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1.
Nature ; 598(7881): 510-514, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34646013

RESUMO

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.


Assuntos
Competição entre as Células , Proliferação de Células , Células Clonais/citologia , Células Clonais/metabolismo , Células Epiteliais/citologia , Neoplasias Esofágicas/patologia , Mutação , Animais , Carcinogênese/imunologia , Morte Celular , Sobrevivência Celular , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/patologia , Epitélio/imunologia , Neoplasias Esofágicas/imunologia , Feminino , Masculino , Camundongos , Fatores de Tempo
2.
Blood ; 141(22): 2738-2755, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36857629

RESUMO

Primary resistance to tyrosine kinase inhibitors (TKIs) is a significant barrier to optimal outcomes in chronic myeloid leukemia (CML), but factors contributing to response heterogeneity remain unclear. Using single-cell RNA (scRNA) sequencing, we identified 8 statistically significant features in pretreatment bone marrow, which correlated with either sensitivity (major molecular response or MMR) or extreme resistance to imatinib (eventual blast crisis [BC] transformation). Employing machine-learning, we identified leukemic stem cell (LSC) and natural killer (NK) cell gene expression profiles predicting imatinib response with >80% accuracy, including no false positives for predicting BC. A canonical erythroid-specifying (TAL1/KLF1/GATA1) regulon was a hallmark of LSCs from patients with MMR and was associated with erythroid progenitor [ERP] expansion in vivo (P < .05), and a 2- to 10-fold (6.3-fold in group A vs 1.09-fold in group C) erythroid over myeloid bias in vitro. Notably, ERPs demonstrated exquisite TKI sensitivity compared with myeloid progenitors (P < .001). These LSC features were lost with progressive resistance, and MYC- and IRF1-driven inflammatory regulons were evident in patients who progressed to transformation. Patients with MMR also exhibited a 56-fold expansion (P < .01) of a normally rare subset of hyperfunctional adaptive-like NK cells, which diminished with progressive resistance, whereas patients destined for BC accumulated inhibitory NKG2A+ NK cells favoring NK cell tolerance. Finally, we developed antibody panels to validate our scRNA-seq findings. These panels may be useful for prospective studies of primary resistance, and in assessing the contribution of predetermined vs acquired factors in TKI response heterogeneity.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Estudos Prospectivos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Crise Blástica , Resistencia a Medicamentos Antineoplásicos/genética
3.
Med J Malaysia ; 78(3): 336-343, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37271843

RESUMO

INTRODUCTION: Effective smoking cessation programmes are essential for assisting smokers in quitting, indirectly lowering mortality and morbidity associated with smoking. Numerous studies have indicated positive outcomes when using mindfulness treatment (MT) to treat psychological or behavioural health issues. Although to date, no study has looked at the effectiveness of online MT for quitting smoking while addressing mental health, particularly among the Asian population. Therefore, this study compares the efficiency of online MT to traditional counselling therapy (CT) in aiding smoking cessation programmes while also addressing mental health. MATERIALS AND METHODS: A randomised control study with a two-group, single-blind design and baseline evaluation was selected. Social media sites were used to advertise for participants, who were then admitted after meeting the requirements. Participants who met the eligibility requirements were randomly split into two groups. Each group received a total of three sessions of online therapy (MT or CT), once every two weeks, as well as one phone call per week as reinforcement. At the beginning and end of the intervention, participants completed questionnaires (1st week and 5th week). Generalized Estimating Equation (GEE) statistical analysis was used to analyse all the variables. RESULTS: The MT group experienced a statistically significant decrease in cigarette consumption (ß: -3.50, 95% Wald CI: - 4.62, -2.39) compared to the CT group over time. Furthermore, the MT group demonstrated significant improvements in their scores for the AAQ-2, anxiety, stress, depression and mindfulness compared to the CT group. CONCLUSION: Online MT is more successful at assisting smokers in lowering their daily cigarette intake and supporting their mental health during the smoking cessation process. Further longitudinal comparisons of the effectiveness of online MT should be undertaken using online platforms in future studies.


