An academic hospitalist model to improve healthcare worker communication and learner education: Results from a quasi‐experimental study at a veterans affairs medical center

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102160/1/jhm2105.pd

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis.

Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway's substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting

Implicit motor imagery performance is impaired in people with chronic, but not acute, neck pain

Data source: Supplemental information, https://doi.org/10.7717/peerj.8553Background: People with chronic neck pain have impaired proprioception (i.e., sense of neck position). It is unclear whether this impairment involves disruptions to the proprioceptive representation in the brain, peripheral factors, or both. Implicit motor imagery tasks, namely left/right judgements of body parts, assess the integrity of the proprioceptive represention. Previous studies evaluating left/right neck judgements in people with neck pain are conflicting. We conducted a large online study to comprehensively address whether people with neck pain have altered implicit motor imagery performance. Methods: People with and without neck pain completed online left/right neck judgement tasks followed by a left/right hand judgement task (control). Participants judged whether the person in the image had their head rotated to their left or right side (neck task) or whether the image was of a left hand or a right hand (hand task). Participants were grouped on neck pain status (no pain; <3 months- acute; ≥3 months-chronic) and pain location (none, left-sided, right-sided, bilateral). Outcomes included accuracy (primary) and response time (RT; secondary). Our hypotheses-that (i) chronic neck pain is associated with disrupted performance for neck images and (ii) the disruption is dependent on the side of usual pain, were tested with separate ANOVAs. Results: A total of 1,404 participants were recruited: 105 reported acute neck pain and 161 reported chronic neck pain. When grouped on neck pain status, people with chronic neck pain were less accurate than people without neck pain (p = 0.001) for left/right neck judgements, but those with acute neck pain did not differ from those without neck pain (p = 0.14) or with chronic neck pain (p = 0.28). Accuracy of left/right hand judgements did not differ between groups (p = 0.58). RTs did not differ between groups for any comparison. When grouped on neck pain location, people were faster and more accurate at identifying right-turning neck images than left-turning neck images, regardless of history or location of pain (p < 0.001 for both); people with no pain were more accurate and faster than people with bilateral neck pain (p = 0.001, p = 0.015) and were faster than those with left-sided neck pain (p = 0.021); people with right-sided neck pain were more accurate than people with bilateral neck pain (p = 0.018). Lastly, there was a significant interaction between neck image and side of neck pain: People with right-sided neck pain were more accurate at identifying right-sided neck turning images than people with left-sided neck pain (p = 0.008), but no different for left-sided neck turning images (p = 0.62). Conclusions: There is evidence of impaired implicit motor imagery performance in people with chronic neck pain, which may suggest disruptions to proprioceptive representation of the neck. These disruptions seem specific to the neck (performance on hand images intact) but non-specific to the exact location of neck pain

Relative Frequencies of Alloantigen-Specific Helper CD4 T Cells and B Cells Determine Mode of Antibody-Mediated Allograft Rejection.

Humoral alloimmunity is now recognized as a major determinant of transplant outcome. MHC glycoprotein is considered a typical T-dependent antigen, but the nature of the T cell alloresponse that underpins alloantibody generation remains poorly understood. Here, we examine how the relative frequencies of alloantigen-specific B cells and helper CD4 T cells influence the humoral alloimmune response and how this relates to antibody-mediated rejection (AMR). An MHC-mismatched murine model of cardiac AMR was developed, in which T cell help for alloantibody responses in T cell deficient (Tcrbd-/-) C57BL/6 recipients against donor H-2Kd MHC class I alloantigen was provided by adoptively transferred "TCR75" CD4 T cells that recognize processed H-2Kd allopeptide via the indirect-pathway. Transfer of large numbers (5 × 105) of TCR75 CD4 T cells was associated with rapid development of robust class-switched anti-H-2Kd humoral alloimmunity and BALB/c heart grafts were rejected promptly (MST 9 days). Grafts were not rejected in T and B cell deficient Rag2-/- recipients that were reconstituted with TCR75 CD4 T cells or in control (non-reconstituted) Tcrbd-/- recipients, suggesting that the transferred TCR75 CD4 T cells were mediating graft rejection principally by providing help for effector alloantibody responses. In support, acutely rejecting BALB/c heart grafts exhibited hallmark features of acute AMR, with widespread complement C4d deposition, whereas cellular rejection was not evident. In addition, passive transfer of immune serum from rejecting mice to Rag2-/- recipients resulted in eventual BALB/c heart allograft rejection (MST 20 days). Despite being long-lived, the alloantibody responses observed at rejection of the BALB/c heart grafts were predominantly generated by extrafollicular foci: splenic germinal center (GC) activity had not yet developed; IgG secreting cells were confined to the splenic red pulp and bridging channels; and, most convincingly, rapid graft rejection still occurred when recipients were reconstituted with similar numbers of Sh2d1a-/- TCR75 CD4 T cells that are genetically incapable of providing T follicular helper cell function for generating GC alloimmunity. Similarly, alloantibody responses generated in Tcrbd-/- recipients reconstituted with smaller number of wild-type TCR75 CD4 T cells (103), although long-lasting, did not have a discernible extrafollicular component, and grafts were rejected much more slowly (MST 50 days). By modeling antibody responses to Hen Egg Lysozyme protein, we confirm that a high ratio of antigen-specific helper T cells to B cells favors development of the extrafollicular response, whereas GC activity is favored by a relatively high ratio of B cells. In summary, a relative abundance of helper CD4 T cells favors development of strong extrafollicular alloantibody responses that mediate acute humoral rejection, without requirement for GC activity. This work is composed of two parts, of which this is Part I. Please read also Part II: Chhabra et al., 2019

