisciplinary teams in specialist clinics which they frequent.

Health Care Needs of Deaf Signers: The Case for Culturally Competent Health Care Providers.

There is a need for culturally competent health care providers (HCPs) to provide care to deaf signers, who are members of a linguistic and cultural minority group. Many deaf signers have lower health literacy levels due to deprivation of incidental learning opportunities and inaccessibility of health-related materials, increasing their risk for poorer health outcomes. Communication barriers arise because HCPs are ill-prepared to serve this population, with deaf signers reporting poor-quality interactions. This has translated to errors in diagnosis, patient nonadherence, and ineffective health information, resulting in mistrust of the health care system and reluctance to seek treatment. Sign language interpreters have often not received in-depth medical training, compounding the dynamic process of medical interpreting. HCPs should thus become more culturally competent, empowering them to provide cultural- and language-concordant services to deaf signers. HCPs who received training in cultural competency showed increased knowledge and confidence in interacting with deaf signers. Similarly, deaf signers reported more positive experiences when interacting with medically certified interpreters, HCPs with sign language skills, and practitioners who made an effort to improve communication. However, cultural competency programs within health care education remain inconsistent. Caring for deaf signers requires complex, integrated competencies that need explicit attention and practice repeatedly in realistic, authentic learning tasks ordered from simple to complex. Attention to the needs of deaf signers can start early in the curriculum, using examples of deaf signers in lectures and case discussions, followed by explicit discussions of Deaf cultural norms and the potential risks of low written and spoken language literacy. Students can subsequently engage in role plays with each other or representatives of the local signing deaf community. This would likely ensure that future HCPs are equipped with the knowledge and skills necessary to provide appropriate care and ensure equitable health care access for deaf signers.

Assessment of community pharmacists' communication and comfort levels when interacting with Deaf and hard of hearing patients.

BACKGROUND: Deaf and hard of hearing patients who use sign language face considerable communication barriers while accessing pharmacy services. Low comfort-levels between community pharmacists and Deaf and hard of hearing patients result in poor interactions and increase patient safety risks. OBJECTIVE: 1) To examine the way community pharmacists interact with Deaf and hard of hearing patients in Malaysia, and their level of comfort in such interactions. 2) To examine how comfort-levels vary by the preferred communication methods, resources and employer support. METHODS: This cross-sectional study was conducted among registered community pharmacists practicing in Malaysia. Questionnaire items included comfort-levels of community pharmacists when interacting with Deaf and hard of hearing patients, used and preferred communication methods, necessary resources, and perceived employer's level of support. Based on the list of registered pharmacies, the questionnaire with a pre-paid return envelope was mailed out while pharmacies close to the university were approached in person. This questionnaire was distributed online using Google Form. Comparisons between comfort-levels and study parameters were analyzed using independent t-tests and ANOVA. RESULTS: A total of 297 community pharmacists responded (response rate 29.2%). Higher comfort-levels were reported in those who had received between 1 to 5 prescriptions as compared to those who did not receive prescriptions from Deaf and hard of hearing patients (MD= -0.257, SD=0.104, p=0.042). More than 80% used written information and only 3.4% had used the services of a qualified sign language interpreter throughout their community pharmacist career. Significantly lower comfort-levels (p=0.0004) were reported in community pharmacists who perceived training in sign language as a necessity to interact with Deaf and hard of hearing patients (M=3.6, SD=0.9) versus those who were not interested in sign language training (M=3.8, SD=0.6). CONCLUSIONS: The results suggest that community pharmacists were neither extremely comfortable nor averse when interacting with Deaf and hard of hearing patients. The lack of significant findings in terms of comfort-levels may indicate other potential drivers for their choice of communication method when interacting with Deaf and hard of hearing patients.