Assuntos
Atenção Plena , Abandono do Hábito de Fumar , Humanos , Abandono do Hábito de Fumar/psicologia , Saúde Mental , Método Simples-Cego , Fumar/psicologia
4.
Med J Malaysia ; 78(5): 602-608, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37775486

RESUMO

INTRODUCTION: Previous trials and real-world studies have shown that nirmatrelvir/ritonavir (Paxlovid®) reduces hospitalisation and deaths in symptomatic, high-risk, nonsevere COVID-19 patients. However, there was a scarcity of data on its effectiveness in the local setting. This study aimed to determine the effectiveness of Paxlovid® in reducing hospitalisation and mortality among COVID-19 patients and to identify the types of adverse events that occur after taking Paxlovid®. MATERIALS AND METHODS: A two-arm prospective cohort study was conducted among adult patients with COVID-19 categories 2 and 3 treated with Paxlovid® and a matched control group. A standard risk-stratified scoring system was used to establish Paxlovid® eligibility. All patients who were prescribed Paxlovid® and took at least one dose of Paxlovid® were included in the study. The control patients were selected from a centralised COVID-19 patient registry and matched based on age, gender and COVID-19 stage severity. RESULTS: A total of 552 subjects were included in the study and evenly allocated to the treatment and control groups. There was no statistically significant difference in 28-day hospitalisation after diagnosis [Paxlovid®: 26 (9.4%), Control: 34 (12.3%), OR: 0.74; 95%CI, 0.43-1.27; p=0.274] or all-cause death [Paxlovid®: 2 (0.7%), Control: 3 (1.1%), OR 1.51; 95%CI, 0.25-9.09; p=0.999]. There was no significant reduction in hospitalisation duration, intensive care unit admission events or supplementary oxygen requirement in the treatment arm. Ethnicity, COVID-19 severity at diagnosis, comorbidities and vaccination status were predictors of hospitalisation events. CONCLUSION: In this two-arm study, Paxlovid® did not significantly lower the incidence of hospitalisation, all-cause death and the need for supplemental oxygen. Adverse effects were frequent but not severe. Paxlovid® efficacy varied across settings and populations, warranting further real-world investigations.


Assuntos
COVID-19 , Ritonavir , Adulto , Humanos , Ritonavir/uso terapêutico , Tratamento Farmacológico da COVID-19 , Estudos Prospectivos , Hospitalização
5.
Blood ; 135(26): 2337-2353, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32157296

RESUMO

Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.


Assuntos
Crise Blástica/genética , Regulação Leucêmica da Expressão Gênica/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Complexo Repressor Polycomb 1/fisiologia , Complexo Repressor Polycomb 2/fisiologia , Diferenciação Celular , Imunoprecipitação da Cromatina , Metilação de DNA , Conjuntos de Dados como Assunto , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Dosagem de Genes , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 2/genética , Transcriptoma , Sequenciamento do Exoma , Sequenciamento Completo do Genoma
6.
Haematologica ; 107(2): 358-370, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34615339

RESUMO

Cancer treatment is constantly evolving from a one-size-fits-all towards bespoke approaches for each patient. In certain solid cancers, including breast and lung, tumor genome profiling has been incorporated into therapeutic decision-making. For chronic phase chronic myeloid leukemia (CML), while tyrosine kinase inhibitor therapy is the standard treatment, current clinical scoring systems cannot accurately predict the heterogeneous treatment outcomes observed in patients. Biomarkers capable of segregating patients according to outcome at diagnosis are needed to improve management, and facilitate enrollment in clinical trials seeking to prevent blast crisis transformation and improve the depth of molecular responses. To this end, gene expression (GE) profiling studies have evaluated whether GE signatures at diagnosis are clinically informative. Patient material from a variety of sources has been profiled using microarrays, RNA sequencing and, more recently, single-cell RNA sequencing. However, differences in the cell types profiled, the technologies used, and the inherent complexities associated with the interpretation of genomic data pose challenges in distilling GE datasets into biomarkers with clinical utility. The goal of this paper is to review previous studies evaluating GE profiling in CML, and explore their potential as risk assessment tools for individualized CML treatment. We also review the contribution that acquired mutations, including those seen in clonal hematopoiesis, make to GE profiles, and how a model integrating contributions of genetic and epigenetic factors in resistance to tyrosine kinase inhibitors and blast crisis transformation can define a route to GE-based biomarkers. Finally, we outline a four-stage approach for the development of GE-based biomarkers in CML.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Biomarcadores , Crise Blástica/tratamento farmacológico , Epigênese Genética , Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
7.
Int J Mol Sci ; 23(3)2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35163134

