RACER-m leverages structural features for sparse T cell specificity prediction.

Reliable prediction of T cell specificity against antigenic signatures is a formidable task, complicated by the immense diversity of T cell receptor and antigen sequence space and the resulting limited availability of training sets for inferential models. Recent modeling efforts have demonstrated the advantage of incorporating structural information to overcome the need for extensive training sequence data, yet disentangling the heterogeneous TCR-antigen interface to accurately predict MHC-allele-restricted TCR-peptide interactions has remained challenging. Here, we present RACER-m, a coarse-grained structural model leveraging key biophysical information from the diversity of publicly available TCR-antigen crystal structures. Explicit inclusion of structural content substantially reduces the required number of training examples and maintains reliable predictions of TCR-recognition specificity and sensitivity across diverse biological contexts. Our model capably identifies biophysically meaningful point-mutant peptides that affect binding affinity, distinguishing its ability in predicting TCR specificity of point-mutants from alternative sequence-based methods. Its application is broadly applicable to studies involving both closely related and structurally diverse TCR-peptide pairs.

Broad human and animal coronavirus neutralisation by SARS-CoV-2 S2-targeted vaccination

Several common-cold coronaviruses (HCoVs) are endemic in humans and several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current Coronavirus disease 2019 (COVID-19) pandemic. Whilst antibody cross-reactivity with the Spike glycoproteins (S) of diverse coronaviruses has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to or mediate protection, when induced naturally or through vaccination. Using a mouse model, we show that prior HCoV-OC43 S immunity primes neutralising antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, mouse vaccination with SARS-CoV-2 S2 elicits antibodies that neutralise diverse animal and human alphacoronaviruses and betacoronaviruses in vitro, and protects against SARS-CoV-2 challenge in vivo. Lastly, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induces stronger and broader neutralising antibody response than booster Wuhan S vaccination, suggesting it may prevent repertoire focusing caused by repeated homologous vaccination. The data presented here establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern (VOCs), as well as to unpredictable, yet inevitable future coronavirus zoonoses.

Alternate careers for medical graduates and house officers in Malaysia.

INTRODUCTION: In recent years, many unresolved issues pertaining to house officers in Malaysia have led to a longer waiting time and a 'glut' of medical graduates with a surprising 20% dropout amongst those who join the housemanship programme. This appears to reflect the changing times, mindsets and work expectations of millennials who comprise this cohort reflecting a need to consider possibilities of career shifts especially so in these uncertain times. This study explores the perceptions, awareness and interest in alternative career options amongst recent graduates and house officers. MATERIALS AND METHODS: This was a study done between 2018 and 2019 using a questionnaire which was shared on various social platforms. Data analysis was done using Excel spreadsheet. RESULTS: A total of 450 house officers and 657 medical graduates responded. Expectedly 66.8% claimed lifelong passion whilst another 12.1% claimed family influence as their reason to do medicine. Most were aware of their career challenges and 40% of them were keen to consider career change and reskilling indicating a possible shift from traditional expectations of a medical career. CONCLUSION: Whilst medicine is often considered a true calling, current challenges will require mental and emotional flexibility to explore other career opportunities. Thus, engagement programmes should be directed at medical graduates and house officers to identify and support those open to career transitions. This will help address current issues of internship bottleneck and rising dropout rates amongst internees. Early career change engagements will give them insight into their true career goals whilst opening up opportunities for those who wish to change.

Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains

We examined the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.7 that arose in the United Kingdom and spread globally. Antibodies elicited by B.1.1.7 infection exhibited significantly reduced recognition and neutralisation of parental strains or of the South Africa B.1.351 variant, than of the infecting variant. The drop in cross-reactivity was more pronounced following B.1.1.7 than parental strain infection, indicating asymmetric heterotypic immunity induced by SARS-CoV-2 variants.

Favourable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases

Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained and the impact of underlying immune dysfunction or suppression unknown. Here, we examined the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE), against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group. Despite immune dysfunction and immunosuppressive treatment, JIA, JDM and JSLE patients mounted comparable or stronger responses than healthier peers, dominated by IgG antibodies to HCoV-OC43 spike, and harboured IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM and JSLE patients, arguing against increased exposure. Consequently, autoimmune rheumatic diseases and their treatment were associated with a favourable ratio of spike to nucleoprotein antibodies.

