Glee in threes: Positive affect synchrony in parent-infant triads is moderated by maternal hair cortisol and parenting stress.

BACKGROUND: Positive affect synchrony, or the reciprocal exchange of positive affect during free play, can scaffold infants' socioemotional development. However, parental stress may compromise the expression and exchange of positive affect within families. The current study assesses whether parenting stress and hair cortisol are associated with positive affect synchrony during a triadic play interaction. METHOD: Within 70 different-sex dyads consisting of first-time parents and their six-month-old infants who participated in a four-minute laboratory-based free-play task, facial affect of each member of the triad was observationally microcoded at the second-by-second level. Hair samples were collected from mothers and fathers for cortisol assay, and parents completed a self-report measure of parenting stress. RESULTS: Using dynamic structural equation modeling (DSEM), we found positive between-level and within-level affect synchrony across all family members, with one exception: infants' affect did not predict fathers' affect at the following timepoint. Mother-to-infant affect synchrony was greater in mothers with higher hair cortisol. Similarly, mothers with higher parenting stress tended to have greater infant-to-mother affect synchrony, and had infants that displayed less overall positive affect across the interaction. CONCLUSION: We found evidence for bidirectional, time-lagged synchrony in the momentary positive affect of mothers, fathers, and infants. Maternal hair cortisol concentration and parenting stress seem to increase affect synchrony between mothers and infants- suggesting that parental stress may correlate with greater affective attunement, but less overall positive affect in infants.

Deep phenotyping of the lipidomic response in COVID-19 and non-COVID-19 sepsis.

BACKGROUND: Lipids may influence cellular penetrance by viral pathogens and the immune response that they evoke. We deeply phenotyped the lipidomic response to SARs-CoV-2 and compared that with infection with other pathogens in patients admitted with acute respiratory distress syndrome to an intensive care unit (ICU). METHODS: Mass spectrometry was used to characterise lipids and relate them to proteins, peripheral cell immunotypes and disease severity. RESULTS: Circulating phospholipases (sPLA2, cPLA2 (PLA2G4A) and PLA2G2D) were elevated on admission in all ICU groups. Cyclooxygenase, lipoxygenase and epoxygenase products of arachidonic acid (AA) were elevated in all ICU groups compared with controls. sPLA2 predicted severity in COVID-19 and correlated with TxA2, LTE4 and the isoprostane, iPF2α-III, while PLA2G2D correlated with LTE4. The elevation in PGD2, like PGI2 and 12-HETE, exhibited relative specificity for COVID-19 and correlated with sPLA2 and the interleukin-13 receptor to drive lymphopenia, a marker of disease severity. Pro-inflammatory eicosanoids remained correlated with severity in COVID-19 28 days after admission. Amongst non-COVID ICU patients, elevations in 5- and 15-HETE and 9- and 13-HODE reflected viral rather than bacterial disease. Linoleic acid (LA) binds directly to SARS-CoV-2 and both LA and its di-HOME products reflected disease severity in COVID-19. In healthy marines, these lipids rose with seroconversion. Eicosanoids linked variably to the peripheral cellular immune response. PGE2, TxA2 and LTE4 correlated with T cell activation, as did PGD2 with non-B non-T cell activation. In COVID-19, LPS stimulated peripheral blood mononuclear cell PGF2α correlated with memory T cells, dendritic and NK cells while LA and DiHOMEs correlated with exhausted T cells. Three high abundance lipids - ChoE 18:3, LPC-O-16:0 and PC-O-30:0 - were altered specifically in COVID. LPC-O-16:0 was strongly correlated with T helper follicular cell activation and all three negatively correlated with multi-omic inflammatory pathways and disease severity. CONCLUSIONS: A broad based lipidomic storm is a predictor of poor prognosis in ARDS. Alterations in sPLA2, PGD2 and 12-HETE and the high abundance lipids, ChoE 18:3, LPC-O-16:0 and PC-O-30:0 exhibit relative specificity for COVID-19 amongst such patients and correlate with the inflammatory response to link to disease severity.