RESUMO

Multiple myeloma (MM) is a hematological disease marked by abnormal growth of B cells in bone marrow. Inherent chromosomal instability and DNA damage are major hallmarks of MM, which implicates an aberrant DNA repair mechanism. Studies have implicated a role for CDK12 in the control of expression of DNA damage response genes. In this study, we examined the effect of a small molecule inhibitor of CDK12-THZ531 on MM cells. Treatment of MM cells with THZ531 led to heightened cell death accompanied by an extensive effect on gene expression changes. In particular, we observed downregulation of genes involved in DNA repair pathways. With this insight, we extended our study to identify synthetic lethal mechanisms that could be exploited for the treatment of MM cells. Combination of THZ531 with either DNA-PK inhibitor (KU-0060648) or PARP inhibitor (Olaparib) led to synergistic cell death. In addition, combination treatment of THZ531 with Olaparib significantly reduced tumor burden in animal models. Our findings suggest that using a CDK12 inhibitor in combination with other DNA repair inhibitors may establish an effective therapeutic regimen to benefit myeloma patients.


Assuntos
Anilidas/farmacologia , Biomarcadores Tumorais/genética , Reparo do DNA , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Pirimidinas/farmacologia , Mutações Sintéticas Letais , Animais , Apoptose , Proteína BRCA1/genética , Proteína BRCA2/genética , Proliferação de Células , Quimioterapia Combinada , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Med J Malaysia ; 77(3): 292-299, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35638484

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that is commonly associated with extra-articular manifestations. Pulmonary disease is frequently encountered, which causes serious morbidity and increases mortality. Among the pulmonary manifestations, interstitial lung disease (ILD) is the most common. We aimed to analyse the frequency and clinical characteristics of a cohort of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD); describe the radiological features of ILD; identify predictive factors for developing ILD; and evaluate the impact of ILD on patient survival. MATERIALS AND METHODS: This retrospective study included all patients with RA who attended the rheumatology clinic of Kuala Lumpur Hospital from 2018 to 2021. RA-ILD was identified from high-resolution computed tomography (HRCT) thorax images evaluated by two thoracic radiologists. Descriptive and logistic regression analyses were conducted using SPSS version 26.0. RESULTS: Of the 732 patients with RA, 7.4% (54) had ILD. Univariate analysis identified Indian ethnicity, rheumatoid factor (RF) positivity, anti-cyclic citrullinated peptide antibody titre, and diabetes mellitus as risk factors for developing ILD. Multivariable logistic regression showed that RA-ILD was positively associated with female gender [Adjusted odds ratio (aOR)=3.40 (95% confidence interval (CI): 1.04, 11.17)], Indian ethnicity [aOR=2.03 (95% CI: 1.16, 3.57)], and positive RF [aOR=2.39 (95% CI: 1.18, 4.87)]. Nonspecific interstitial pneumonia (NSIP) was the predominant HRCT pattern. Majority of patients had limited disease (<20% of lung involvement) and good functional exercise capacity. There was significant improvement (p<0.05) in mean forced vital capacity (FVC) following treatment with immunosuppressive agents. No mortality occurred throughout the median follow-up period of 3.2 years. CONCLUSION: RA patients of Indian ethnicity had an increased risk for developing ILD, suggesting that genetics play a crucial role. Other independent predictors were female gender and RF positivity. The pattern of HRCT thorax and extent of lung involvement influenced prognosis and survival of patients with RA-ILD.


Assuntos
Artrite Reumatoide , Doenças Pulmonares Intersticiais , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico por imagem , Estudos de Coortes , Etnicidade , Feminino , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/etiologia , Masculino , Estudos Retrospectivos
9.
Med J Malaysia ; 76(4): 466-473, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34305106