Rapid Assessment of T-Cell Receptor Specificity of the Immune Repertoire.

Accurate assessment of TCR-antigen specificity at the whole immune repertoire level lies at the heart of improved cancer immunotherapy, but predictive models capable of high-throughput assessment of TCR-peptide pairs are lacking. Recent advances in deep sequencing and crystallography have enriched the data available for studying TCR-p-MHC systems. Here, we introduce a pairwise energy model, RACER, for rapid assessment of TCR-peptide affinity at the immune repertoire level. RACER applies supervised machine learning to efficiently and accurately resolve strong TCR-peptide binding pairs from weak ones. The trained parameters further enable a physical interpretation of interacting patterns encoded in each specific TCR-p-MHC system. When applied to simulate thymic selection of an MHC-restricted T-cell repertoire, RACER accurately estimates recognition rates for tumor-associated neoantigens and foreign peptides, thus demonstrating its utility in helping address the large computational challenge of reliably identifying the properties of tumor antigen-specific T-cells at the level of an individual patient's immune repertoire.

Alternate careers for medical graduates and house officers in Malaysia

@#Introduction: In recent years, many unresolved issues pertaining to house officers in Malaysia have led to a longer waiting time and a ‘glut’ of medical graduates with a surprising 20% dropout amongst those who join the housemanship programme. This appears to reflect the changing times, mindsets and work expectations of millennials who comprise this cohort reflecting a need to consider possibilities of career shifts especially so in these uncertain times. This study explores the perceptions, awareness and interest in alternative career options amongst recent graduates and house officers. Materials and Methods: This was a study done between 2018 and 2019 using a questionnaire which was shared on various social platforms. Data analysis was done using Excel spreadsheet. Results: A total of 450 house officers and 657 medical graduates responded. Expectedly 66.8% claimed lifelong passion whilst another 12.1% claimed family influence as their reason to do medicine. Most were aware of their career challenges and 40% of them were keen to consider career change and reskilling indicating a possible shift from traditional expectations of a medical career. Conclusion: Whilst medicine is often considered a true calling, current challenges will require mental and emotional flexibility to explore other career opportunities. Thus, engagement programmes should be directed at medical graduates and house officers to identify and support those open to career transitions. This will help address current issues of internship bottleneck and rising dropout rates amongst internees. Early career change engagements will give them insight into their true career goals whilst opening up opportunities for those who wish to change.

Adaptive immunity to SARS-CoV-2 in cancer patients: The CAPTURE study

There is a pressing need to characterise the nature, extent and duration of immune response to SARS-CoV-2 in cancer patients and inform risk-reduction strategies and preserve cancer outcomes. CAPTURE is a prospective, longitudinal cohort study of cancer patients and healthcare workers (HCWs) integrating longitudinal immune profiling and clinical annotation. We evaluated 529 blood samples and 1051 oronasopharyngeal swabs from 144 cancer patients and 73 HCWs and correlated with >200 clinical variables. In patients with solid cancers and HCWs, S1-reactive and neutralising antibodies to SARS-CoV-2 were detectable five months post-infection. SARS-CoV-2-specific T-cell responses were detected, and CD4+ T-cell responses correlated with S1 antibody levels. Patients with haematological malignancies had impaired but partially compensated immune responses. Overall, cancer stage, disease status, and therapies did not correlate with immune responses. These findings have implications for understanding individual risks and potential effectiveness of SARS-CoV-2 vaccination in the cancer population.

