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Free-roaming and scavenging lifestyles of Rattus spp. in densely populated urban areas expose them to multiple pathogens that facilitate the transmission of infection to the human population more rapidly, raising public health concerns. There is limited information on the status of rat susceptibility to virus infection, particularly West Nile virus (WNV), herpesvirus, and parvovirus, to prepare for emerging zoonosis. A total of 23 (n = 23) blood samples collected from Rattus spp. in the wet market areas of Klang Valley, Malaysia, were subjected to molecular assay using a one-step reverse transcription-polymerase chain reaction (RT-PCR) to detect the highly conserved region of the WNV capsid and pre-membrane protein via nested polymerase chain reaction (PCR) assay targeting highly conserved amino acid motifs within the herpesviral DNA-directed DNA polymerase gene (DPOL) and polymerase chain reaction (PCR) assay targeting the parvovirus non-structural (NS) protein. As a result, 4 out of 23 (17.39%) rats were positive for herpesvirus DNA, but none were positive for WNV RNA and parvovirus DNA. The positive PCR amplicons of herpesvirus DNA were subjected to partial DNA sequencing analysis, 100% identical to Acomys herpesvirus SVMS 226,222 from Betaherpesvirinae, which is highly suggestive of rat cytomegalovirus (RCMV). This study has successfully demonstrated the presence of RCMV from Rattus spp. in the Klang Valley. The RCMV potentially crosses species barriers and establishes infection, raising public health concerns. The non-viraemic state of WNV or parvovirus infection, low sample size, and limited niche distribution emphasise the need for the expansion of this study in the future.

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Background: Recent reports raise the possibility of cerebral amyloid angiopathy (CAA) leading to intracerebral hemorrhage in young adults following childhood neurosurgery, suggesting transmission of amyloid-β (Aβ) through neurosurgical procedures including dura mater grafting. Parenchymal Aβ deposition, and to a lesser extent tau aggregation, similar to that seen in Alzheimer disease, have also been described. Methods: We conducted a database review of 634 consecutive intracerebral hemorrhage patients aged Results: We identified 3 patients aged in their thirties who presented with spontaneous lobar intracerebral hemorrhage, with imaging or neuropathology consistent with CAA, and a history of childhood neurosurgery. Two of these patients had undergone a dural repair using cadaveric dura mater (Lyodura). In addition to CAA, both patients had neuropathologically confirmed parenchymal Aβ and tau deposits, characteristic of Alzheimer disease. Conclusions: Our findings support the concept of neurosurgical Aβ transmission but suggest that such cases are rare in standard clinical practice.

This study seeks to present the relationship between executive compensation, dividend payout policy and ownership structure of listed firms in Malaysia. We examine a panel data on a sample of 300 of the largest Malaysian public listed companies (PLCs) on Bursa Malaysia for the years 2008 to 2014. Based on 2,009 firm-year observations, our results show consistent empirical positive evidence on the association between dividend payout and executive compensation across all models. However, the results are inconsistent with Bhattacharyya model of dividend payout. Further, there is evidence that government and family ownerships are positively associated with dividend payout. Our results show that the positive relationship between executive compensation and dividend payout is more evident in politically connected firms (PCON firms) which is consistent with the clientele (catering) theory.

Housing affordability has been a troubling issue for both developed and developing countries. Much of the prior literature has used the price-income ratio as the main standard to assess housing affordability, with the median disposable household income of the sample population commonly used. As such, conclusions drawn from macro-level analyses are devoid of practical policy recommendations. This paper attempts to address the housing affordability issue in greater detail by considering age cohorts, income percentiles, and different house types. An analysis was also conducted over the time period from 1995 to 2014 to compare affordability across time. Using the common benchmark of banks, a cut-off ratio of 0.35 for the mortgage installment to income ratio is used as a measure of housing affordability. The results show that for those aged 20-24 and 60-64, housing is severely unaffordable across all house types, except for the 75th income percentile group. The most expensive are semi-detached and detached housing types, which remain unaffordable to all income and age groups, except for the 75th income percentile group aged 30 and above. Terrace and high rise housing types are the most affordable across each income percentile. There is a lack of housing affordability improvement over time even with recent government interventions through affordable housing schemes specifically targeted at the lower income groups. This paper makes several contributions. By analyzing the affordability problem from a more granular perspective, strategies to develop a thriving rental market should be targeted to those in the 20-24 age cohort. A concerted effort in information dissemination by the government must be undertaken to convince would-be house purchasers that the best time, on average, to enter the housing market is when they reach their mid-30s. Emphasis should also be placed on entering housing with high-rise and terrace housing types. This analysis also helps commercial mortgage lenders segment their clienteles and thus helps reduce information asymmetry.