RESUMO

INTRODUCTION: Pregnancy in women with systemic lupus erythematosus (SLE) is known to be associated with adverse pregnancy outcomes (APO). We aimed to determine the frequency of APO, the associated variables and predictors. MATERIALS AND METHODS: This retrospective study included all pregnancies seen at the SLE Clinic, Kuala Lumpur Hospital from January 2008 to May 2020. Maternal outcomes included SLE flare during pregnancy, preeclampsia and eclampsia. Foetal outcomes included foetal loss, preterm birth and small-for-gestational age (SGA) neonates. Clinical and laboratory variables were examined. Variables from univariate analysis were entered into logistic regression model. Odds ratio and 95% confidence interval were reported. RESULTS: Of the 131 pregnancies, 106 (80.9%) were live births. Twenty-six (24.5%) babies were born preterm and 35 (33%) neonates were SGA. Twenty-four (18.3%) women had disease flare during pregnancy, with the majority (22/24) being mild to moderate flares. Four women experienced preeclampsia while none had eclampsia. Predictors of adverse maternal outcomes included high SLEDAI-2K score, proteinuria and hypocomplementemia within 6 months before conception and during pregnancy; history of lupus nephritis (LN), pre-existing hypertension, antiphospholipid syndrome (APS), antiphospholipid antibodies, anti-Ro antibody and anti-RNP antibody. Predictors of adverse foetal outcomes comprised APS, preeclampsia, anti-Sm antibody, history of neuropsychiatric systemic lupus erythematosus (NPSLE) and azathioprine use. CONCLUSION: Pregnancy in SLE women is best deferred until disease activity is in remission for at least 6 months before conception. A history of LN is associated with a 3-fold risk of renal flare during pregnancy. Haematological abnormalities are rare in disease flare during pregnancy.


Assuntos
Lúpus Eritematoso Sistêmico , Complicações na Gravidez , Nascimento Prematuro , Feminino , Humanos , Recém-Nascido , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Malásia/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Estudos Retrospectivos
10.
Cancer Sci ; 111(2): 561-570, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31782583

RESUMO

Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) harboring BIM deletion polymorphism (BIM deletion) have poor responses to EGFR TKI. Mechanistically, the BIM deletion induces preferential splicing of the non-functional exon 3-containing isoform over the functional exon 4-containing isoform, impairing TKI-induced, BIM-dependent apoptosis. Histone deacetylase inhibitor, vorinostat, resensitizes BIM deletion-containing NSCLC cells to EGFR-TKI. In the present study, we determined the safety of vorinostat-gefitinib combination and evaluated pharmacodynamic biomarkers of vorinostat activity. Patients with EGFR-mutated NSCLC with the BIM deletion, pretreated with EGFR-TKI and chemotherapy, were recruited. Vorinostat (200, 300, 400 mg) was given daily on days 1-7, and gefitinib 250 mg was given daily on days 1-14. Vorinostat doses were escalated based on a conventional 3 + 3 design. Pharmacodynamic markers were measured using PBMC collected at baseline and 4 hours after vorinostat dose on day 2 in cycle 1. No dose-limiting toxicities (DLT) were observed in 12 patients. We determined 400 mg vorinostat as the recommended phase II dose (RP2D). Median progression-free survival was 5.2 months (95% CI: 1.4-15.7). Disease control rate at 6 weeks was 83.3% (10/12). Vorinostat preferentially induced BIM mRNA-containing exon 4 over mRNA-containing exon 3, acetylated histone H3 protein, and proapoptotic BIMEL protein in 11/11, 10/11, and 5/11 patients, respectively. These data indicate that RP2D was 400 mg vorinostat combined with gefitinib in BIM deletion/EGFR mutation double-positive NSCLC. BIM mRNA exon 3/exon 4 ratio in PBMC may be a useful pharmacodynamic marker for treatment.


Assuntos
Proteína 11 Semelhante a Bcl-2/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Vorinostat/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Esquema de Medicação , Receptores ErbB/genética , Feminino , Gefitinibe/farmacocinética , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Deleção de Sequência , Análise de Sobrevida , Resultado do Tratamento , Vorinostat/farmacocinética
11.
Phys Rev Lett ; 124(12): 122003, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32281834

RESUMO

We report on a new measurement of the beam transverse single spin asymmetry in electron-proton elastic scattering, A_{⊥}^{ep}, at five beam energies from 315.1 to 1508.4 MeV and at a scattering angle of 30°<θ<40°. The covered Q^{2} values are 0.032, 0.057, 0.082, 0.218, 0.613 (GeV/c)^{2}. The measurement clearly indicates significant inelastic contributions to the two-photon-exchange (TPE) amplitude in the low-Q^{2} kinematic region. No theoretical calculation is able to reproduce our result. Comparison with a calculation based on unitarity, which only takes into account elastic and πN inelastic intermediate states, suggests that there are other inelastic intermediate states such as ππN, KΛ, and ηN. Covering a wide energy range, our new high-precision data provide a benchmark to study those intermediate states.