Tissue-specific and interferon-inducible expression of non-functional ACE2 through endogenous retrovirus co-option

Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), as well as a regulator of several physiological processes. ACE2 has recently been proposed to be interferon-inducible, suggesting that SARS-CoV-2 may exploit this phenomenon to enhance viral spread and questioning the efficacy of interferon treatment in Coronavirus disease 2019 (COVID-19). Using a recent de novo transcript assembly that captured previously unannotated transcripts, we describe a novel isoform of ACE2, generated by co-option of an intronic long terminal repeat (LTR) retroelement promoter. The novel transcript, termed LTR16A1-ACE2, exhibits specific expression patterns across the aerodigestive and gastrointestinal tracts and, importantly, is highly responsive to interferon stimulation. In stark contrast, expression of canonical ACE2 is completely unresponsive to interferon stimulation. Moreover, the LTR16A1-ACE2 translation product is a truncated, unstable ACE2 form, lacking domains required for SARS-CoV-2 binding and therefore unlikely to contribute to or enhance viral infection.

SARS-CoV-2 virus and antibodies in front-line Health Care Workers in an acute hospital in London: preliminary results from a longitudinal study

BackgroundAlthough SARS-CoV-2 infection in Healthcare Workers (HCWs) is a public health concern, there is little description of their longitudinal antibody response in the presence or absence of SARS-CoV-2 and symptoms. We followed HCWs in an acute London hospital to measure seroconversion and RNA detection at the peak of the pandemic. MethodsWe enrolled 200 patient-facing HCWs between 26 March and 8 April 2020 and collected twice-weekly self-administered nose and throat swabs, symptom data and monthly blood samples. Swabs were tested for SARS-CoV-2 by PCR, and serum for antibodies to spike protein by ELISA and flow cytometry. FindingsDuring the first month, 42/200 (21%) HCWs were PCR positive in at least one nose and throat swab. Only 8/42 HCW (19%) who were PCR positive during the study period had symptoms that met current case definition. Of 181 HCWs who provided enrollment and follow-up blood samples, 82/181 (45.3%) were seropositive. In 33 HCWs who had positive serology at baseline but were PCR negative, 32 remained PCR negative. One HCW had a PCR positive swab six days after enrollment, likely representing waning infection. ConclusionThe high seropositivity and RNA detection in these front-line HCWs brings policies to protect staff and patients into acute focus. Our findings have implications for planning for the second wave and for vaccination campaigns in similar settings. The evidence of asymptomatic SARS-CoV-2 infection indicates that asymptomatic HCW surveillance is essential, while our study sets the foundations to answer pertinent questions around the duration of protective immune response and the risk of re-infection.

Evaluation of a bilingual questionnaire-based assessment on hearing in children with speech delay

@#Introduction: To correlate the score obtained using a bilingual (Malay and English) 14 points questionnaire in the detection of hearing loss at the University of Malaya, Medical Centre (UMMC), Kuala Lumpur, Malaysia over a 9 month period. Methods: This is a prospective instrument correlation study done on 93 children aged 1-4 years of age with speech and language delay for at least 3 months. Hearing status was confirmed using otoacoustic emissions, pure tone audiometry and brainstem evoked response (BSER). Hearing status was then compared to the 14-point questionnaire final scores and is statistically correlated. Results: There were 26 patients, 15 males (58%) and 11(42%) females who were diagnosed to have hearing loss. The average age of presentation was 2.49 and conductive hearing loss accounted for about 74% of cases of hearing loss. The mean questionnaire score obtained through our patients was 3.83±1.987. Discriminant analysis suggests that a questionnaire score of above 4 was indicative that the child was suffering from hearing loss. Conclusion: Our study suggests that the low-cost bilingual (Malay and English) questionnaire can be used to detect hearing loss in the Malaysian population and could potentially be useful in rural health centres to help detect hearing loss and to determine the urgency of referral to a tertiary health centre.

A new experience of auditory brainstem implantation in Malaysia.

Auditory brainstem implantation (ABI) is the only solution to restore hearing when cochlear nerves are disrupted together with the pathologies where bilateral cochleae do not provide a suitable location for cochlear implantation. We reported first two successful auditory brainstem implantation cases in patients with neurofibromatosis Type II (NF2) with bilateral acoustic neuroma causing bilateral profound sensorineural hearing loss in Malaysia. A good candidate selection, dedicated surgeons and rehabilitation team as well as strong family support are the crucial factors in achieving the best possible surgical, audiological and speech outcomes.