Assessment of community pharmacists’ communication and comfort levels when interacting with Deaf and hard of hearing patients

Background: Deaf and hard of hearing patients who use sign language face considerable communication barriers while accessing pharmacy services. Low comfort-levels between community pharmacists and Deaf and hard of hearing patients result in poor interactions and increase patient safety risks. Objective: 1) To examine the way community pharmacists interact with Deaf and hard of hearing patients in Malaysia, and their level of comfort in such interactions. 2) To examine how comfort-levels vary by the preferred communication methods, resources and employer support. Methods: This cross-sectional study was conducted among registered community pharmacists practicing in Malaysia. Questionnaire items included comfort-levels of community pharmacists when interacting with Deaf and hard of hearing patients, used and preferred communication methods, necessary resources, and perceived employer’s level of support. Based on the list of registered pharmacies, the questionnaire with a pre-paid return envelope was mailed out while pharmacies close to the university were approached in person. This questionnaire was distributed online using Google Form. Comparisons between comfort-levels and study parameters were analyzed using independent t-tests and ANOVA. Results: A total of 297 community pharmacists responded (response rate 29.2%). Higher comfort-levels were reported in those who had received between 1 to 5 prescriptions as compared to those who did not receive prescriptions from Deaf and hard of hearing patients (MD= -0.257, SD=0.104, p=0.042). More than 80% used written information and only 3.4% had used the services of a qualified sign language interpreter throughout their community pharmacist career. Significantly lower comfort-levels (p=0.0004) were reported in community pharmacists who perceived training in sign language as a necessity to interact with (AU)

Design suggestions for an mHealth app to facilitate communication between pharmacists and the Deaf: perspective of the Deaf community (HEARD Project).

BACKGROUND: Deaf and hard-of-hearing (DHH) patients have trouble communicating with community pharmacists and accessing the healthcare system. This study explored the views on a proposed mobile health (mHealth) app in terms of design and features, that will be able to bridge the communication gap between community pharmacists and DHH patients. METHODS: A community-based participatory research method was utilized. Two focus group discussions (FGDs) were conducted in Malaysian sign language (BIM) with a total of 10 DHH individuals. Respondents were recruited using purposive sampling. Video-recordings were transcribed and analyzed using a thematic approach. RESULTS: Two themes emerged: (I) challenges and scepticism of the healthcare system; and (II) features of the mHealth app. Respondents expressed fears and concerns about accessing healthcare services, and stressed on the need for sign language interpreters. There were also concerns about data privacy and security. With regard to app features, the majority preferred videos instead of text to convey information about their disease and medication, due to their lower literacy levels. CONCLUSIONS: For an mHealth app to be effective, app designers must ensure the app is individualised according to the cultural and linguistic diversity of the target audience. Pharmacists should also educate patients on the potential benefits of the app in terms of assisting patients with their medicine-taking.

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis.

Advanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.

A qualitative study on the design and development of an mHealth app to facilitate communication with the Deaf community: perspective of community pharmacists.

PURPOSE: This study prepares the groundwork on the potential design and development of a mobile health (mHealth) app that will be able to bridge the communication gap between pharmacists and patients who are Deaf and Hard of Hearing (DHoH). PATIENTS AND METHODS: A focus group discussion was conducted with 12 community pharmacists. Participants were recruited using snowball sampling. Audio-recordings were transcribed verbatim, and analyzed using a thematic approach. RESULTS: Three themes were apparent: 1) suggestions for app design and content, 2) perceived benefits of the app, and 3) potential challenges related to the app. Participants believed the app would be able to facilitate and improve communication, and hence relationship, between pharmacists and the DHoH. Potential challenges of the app were highlighted, such as the need for manpower to manage the app, and its cost to this group of economically disadvantaged people. There were also concerns about privacy and security. CONCLUSIONS: This study allowed community pharmacists, one of the end-users of the app, to provide feedback on the contents and design of the app, which would allow them to provide pharmaceutical care services to patients who are DHoH, and better serve them. Potential benefits and challenges of the app were also identified. Undoubtedly, through the mHealth app, community pharmacists will be better equipped to serve and communicate with the DHoH, and this will hopefully translate to improved health outcomes in these patients.

