An algorithm to identify patients aged 0-3 with rare genetic disorders.

BACKGROUND: With over 7000 Mendelian disorders, identifying children with a specific rare genetic disorder diagnosis through structured electronic medical record data is challenging given incompleteness of records, inaccurate medical diagnosis coding, as well as heterogeneity in clinical symptoms and procedures for specific disorders. We sought to develop a digital phenotyping algorithm (PheIndex) using electronic medical records to identify children aged 0-3 diagnosed with genetic disorders or who present with illness with an increased risk for genetic disorders. RESULTS: Through expert opinion, we established 13 criteria for the algorithm and derived a score and a classification. The performance of each criterion and the classification were validated by chart review. PheIndex identified 1,088 children out of 93,154 live births who may be at an increased risk for genetic disorders. Chart review demonstrated that the algorithm achieved 90% sensitivity, 97% specificity, and 94% accuracy. CONCLUSIONS: The PheIndex algorithm can help identify when a rare genetic disorder may be present, alerting providers to consider ordering a diagnostic genetic test and/or referring a patient to a medical geneticist.

Decolonising medical knowledge - The case of breast cancer and ethnicity in the UK.

National and global efforts have led to significant improvements in breast health and diagnosis, globally (Lukong, 2017). These achievements, however, are not even. Focusing on the case of breast cancer in the UK, we argue that enduring forms of medical racism leave Black women more vulnerable to advanced forms of the disease, explaining higher mortality rates and later-stage diagnosis. In particular, we show how a lack of dedicated policy, inadequate data collection, and a lack of representation conspire to place Black women at additional and unnecessary risk of worse breast cancer outcomes. We thus propose key recommendations to address the ethnic disparities in and make steps to decolonise breast cancer care. These are early screening for at-risk groups, community-led interventions, and more and better representation of Black women and their risks in breast cancer resources.

A block randomized controlled trial of a brief smoking cessation counselling and advice through short message service on participants who joined the Quit to Win Contest in Hong Kong.

The present trial examined the effectiveness of brief interventions for smokers who joined the Hong Kong Quit to Win Contest to quit smoking. A block randomized controlled trial allocated 1003 adult daily smokers to three groups: (i) The TEL group (n = 338) received a 5-min nurse-led telephone counselling; (ii) The SMS group (n = 335) received eight text messages through mobile phone and (iii) The CONTROL group (n = 330) did not receive the above interventions. Participants with biochemically verified abstinence at 6-month follow-up could receive cash incentive. The primary outcome was the self-reported 7-day point prevalence (PP) of tobacco abstinence at 6-month follow-up. The abstinence rate in the TEL, SMS and CONTROL group was 22.2, 20.6 and 20.3%, respectively (P for TEL versus CONTROL = 0.32; P for SMS versus CONTROL = 0.40). When abstinence at 2-, 6- and 12-month follow-up was modelled simultaneously, the TEL group had a higher abstinence than the CONTROL group (Adjusted OR = 1.38, 95% CI = 1.01-1.88, P = 0 .04). In the Quit to Win Contest, the brief telephone counselling might have increased abstinence, but the text messages had no significant effect. Further studies on intensive intervention and interactive messaging services are warranted.

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N6-methyladenosine demethylase FTO.

The AlkB family of nucleic acid demethylases are of intense biological and medical interest because of their roles in nucleic acid repair and epigenetic modification. However their functional and molecular mechanisms are unclear, hence, there is strong interest in developing selective inhibitors for them. Here we report the identification of key residues within the nucleotide-binding sites of the AlkB subfamilies that likely determine their substrate specificity. We further provide proof of principle that a strategy exploiting these inherent structural differences can enable selective and potent inhibition of the AlkB subfamilies. This is demonstrated by the first report of a subfamily-selective and cell-active FTO inhibitor 12. The distinct selectivity of 12 for FTO against other AlkB subfamilies and 2OG oxygenases shall be of considerable interest with regards to its potential use as a functional probe. The strategy outlined here is likely applicable to other AlkB subfamilies, and, more widely, to other 2OG oxygenases.

Concordance between telephone survey classification and face-to-face interview diagnosis of one-year major depressive episode in Hong Kong.