Evaluation of CDK12 protein expression as a potential novel biomarker for DNA damage response-targeted therapies in breast cancer

Disruption of Cyclin-Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and PARP1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by IHC in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer-specific survival taking HER2 status into account; however, absent CDK12 protein expression significantly correlated with a triple-negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK, and γH2AX, suggesting a novel mechanism of CDK12-associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in breast cancer is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple-negative breast cancers.</p

‘I did not think they could help me’ : Autistic adults’ reasons for not seeking public healthcare when they last experienced suicidality

With autistic people at increased risk of dying by suicide, understanding barriers to help-seeking is crucial for suicide prevention efforts. Using an online survey designed in consultation with autistic people, we examined reasons why autistic adults living in the United Kingdom did not seek help from the National Health Service (NHS) when they last experienced suicidal thoughts or behaviours. Participants who disaffirmed help-seeking from the NHS (n = 754) were able to select from a prepopulated list of 20 reasons why and to enter their own. The three most commonly endorsed reasons were ‘I tried to cope and manage my feelings by myself’, ‘I did not think they could help me’ and ‘The waiting list is too long – no point’. Endorsement of reasons differed significantly with gender identity, age group and degree of lifetime suicidality. Four themes emerged from analysis of free-form responses: NHS is ineffective , NHS as antagonistic, Fear and consequences and Barriers to access . These findings highlight the need to foster more flexible healthcare systems capable of supporting autistic people, and that autistic people view as trustworthy and effective, to enable help-seeking behaviours with the potential to save lives. Lay abstract Autistic people are more likely than non-autistic people to think about, attempt and die by suicide. For people in crisis, public healthcare services are, in theory, a source of help. In reality, many non-autistic people do not seek help from healthcare services. We wanted to understand why autistic people living in the United Kingdom may not seek help from the National Health Service (NHS) when suicidal and if these reasons differed by characteristics like age and gender. This study tried to answer these questions using responses from a survey co-designed with autistic people about various aspects of suicidal experiences. Participants were able to select from a list of 20 reasons and enter their own explanations (free-form responses) why they did not seek NHS support when suicidal. Our findings show that the most common reasons were that people tried to cope and manage by themselves; they did not think the NHS could help; and they thought the waiting list was too long. Reasons for not seeking help differed by age and gender, as well as lifetime history of suicidal thoughts and behaviour. For example, cisgender women and transgender/gender-divergent participants were more likely to say that previous bad experiences with the NHS prevented them from seeking help, and people with experience of suicide attempts were more likely to have been turned away by the NHS in the past. The free-form responses showed that many participants believed the NHS was ineffective, had previously had negative experiences with the NHS, worried about the consequences of help-seeking and experienced barriers that prevented help-seeking. This work highlights the crucial change and work required to make the NHS safe and accessible for autistic people so they can reach out for help when suicidal

‘I did not think they could help me’: Autistic adults’ reasons for not seeking public healthcare when they last experienced suicidality