Deep Phenotyping of the Lipidomic Response in COVID and non-COVID Sepsis.

Lipids may influence cellular penetrance by pathogens and the immune response that they evoke. Here we find a broad based lipidomic storm driven predominantly by secretory (s) phospholipase A 2 (sPLA 2 ) dependent eicosanoid production occurs in patients with sepsis of viral and bacterial origin and relates to disease severity in COVID-19. Elevations in the cyclooxygenase (COX) products of arachidonic acid (AA), PGD 2 and PGI 2 , and the AA lipoxygenase (LOX) product, 12-HETE, and a reduction in the high abundance lipids, ChoE 18:3, LPC-O-16:0 and PC-O-30:0 exhibit relative specificity for COVID-19 amongst such patients, correlate with the inflammatory response and link to disease severity. Linoleic acid (LA) binds directly to SARS-CoV-2 and both LA and its di-HOME products reflect disease severity in COVID-19. AA and LA metabolites and LPC-O-16:0 linked variably to the immune response. These studies yield prognostic biomarkers and therapeutic targets for patients with sepsis, including COVID-19. An interactive purpose built interactive network analysis tool was developed, allowing the community to interrogate connections across these multiomic data and generate novel hypotheses.

Patients' Perspectives on Life and Recovery 1 Year After COVID-19 Hospitalization.

BACKGROUND: Many patients hospitalized for COVID-19 experience prolonged symptoms months after discharge. Little is known abou t patients' personal experiences recovering from COVID-19 in the United States (US), where medically underserved populations are at particular risk of adverse outcomes. OBJECTIVE: To explore patients' perspectives on the impact of COVID-19 hospitalization and barriers to and facilitators of recovery 1 year after hospital discharge in a predominantly Black American study population with high neighborhood-level socioeconomic disadvantage. DESIGN: Qualitative study utilizing individual, semi-structured interviews. PARTICIPANTS: Adult patients hospitalized for COVID-19 approximately 1 year after discharge home who were engaged in a COVID-19 longitudinal cohort study. APPROACH: The interview guide was developed and piloted by a multidisciplinary team. Interviews were audio-recorded and transcribed. Data were coded and organized into discrete themes using qualitative content analysis with constant comparison techniques. KEY RESULTS: Of 24 participants, 17 (71%) self-identified as Black, and 13 (54%) resided in neighborhoods with the most severe neighborhood-level socioeconomic disadvantage. One year after discharge, participants described persistent deficits in physical, cognitive, or psychological health that impacted their current lives. Repercussions included financial suffering and a loss of identity. Participants reported that clinicians often focused on physical health over cognitive and psychological health, an emphasis that posed a barrier to recovering holistically. Facilitators of recovery included robust financial or social support systems and personal agency in health maintenance. Spirituality and gratitude were common coping mechanisms. CONCLUSIONS: Persistent health deficits after COVID-19 resulted in downstream consequences in participants' lives. Though participants received adequate care to address physical needs, many described persistent unmet cognitive and psychological needs. A more comprehensive understanding of barriers and facilitators for COVID-19 recovery, contextualized by specific healthcare and socioeconomic needs related to socioeconomic disadvantage, is needed to better inform intervention delivery to patients that experience long-term sequelae of COVID-19 hospitalization.

Validating a Proteomic Signature of Severe COVID-19.