BACKGROUND: Community-based telephone surveys of depression have generated reliable findings but their concordance with standardized clinical diagnostic interviews is uncommonly examined, especially in non-western populations. METHOD: 106 consenting participants from a previous telephone-based population survey of major depressive episode (MDE) using a structured questionnaire were re-assessed face-to-face by clinical interviewers using the Structured Clinical Interview for DSM-IV Axis I Disorder (SCID-I). Receiver operating characteristic and other predictive indicators were used to investigate the concordance between the telephone survey instrument and SCID interview. RESULT: The telephone survey instrument adequately classified MDE when the DSM-IV symptom number standard was fulfilled at moderate to severe levels of distress and impairment. It performed best when the cut-off was set at a severe level of distress or impairment in any one of four domains of functioning (AUC=0.76). Feeling useless, fatigue, loss of motivation and difficulty in concentration were the most prominent items for increasing the certainty of SCID-MDE diagnosis. CONCLUSION: Classification of MDE by telephone-based structured interview of MDE exhibited generally good agreement with face-to-face clinical interview diagnosis in the Chinese population of Hong Kong. Further research on the telephone-based methodology should address inter-rater reliability, specificity of diagnosis, and variability of concordance across different mental disorder diagnoses and criteria of clinically significant impairment.

Concordance between telephone survey classification and face-to-face structured clinical interview in the diagnosis of generalized anxiety disorder in Hong Kong.

Telephone surveys of estimating mental disorders have been found to generate comparable findings to large-scale community surveys but the concordance between telephone instruments and clinical interviews is rarely examined. In this study, 100 Chinese respondents who had taken part in a telephone-based population survey of generalized anxiety disorder (GAD) in Hong Kong were administered the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) by clinical interviewers. The discriminability and predictive indicators of the telephone survey instrument were assessed using receiver operating characteristic analysis. Results showed that the telephone survey instrument identified individuals with a positive SCID diagnosis of GAD better than those without. Although its individual questions performed well in identifying the endorsement of the corresponding core SCID criterion of GAD, further studies are needed to find out the optimal combination of questions in the telephone instrument for identifying GAD in community surveys.

In vivo modulation of T cell responses and protective immunity by TCR antagonism during infection.

Infectious agents are known to express altered peptide ligands that antagonize T cells in vitro; however, direct evidence of TCR antagonism during infection is still lacking, and its importance in the context of infection remains to be established. In this study, we used a murine model of infection with recombinant Listeria monocytogenes and addressed three issues that are critical for assessing the role of TCR antagonism in the modulation of the immune response. First, we demonstrated that the antagonist peptide efficiently inhibited the ability of the agonist to prime naive TCR-transgenic T cells in vivo. Second, we showed clonal memory T cells were antagonized during recall responses, resulting in loss of protective immunity. Lastly, we observed that even in the context of a polyclonal response, TCR antagonism greatly inhibits the agonist-specific response, leading to altered hierarchy of immunodominance and reduced T cell memory and protective immunity. These results provide direct evidence of clonal TCR antagonism of naive and memory CD8 T cells during infection and demonstrate the effect of TCR antagonism on protective immunity. Thus, agonist/antagonist interactions may play an important role in determining the immunodominance and repertoire of T cell targets, and evaluation of immune responses and vaccine strategies may require examination of not only agonists but also antagonists and their interactions during an infection.

Activation of antigen-specific CD8 T cells results in minimal killing of bystander bacteria.

Memory CD8 T cells play a critical role in protective immunity against intracellular pathogens. In addition to their ability to specifically recognize and lyse infected targets, activated CD8 T cells secrete cytokines that induce phagocytic cells to engulf and kill bacterial pathogens. In this study, we asked whether activation of Ag-specific CD8 T cells results in nonspecific killing of bystander bacteria during a mixed infection. Mice with epitope-specific memory CD8 T cells were coinfected with two isogenic strains of recombinant Listeria monocytogenes that differ in the cognate epitope. Recall responses by epitope-specific CD8 T cells rapidly inhibited the growth of epitope-bearing bacteria, impeding the course of infection within 6 h after challenge. This rapid inhibition was highly specific and did not affect the growth of coinfecting bacteria without the epitope. CTL recall did not enhance activation of innate immune cells, as evidenced by the absence of inducible NO synthase production in infectious foci. Our observations demonstrate the remarkable specificity of the bactericidal mechanisms of CTL and reveal the possibility for escape mutants to prevail in the hostile environment of a specific immune response. This implication has a bearing on subunit vaccine design strategies and understanding failure of immunization against bacterial infection.

Selective depletion of nonspecific T cells during the early stage of immune responses to infection.

Transient T cell depletion occurs before the development of an effective immune response to infection. In this study we show that most T cells, regardless of specificity, are induced to express early activation markers soon after infection with Listeria monocytogenes or lymphocytic choriomeningitis virus. Ag-specific T cells are further activated to display late activation markers and undergo extensive proliferation. As Ag-specific T cells begin to expand, nonspecific T cells are depleted en masse and exhibit no sign of further activation or proliferation before their depletion. This selective depletion of nonspecific T cells is due to in situ death via apoptosis, as visualized by confocal microscopy. Thus, early activation and subsequent depletion of nonspecific T cells are integral parts of the immune response to proinflammatory infections. These results have important implications for our understanding of early events in the development of a robust T cell response.