The aim of this study is to evaluate factors contributing to poor academic performance of students in higher education. Data was collected in 2017 from 216 students enrolled in different programmes at a higher education provider in New Zealand. The effect of factors relating to family obligations, work and social commitments, and financial concerns were analysed. Results showed significant relationship between academic performance of students and their attendance. Other significant findings included the relationship between attendance and the level of study; work shift; ethnicity; whether participants had any dependents; and how studies were funded. Implications and limitations of this study are presented.

Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0–8) were treated with daily tamoxifen (20 mg) and venetoclax (200–800 mg). Apart from uncomplicated “on-target” lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations. Significance: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors. See related commentary by Drago et al., p. 323. This article is highlighted in the In This Issue feature, p. 305

Background: Venetoclax, a potent and selective inhibitor of the survival protein BCL-2 (recently approved in CLL and in development in other hematopoietic malignancies), has yet to be evaluated in pts with solid tumors. BCL-2 is overexpressed in ˜85% of ER+ breast cancer. Pre-clinical findings using patient-derived xenograft breast tumor models suggest that venetoclax synergizes with endocrine therapy by increasing apoptosis. Here we report mBEP, an investigator-initiated phase 1b study of venetoclax with tamoxifen in 33 pts with ER+ (>1%), BCL-2+ (>10%, 2-3+ intensity) and HER2– MBC. Methods: We conducted a 3+3 dose escalation study comprising cohorts receiving venetoclax 200, 400, 600 or 800 mg/d with tamoxifen 20 mg/d (continued until progression). The primary endpoint was to determine the maximum tolerated dose (MTD), define dose-limiting toxicities (DLTs) and identify the recommended phase 2 dose (RP2D). In a dose expansion phase (at the RP2D), secondary endpoints including safety and tolerability, response at 24 wks (RECIST v1.1), clinical benefit rate (CBR) and progression-free survival (PFS) were studied. Results: In the escalation phase (n=15 pts), treatment was well tolerated with no DLTs or high-grade (Gd 3/4) adverse events observed, apart from asymptomatic on-target lymphopenia (Gd 3, 2/15 pts). MTD was not reached. The 800 mg/d dose was selected as the RP2D and the cohort expanded to include 24 pts with ≥24 wks follow up (range 24-105 wks). Fifteen pts had received prior regimens for MBC (median 3, range 1-9) that included tamoxifen in 5/15. For the RP2D cohort (n=24), overall responses (OR) included 1 CR (4%) and 12 PR (50%), with 5 SD (21%), corresponding to a CBR of 75%. The 9 pts treated in the first line setting experienced a 78% OR (7/9 pts) and 11% SD (1/9 pts), equating to an 89% CBR. The data are immature for determining median PFS for the RP2D cohort (currently 40+ wks). Treatment responses were pre-empted by metabolic responses (FDG-PET) at 4 wks (seen in 13/16 (81%) pts studied), and correlated with serial changes in circulating tumor DNA (ctDNA). Intriguingly, responses and clinical benefit were observed in pts with plasma-detected ESR1 mutations (4/10 and 7/10, respectively). The most common treatment-related AEs (CTCAE v4.0) for all pts were lymphopenia in 29/33 (88%; 57% Gd 1-2, 30% Gd 3-4), neutropenia in 24/33 (73%; 67% Gd 1-2, 6% Gd 3), nausea in 22/33 (67%; all ≤Gd 2), anemia in 13/33 (39%; 33% Gd 1-2, 6% G3), thrombocytopenia in 11/33 (33%; all ≤Gd 2), vomiting in 11/33 (33%, all ≤Gd 2), diarrhea in 10/33 (30%; 24% Gd 1-2, 6% Gd 3), infection in 9/33 (27%; 18% Gd 2, 9% Gd 3) and fatigue in 7/33 (21%; all ≤Gd 2). There was one possible treatment-related SAE (infection). Conclusions: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits remarkable activity in ER+ and BCL-2+ MBC. These findings support further investigation of combination therapy for patients with BCL-2-positive breast cancer. Sponsor: The Royal Melbourne Hospital (ACTRN12615000702516) Citation Format: Lindeman GJ, Lok SW, Whittle JR, Siow ZR, Bergin AR, Dawson S-J, Desai J, Gray DH, Liew D, Mann GB, Murugasu A, Roberts AW, Rosenthal MA, Shackleton K, Sherman P, Silva MJ, Teh C, Travers A, Vaillant F, Visvader JE. A phase 1b dose-escalation and expansion study of the BCL-2 inhibitor venetoclax combined with tamoxifen in ER and BCL-2–positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-06.