12.
Med J Malaysia ; 75(2): 164-166, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32281599

RESUMO

We present a rare case of post-antiretroviral therapy (ART) paradoxically worsening of radiological findings in a patient with advanced HIV-infection on treatment for Rhodococcus pneumonia who was misdiagnosed with pulmonary tuberculosis. Despite clinical improvement, serial chest radiographs showed deteriorations a month after starting ART. This was attributed to Immune Reconstitution Inflammatory Syndrome (IRIS) which spontaneously resolved without any treatment.


Assuntos
Infecções por Actinomycetales/diagnóstico , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Síndrome Inflamatória da Reconstituição Imune/fisiopatologia , Radiografia Torácica , Rhodococcus , Adulto , Erros de Diagnóstico , Humanos , Síndrome Inflamatória da Reconstituição Imune/diagnóstico por imagem , Masculino , Avaliação de Resultados em Cuidados de Saúde
13.
Med J Malaysia ; 75(4): 349-355, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32723993

RESUMO

OBJECTIVES: High rates of syphilis have been reported worldwide among men who have sex with men (MSM). This study aims to describe the clinical pattern and treatment response of syphilis among human immunodeficiency virus (HIV)-infected MSM in Malaysia. METHODS: This is a retrospective study on all HIV-infected MSM with syphilis between 2011 and 2015. Data was collected from case notes in five centres namely Hospital Kuala Lumpur, Hospital Sultanah Bahiyah, Hospital Umum Sarawak, University of Malaya Medical Centre and Hospital Sungai Buloh. RESULTS: A total of 294 HIV seropositive MSM with the median age of 29 years (range 16-66) were confirmed to have syphilis. Nearly half (47.6%) were in the age group of 20-29 years. About a quarter (24.1%) was previously infected with syphilis. Eighty-three patients (28.2%) had other concomitant sexually transmitted infection with genital warts being the most frequently reported (17%). The number of patients with early and late syphilis in our cohort were almost equal. The median pre-treatment non-treponemal antibody titre (VDRL or RPR) for early syphilis (1:64) was significantly higher than for late syphilis (1:8) (p<0.0001). The median CD4 count and the number of patients with CD4 <200/µl in early syphilis were comparable to late syphilis. Nearly four-fifth (78.9%) received benzathine-penicillin only, 5.8% doxycycline, 1.4% Cpenicillin, 1% procaine penicillin, and 12.4% a combination of the above medications. About 44% received treatment and were lost to follow-up. Among those who completed 1 -year follow-up after treatment, 72.3% responded to treatment (serological non-reactive - 18.2%, four-fold drop in titre - 10.9%; serofast - 43.6%), 8.5% failed treatment and 17% had re-infection. Excluding those who were re-infected, lost to follow-up and died, the rates of treatment failure were 12.1% and 8.8% for early and late syphilis respectively (p=0.582). CONCLUSION: The most common stage of syphilis among MSM with HIV was latent syphilis. Overall, about 8.5% failed treatment at 1-year follow-up.


Assuntos
Infecções por HIV , Homossexualidade Masculina , Sífilis , Adolescente , Adulto , Idoso , Comorbidade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Malásia/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sífilis/tratamento farmacológico , Sífilis/epidemiologia , Adulto Jovem
14.
Int Nurs Rev ; 66(4): 514-522, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31184377