COVID-19 is a heterogenous disease. Biomarker-based approaches may identify patients at risk for severe disease, who may be more likely to benefit from specific therapies. Our objective was to identify and validate a plasma protein signature for severe COVID-19. DESIGN: Prospective observational cohort study. SETTING: Two hospitals in the United States. PATIENTS: One hundred sixty-seven hospitalized adults with COVID-19. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We measured 713 plasma proteins in 167 hospitalized patients with COVID-19 using a high-throughput platform. We classified patients as nonsevere versus severe COVID-19, defined as the need for high-flow nasal cannula, mechanical ventilation, extracorporeal membrane oxygenation, or death, at study entry and in 7-day intervals thereafter. We compared proteins measured at baseline between these two groups by logistic regression adjusting for age, sex, symptom duration, and comorbidities. We used lead proteins from dysregulated pathways as inputs for elastic net logistic regression to identify a parsimonious signature of severe disease and validated this signature in an external COVID-19 dataset. We tested whether the association between corticosteroid use and mortality varied by protein signature. One hundred ninety-four proteins were associated with severe COVID-19 at the time of hospital admission. Pathway analysis identified multiple pathways associated with inflammatory response and tissue repair programs. Elastic net logistic regression yielded a 14-protein signature that discriminated 90-day mortality in an external cohort with an area under the receiver-operator characteristic curve of 0.92 (95% CI, 0.88-0.95). Classifying patients based on the predicted risk from the signature identified a heterogeneous response to treatment with corticosteroids (p = 0.006). CONCLUSIONS: Inpatients with COVID-19 express heterogeneous patterns of plasma proteins. We propose a 14-protein signature of disease severity that may have value in developing precision medicine approaches for COVID-19 pneumonia.

Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study.

PURPOSE: Although dozens of studies have associated vancomycin + piperacillin-tazobactam with increased acute kidney injury (AKI) risk, it is unclear whether the association represents true injury or a pseudotoxicity characterized by isolated effects on creatinine secretion. We tested this hypothesis by contrasting changes in creatinine concentration after antibiotic initiation with changes in cystatin C concentration, a kidney biomarker unaffected by tubular secretion. METHODS: We included patients enrolled in the Molecular Epidemiology of SepsiS in the ICU (MESSI) prospective cohort who were treated for ≥ 48 h with vancomycin + piperacillin-tazobactam or vancomycin + cefepime. Kidney function biomarkers [creatinine, cystatin C, and blood urea nitrogen (BUN)] were measured before antibiotic treatment and at day two after initiation. Creatinine-defined AKI and dialysis were examined through day-14, and mortality through day-30. Inverse probability of treatment weighting was used to adjust for confounding. Multiple imputation was used to impute missing baseline covariates. RESULTS: The study included 739 patients (vancomycin + piperacillin-tazobactam n = 297, vancomycin + cefepime n = 442), of whom 192 had cystatin C measurements. Vancomycin + piperacillin-tazobactam was associated with a higher percentage increase of creatinine at day-two 8.04% (95% CI 1.21, 15.34) and higher incidence of creatinine-defined AKI: rate ratio (RR) 1.34 (95% CI 1.01, 1.78). In contrast, vancomycin + piperacillin-tazobactam was not associated with change in alternative biomarkers: cystatin C: - 5.63% (95% CI - 18.19, 8.86); BUN: - 4.51% (95% CI - 12.83, 4.59); or clinical outcomes: dialysis: RR 0.63 (95% CI 0.31, 1.29); mortality: RR 1.05 (95%CI 0.79, 1.41). CONCLUSIONS: Vancomycin + piperacillin-tazobactam was associated with creatinine-defined AKI, but not changes in alternative kidney biomarkers, dialysis, or mortality, supporting the hypothesis that vancomycin + piperacillin-tazobactam effects on creatinine represent pseudotoxicity.

The Role of Implicit Bias in Surgical Resident Evaluations.