Plasma metabolomics in adults with cystic fibrosis during a pulmonary exacerbation: A pilot randomized study of high-dose vitamin D3 administration.

BACKGROUND: Cystic fibrosis (CF) is a chronic catabolic disease often requiring hospitalization for acute episodes of worsening pulmonary exacerbations. Limited data suggest that vitamin D may have beneficial clinical effects, but the impact of vitamin D on systemic metabolism in this setting is unknown. OBJECTIVE: We used high-resolution metabolomics (HRM) to assess the impact of baseline vitamin D status and high-dose vitamin D3 administration on systemic metabolism in adults with CF with an acute pulmonary exacerbation. DESIGN: Twenty-five hospitalized adults with CF were enrolled in a randomized trial of high-dose vitamin D3 (250,000IU vitamin D3 bolus) versus placebo. Age-matched healthy subjects served as a reference group for baseline comparisons. Plasma was analyzed with liquid chromatography/ultra-high resolution mass spectrometry. Using recent HRM bioinformatics and metabolic pathway enrichment methods, we examined associations with baseline vitamin D status (sufficient vs. deficient per serum 25-hydroxyvitamin D concentrations) and the 7-day response to vitamin D3 supplementation. RESULTS: Several amino acids and lipid metabolites differed between CF and healthy control subjects, indicative of an overall catabolic state. In CF subjects, 343 metabolites differed (P<0.05) by baseline vitamin D status and were enriched within 7 metabolic pathways including fatty acid, amino acid, and carbohydrate metabolism. A total of 316 metabolites, which showed enrichment for 15 metabolic pathways-predominantly representing amino acid pathways-differed between the vitamin D3- and placebo-treated CF subjects over time (P<0.05). In the placebo group, several tricarboxylic acid cycle intermediates increased while several amino acid-related metabolites decreased; in contrast, little change in these metabolites occurred with vitamin D3 treatment. CONCLUSIONS: Numerous metabolic pathways detected by HRM varied in association with vitamin D status and high-dose vitamin D3 supplementation in adults with CF experiencing a pulmonary exacerbation. Overall, these pilot data suggest an anti-catabolic effect of high-dose vitamin D3 in this clinical setting.

The Epidemiology of Hand, Foot and Mouth Disease in Asia: A Systematic Review and Analysis.

CONTEXT: Hand, foot and mouth disease (HFMD) is a widespread pediatric disease caused primarily by human enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16). OBJECTIVE: This study reports a systematic review of the epidemiology of HFMD in Asia. DATA SOURCES: PubMed, Web of Science and Google Scholar were searched up to December 2014. STUDY SELECTION: Two reviewers independently assessed studies for epidemiologic and serologic information about prevalence and incidence of HFMD against predetermined inclusion/exclusion criteria. DATA EXTRACTION: Two reviewers extracted answers for 8 specific research questions on HFMD epidemiology. The results are checked by 3 others. RESULTS: HFMD is found to be seasonal in temperate Asia with a summer peak and in subtropical Asia with spring and fall peaks, but not in tropical Asia; evidence of a climatic role was identified for temperate Japan. Risk factors for HFMD include hygiene, age, gender and social contacts, but most studies were underpowered to adjust rigorously for confounding variables. Both community-level and school-level transmission have been implicated, but their relative importance for HFMD is inconclusive. Epidemiologic indices are poorly understood: No supporting quantitative evidence was found for the incubation period of EV-A71; the symptomatic rate of EV-A71/Coxsackievirus A16 infection was from 10% to 71% in 4 studies; while the basic reproduction number was between 1.1 and 5.5 in 3 studies. The uncertainty in these estimates inhibits their use for further analysis. LIMITATIONS: Diversity of study designs complicates attempts to identify features of HFMD epidemiology. CONCLUSIONS: Knowledge on HFMD remains insufficient to guide interventions such as the incorporation of an EV-A71 vaccine in pediatric vaccination schedules. Research is urgently needed to fill these gaps.