RESUMO

BACKGROUND: The ageing population and the changing disease profile have been driving the demand for community nurses. However, few nursing students in Singapore aspire to have a career in community nursing following graduation. OBJECTIVES: To explore undergraduate nursing students' perceptions of a career in community nursing and to identify strategies to promote community nursing among nursing students. METHODS: An exploratory qualitative design was used. Four focus group discussions were conducted with a purposive sample of 24 undergraduate nursing students from a university. Interview transcripts were analysed using thematic analysis. FINDINGS: Four key themes emerged as follows: 'mid-life career', 'limited career progression', 'a difficult transition' and 'international nurses-dominated workforce'. DISCUSSION: While most participants rejected a career in community nursing immediately after graduation, they planned to join it at the later stages of their lives to accommodate changing life priorities. Limited career progression and increased difficulty in career transition from community nursing to acute care nursing were identified as deterrent factors in the participants' choices of community nursing as a career. Feelings of marginalization and a lack of role models in community nursing were perceived to be the result of the international nurses-dominated community workforce. CONCLUSION: Community nursing remains an underrated career. There is a need to foster an optimistic career outlook and mobility in community nursing to entice nursing students into this career track. IMPLICATIONS FOR NURSING POLICY: Strategies to enhance community nursing recruitment should focus on providing more quality and diverse community placement opportunities in various community care settings, implementing a clearly defined career developmental plan to elucidate the role of community nurses, and improving community care and cultural competencies to develop a skilled and diverse community nursing workforce.


Assuntos
Escolha da Profissão , Enfermagem em Saúde Comunitária/educação , Estudantes de Enfermagem/psicologia , Mobilidade Ocupacional , Bacharelado em Enfermagem , Feminino , Grupos Focais , Humanos , Masculino , Pesquisa Qualitativa , Singapura , Adulto Jovem
15.
Med J Malaysia ; 74(2): 116-120, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31079121

RESUMO

INTRODUCTION: This study evaluates factors that influence door to operation theatre (OT) time in a tertiary referral centre following activation of trauma team. Specific factors observed in this study were association of the injury severity score (ISS), activation of trauma team and the number of referred specialty to door to operation theatre time. METHODS: Retrospective chart review that evaluates all trauma patients which required immediate operative intervention from January 2011 to December 2015. Trauma patients were selected from the resuscitation log book and data were collected by chart review of selected patients. RESULTS: Only 5 out of 279 patients (1.8%) achieved optimal door to OT time. (<60 minutes) Mean door to OT time was 299.27 minutes (95% CI: 280.52, 318.52). Trauma team activation has shown significant improvement in door to OT time (p=0.047). Time of multiple team referrals (p=0.023) and time of operative decision (p<0.001) both had significant impact on door to OT time. Other factors included were demographics, ISS score, Glasgow Coma Scale (GCS), mechanism of injury and systolic blood pressure on arrival all which showed no significance. CONCLUSION: Trauma team activation in a tertiary centre improved trauma care by reducing door to OT time to less than 60 minutes. Implementation of an effective trauma team activation system in all hospitals throughout Malaysia is recommended.


Assuntos
Salas Cirúrgicas/estatística & dados numéricos , Centros de Traumatologia/estatística & dados numéricos , Ferimentos e Lesões/cirurgia , Adulto , Feminino , Escala de Coma de Glasgow , Humanos , Escala de Gravidade do Ferimento , Masculino , Ressuscitação/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Tempo
16.
Med J Malaysia ; 74(6): 492-498, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31929474

RESUMO

INTRODUCTION: Numerous studies have found that a majority of systemic lupus erythematosus (SLE) patients have suboptimal vitamin D levels. The major contributory factor is most likely attributed to sun protection measures in order to avoid SLE flares. The objectives of this research included the assessment of vitamin D status and its association with clinical manifestations of SLE, cardiovascular risk factors, autoantibodies, SLE disease activity and damage accrual. METHOD: This retrospective study involved SLE patients who attended the Rheumatology Clinic at the Hospital Kuala Lumpur from January 2014 to December 2016. Vitamin D was categorised as normal, insufficient or deficient, and the clinical variables were compared across vitamin D categories with chi-squared tests and Pearson correlation coefficient. RESULTS: We included 216 patients. The mean 25(OH)D concentration was 51.3(Standard Deviation; SD 14.8) nmol/L. Fifty (23.1%) patients had vitamin D deficiency, 120 (55.6%) had vitamin D insufficiency, while 46 (21.3%) had adequate vitamin D levels. There were statistically significant associations between vitamin D status and ethnic group, lupus nephritis and hypertension. No correlations were observed between vitamin D status with SLEDAI score (Pearson correlation coefficient -0.015, p=0.829) as well as SDI score (Pearson correlation coefficient -0.017, p=0.801). CONCLUSION: SLE patients should be screened for vitamin D concentrations and their levels optimised.