With autistic people at increased risk of dying by suicide, understanding barriers to help-seeking is crucial for suicide prevention efforts. Using an online survey designed in consultation with autistic people, we examined reasons why autistic adults living in the United Kingdom did not seek help from the National Health Service (NHS) when they last experienced suicidal thoughts or behaviours. Participants who disaffirmed help-seeking from the NHS (n = 754) were able to select from a prepopulated list of 20 reasons why and to enter their own. The three most commonly endorsed reasons were ‘I tried to cope and manage my feelings by myself’, ‘I did not think they could help me’ and ‘The waiting list is too long – no point’. Endorsement of reasons differed significantly with gender identity, age group and degree of lifetime suicidality. Four themes emerged from analysis of free-form responses: NHS is ineffective, NHS as antagonistic, Fear and consequences and Barriers to access. These findings highlight the need to foster more flexible healthcare systems capable of supporting autistic people, and that autistic people view as trustworthy and effective, to enable help-seeking behaviours with the potential to save lives. Lay abstract Autistic people are more likely than non-autistic people to think about, attempt and die by suicide. For people in crisis, public healthcare services are, in theory, a source of help. In reality, many non-autistic people do not seek help from healthcare services. We wanted to understand why autistic people living in the United Kingdom may not seek help from the National Health Service (NHS) when suicidal and if these reasons differed by characteristics like age and gender. This study tried to answer these questions using responses from a survey co-designed with autistic people about various aspects of suicidal experiences. Participants were able to select from a list of 20 reasons and enter their own explanations (free-form responses) why they did not seek NHS support when suicidal. Our findings show that the most common reasons were that people tried to cope and manage by themselves; they did not think the NHS could help; and they thought the waiting list was too long. Reasons for not seeking help differed by age and gender, as well as lifetime history of suicidal thoughts and behaviour. For example, cisgender women and transgender/gender-divergent participants were more likely to say that previous bad experiences with the NHS prevented them from seeking help, and people with experience of suicide attempts were more likely to have been turned away by the NHS in the past. The free-form responses showed that many participants believed the NHS was ineffective, had previously had negative experiences with the NHS, worried about the consequences of help-seeking and experienced barriers that prevented help-seeking. This work highlights the crucial change and work required to make the NHS safe and accessible for autistic people so they can reach out for help when suicidal

Relative Frequencies of Alloantigen-Specific Helper CD4 T Cells and B Cells Determine Mode of Antibody-Mediated Allograft Rejection

Humoral alloimmunity is now recognized as a major determinant of transplant outcome. MHC glycoprotein is considered a typical T-dependent antigen, but the nature of the T cell alloresponse that underpins alloantibody generation remains poorly understood. Here, we examine how the relative frequencies of alloantigen-specific B cells and helper CD4 T cells influence the humoral alloimmune response and how this relates to antibody-mediated rejection (AMR). An MHC-mismatched murine model of cardiac AMR was developed, in which T cell help for alloantibody responses in T cell deficient (Tcrbd−/−) C57BL/6 recipients against donor H-2Kd MHC class I alloantigen was provided by adoptively transferred “TCR75” CD4 T cells that recognize processed H-2Kd allopeptide via the indirect-pathway. Transfer of large numbers (5 × 105) of TCR75 CD4 T cells was associated with rapid development of robust class-switched anti-H-2Kd humoral alloimmunity and BALB/c heart grafts were rejected promptly (MST 9 days). Grafts were not rejected in T and B cell deficient Rag2−/− recipients that were reconstituted with TCR75 CD4 T cells or in control (non-reconstituted) Tcrbd−/− recipients, suggesting that the transferred TCR75 CD4 T cells were mediating graft rejection principally by providing help for effector alloantibody responses. In support, acutely rejecting BALB/c heart grafts exhibited hallmark features of acute AMR, with widespread complement C4d deposition, whereas cellular rejection was not evident. In addition, passive transfer of immune serum from rejecting mice to Rag2−/− recipients resulted in eventual BALB/c heart allograft rejection (MST 20 days). Despite being long-lived, the alloantibody responses observed at rejection of the BALB/c heart grafts were predominantly generated by extrafollicular foci: splenic germinal center (GC) activity had not yet developed; IgG secreting cells were confined to the splenic red pulp and bridging channels; and, most convincingly, rapid graft rejection still occurred when recipients were reconstituted with similar numbers of Sh2d1a−/− TCR75 CD4 T cells that are genetically incapable of providing T follicular helper cell function for generating GC alloimmunity. Similarly, alloantibody responses generated in Tcrbd−/− recipients reconstituted with smaller number of wild-type TCR75 CD4 T cells (103), although long-lasting, did not have a discernible extrafollicular component, and grafts were rejected much more slowly (MST 50 days). By modeling antibody responses to Hen Egg Lysozyme protein, we confirm that a high ratio of antigen-specific helper T cells to B cells favors development of the extrafollicular response, whereas GC activity is favored by a relatively high ratio of B cells. In summary, a relative abundance of helper CD4 T cells favors development of strong extrafollicular alloantibody responses that mediate acute humoral rejection, without requirement for GC activity.This work is composed of two parts, of which this is Part I. Please read also Part II: Chhabra et al., 2019