Highlights • MMR vaccine uptake rates have dropped between 25.64% - 73.55% during COVID-19. • A measles epidemic is a possibility due to reduction in community herd immunity. • Urgent public health efforts are needed to maintain efficacious vaccine coverage., Although the direct health impact of Coronavirus disease (COVID-19) pandemic on child health is low, there are indirect impacts across many aspects. We compare childhood vaccine uptake in three types of healthcare facilities in Singapore - public primary care clinics, a hospital paediatric unit, and private paediatrician clinics - from January to April 2020, to baseline, and calculate the impact on herd immunity for measles. We find a 25.6% to 73.6% drop in Measles-Mumps-Rubella (MMR) uptake rates, 0.4 – 10.3% drop for Diphtheria-Tetanus-Pertussis-inactivated Polio-Haemophilus influenza (5-in-1), and 8.0-67.8% drop for Pneumococcal conjugate vaccine (PCV) across all 3 sites. Consequent herd immunity reduces to 74 - 84% among 12-month- to 2-year-olds, well below the 95% coverage that is protective for measles. This puts the whole community at risk for a measles epidemic. Public health efforts are urgently needed to maintain efficacious coverage for routine childhood vaccines during the COVID-19 pandemic.

We read with interest the article by Almradi et al1 regarding consensus statements to standardise the assessment of histological disease activity in clinical trials of patients with Crohn's disease (CD).

The current model for breast cancer progression proposes independent “low‐grade (LG) like” and “high‐grade (HG) like” pathways but lacks a known precursor to HG cancer. We applied low coverage whole genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. 14/20 isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG‐like CNA than LG DCIS (eg. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent “low‐grade like” and “high‐grade like” pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH could be more clinically significant than LG DCIS, requiring biomarkers for personalising management.

The current model for breast cancer progression proposes independent 'low grade (LG)-like' and 'high grade (HG)-like' pathways but lacks a known precursor to HG cancer. We applied low-coverage whole-genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. Fourteen out of twenty isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG-like CNA than LG DCIS (e.g. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent 'low grade-like' and 'high grade-like' pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH cases could be more clinically significant than LG DCIS, requiring biomarkers for personalising management. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Over the recent years, the globalization has created people to become increasing mobile within and across borders in response to the social and economic challenges. Employment has been regarded as the heart of most human movement in the 21st century and has allowed host countries led by organizations to seek foreign professionals to overcome shortfall of among competent professionals. The demand for efficiency in production and services as well as with global competition has geared greater professionals’ mobility. As a result most of the developing countries have regarded this outflow or professional mobility that explains the departure or emigration of their competent professionals from their country to another country as brain drain. Similarly, Malaysia is one of the developing country from South East Asia has not been spared from this phenomenon. There are various socioeconomic factors that have been associated with the recent brain drain of Malaysians. However, it has been argued that the dominant factor of the recent brain drain in Malaysia would be the level of income in Malaysia. In recent years, Malaysians professionals have favored New Zealand as proven from the growth rate of Malaysians migrating to New Zealand. The high incomes and quality lifestyle in New Zealand as well as other factors have urged many Malaysians to move to New Zealand. Thus, this paper explores the determinants of income towards brain drain of Malaysians from the perspectives of Malaysians in New Zealand.

Supplemental digital content is available in the text., Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

Over the recent years, the globalization has created people to become increasing mobile within and across borders in response to the social and economic challenges. Employment has been regarded as the heart of most human movement in the 21st century and has allowed host countries led by organizations to seek foreign professionals to overcome shortfall of among competent professionals. The demand for efficiency in production and services as well as with global competition has geared greater professionals’ mobility. As a result most of the developing countries have regarded this outflow or professional mobility that explains the departure or emigration of their competent professionals from their country to another country as brain drain. Similarly, Malaysia is one of the developing country from South East Asia has not been spared from this phenomenon. There are various socioeconomic factors that have been associated with the recent brain drain of Malaysians. However, it has been argued that the dominant factor of the recent brain drain in Malaysia would be the level of income in Malaysia. In recent years, Malaysians professionals have favored New Zealand as proven from the growth rate of Malaysians migrating to New Zealand. The high incomes and quality lifestyle in New Zealand as well as other factors have urged many Malaysians to move to New Zealand. Thus, this paper explores the determinants of income towards brain drain of Malaysians from the perspectives of Malaysians in New Zealand.