Assuntos
Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/complicações , Deficiência de Vitamina D/sangue , Vitamina D/farmacocinética , Adulto , Feminino , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/etiologia , Vitaminas/farmacocinética
17.
Med J Malaysia ; 74(6): 558-560, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31929491

RESUMO

Both diffuse idiopathic skeletal hyperostosis and ankylosing spondylitis present with similar clinical manifestations of restricted spinal mobility and postural abnormalities, and radiographic resemblances including axial spine involvement and enthesopathy. Nonetheless, they are two entirely different diseases. We report an unusual case of DISH in a young woman whose diagnosis was established based on radiologic features. This case report aims to highlight the under-recognised radiologic aspects of the differential diagnosis between DISH and AS in order to avoid an inaccurate diagnosis.


Assuntos
Vértebras Cervicais/diagnóstico por imagem , Hiperostose Esquelética Difusa Idiopática/diagnóstico , Vértebras Lombares/diagnóstico por imagem , Síndrome do Ovário Policístico/complicações , Espondilite Anquilosante/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Hiperostose Esquelética Difusa Idiopática/complicações , Síndrome do Ovário Policístico/diagnóstico , Radiografia
18.
Phys Rev Lett ; 119(1): 012501, 2017 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-28731753

RESUMO

New measurements of the beam normal single spin asymmetry in the electron elastic and quasielastic scattering on the proton and deuteron, respectively, at large backward angles and at ⟨Q^{2}⟩=0.22 (GeV/c)^{2} and ⟨Q^{2}⟩=0.35 ( GeV/c)^{2} are reported. The experimentally observed asymmetries are compared with the theoretical calculation of Pasquini and Vanderhaeghen [Phys. Rev. C 70, 045206 (2004).PRVCAN0556-281310.1103/PhysRevC.70.045206]. The agreement of the measurements with the theoretical calculations shows a dominance of the inelastic intermediate excited states of the nucleon, πN and the Δ resonance. The measurements explore a new, important parameter region of the exchanged virtual photon virtualities.

19.
Br J Dermatol ; 177(2): 531-534, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28029683

RESUMO

Cronkhite-Canada syndrome is an acquired inflammatory polyposis syndrome in which alopecia, onychomadesis and hyperpigmentation occur concurrently with gastrointestinal symptoms. The pathophysiology of alopecia in Cronkhite-Canada syndrome has not been definitively elucidated. We present evidence for alopecia areata incognita as a possible mechanism of hair loss.


Assuntos
Alopecia em Áreas/complicações , Polipose Intestinal/complicações , Transtornos da Pigmentação/complicações , Anti-Inflamatórios não Esteroides/administração & dosagem , Feminino , Glucocorticoides/administração & dosagem , Humanos , Mesalamina/administração & dosagem , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Síndrome , Vitaminas/administração & dosagem
20.
Phys Chem Chem Phys ; 19(17): 10748-10752, 2017 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-28111681

RESUMO

Nanodiamonds with dimensions down to a few tens of nanometers containing nitrogen-vacancy (NV) color centers have revealed their potential as powerful and versatile quantum sensors with a unique combination of spatial resolution and sensitivity. The NV centers allow transducing physical properties, such as strain, temperature, and electric or magnetic field, to an optical transition that can be detected in the single photon range. For example, this makes it possible to sense a single electron spin or a few nuclear spins by detecting their magnetic resonance. The location and orientation of these defects with respect to the diamond surface play a crucial role in interpreting the data and predicting their sensitivities. Despite its relevance, the geometry of these nanodiamonds has never been thoroughly investigated. Without accurate data, spherical models have been applied to interpret or predict results in the past. With the use of High Resolution Transmission Electron Microscopy (HR-TEM), Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM), we investigated nanodiamonds with an average hydrodynamic diameter of 25 nm (the most common type for quantum sensing) and found a flake-like geometry, with 23.2 nm and 4.5 nm being the average lateral and vertical dimensions. We have also found evidence for a preferred crystallographic orientation of the main facet in the (110) direction. Furthermore, we discuss the consequences of this difference in geometry on diamond-based applications. Shape not only influences the creation efficiency of nitrogen-vacancy centers and their quantum coherence properties (and thus sensing performance), but also the optical properties of the nanodiamonds, their interaction with living cells, and their surface chemistry.

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