BACKGROUND: Implicit bias is a key factor preventing the advancement and retention of women and underrepresented minorities in academic surgery. PURPOSE: We examined the role of implicit bias in the technical component of the residency performance evaluation. The Fundamentals of Laparoscopic Surgery (FLS) score, an objective measure of technical performance, was compared to the subjective technical skills (TS) score given by attending surgeons. PROCEDURES: FLS scores and the average TS scores from chief resident evaluations at a university program were analyzed from 2015 to 2019 (n = 29 residents; female 22%, underrepresented minorities 27%).  The average TS score for each resident was calculated, scores dichotomized above and below the mean for the program and analyzed across gender and racial identity. MAIN FINDINGS: There were no significant differences in FLS or TS scores between male and female trainees or racial identity. The Kappa correlation coefficient between the 2 dichotomized scores was significantly lower for female (-0.50) versus male (0.23) trainees (p < 0.01); it was not significantly different between racial groups (p = 0.34). PRINCIPAL CONCLUSIONS: There was statistically significant difference in agreement between the FLS and TS scores of individual female and male trainees, suggesting the presence of implicit bias in our pilot study. Further research with a larger sample size is warranted. OBJECTIVE: To investigate the presence of implicit bias against women and underrepresented minorities in the technical component of the residency performance evaluation. We hypothesized that women and underrepresented racial minorities would have lower subjective technical skills (TS) scores as compared to their objective FLS scores, relative to the mean for the training program. DESIGN: FLS scores and the average TS scores from chief resident performance evaluations were analyzed from 2015-2019. Both FLS and the average TS scores were dichotomized above and below the mean for the program and analyzed across gender and racial identity.  Research was approved by institutional IRB. SETTING: This study was conducted at the University of Arizona General Surgery Residency Program at Banner University Medical Center in Tucson, Arizona. This is a tertiary care university training program. PARTICIPANTS: Educational records of graduated general surgery chief residents from 2015 to 2019 were accessed for the study. We analyzed 37 TS scores from attending performance evaluations and 29 FLS scores reported to the program during the study period (22% female, 27% underrepresented racial minorities). RESULTS: There were no significant differences in FLS or TS scores between male and female trainees or racial identity. The Kappa correlation coefficient between the 2 dichotomized scores was significantly lower for female (-0.50) versus male (0.23) trainees (p < 0.01); it was not significantly different between racial groups (p = 0.34). CONCLUSIONS: There was a statistically significant difference in agreement between the FLS and TS score of individual female and male trainees, suggesting the presence of implicit bias in this pilot study. Further research with a larger sample size is warranted.

Physical touch during father-infant interactions is associated with paternal oxytocin levels.

INTRODUCTION: Physical connection, particularly parent-to-infant touch, is critical for the well-being of infants and may support the development of the parent-infant bond. Physical touch has also been found to stimulate oxytocin levels. This study tested whether fathers' micro-coded touch behaviors during parent-child interaction predicted their subsequent oxytocin levels. We also compared two widely-used methods of oxytocin immunoassay that have been found to yield discrepant results in past studies. METHODS: Among 45 fathers and their six-month-old infants, we micro-coded paternal physical touch at 1/10 s intervals during a laboratory-based free-play interaction. Paternal oxytocin was measured via blood plasma and was processed both with and without the extraction step prior to immunoassay so that results from the two methods could be compared. RESULTS: Unextracted and extracted oxytocin were moderately correlated within our sample. Fathers who engaged in more playful proprioceptive touch showed higher levels of both unextracted and extracted oxytocin. Gentle affectionate touch and functional proprioceptive touch predicted higher unextracted but not extracted oxytocin levels. Fathers who did not engage in physical touch showed lower levels of both unextracted and extracted oxytocin. CONCLUSION: Results are consistent with previous work showing that physical touch, particularly playful proprioceptive touch, is associated with higher oxytocin levels in fathers. These results replicate previous research using unextracted oxytocin measurement, and extend this work, showing that many but not all associations hold when using the more rigorous method of extraction when measuring oxytocin.

When are you too old to get a kidney transplants?

PURPOSE OF REVIEW: With the increasing incidence and prevalence of ESRD in the elderly, we are now transplanting more elderly patients. Although we know from previous reports that transplantation provides increased survival advantage and/or quality of life when compared to being on dialysis, we also know that transplantation is not the best option for all patients. In this review, we try to identify the upper age limit (if any) for deceased donor renal transplantation, predictive factors that can identify the risks for transplant outcomes, frailty, and immunosenescence. RECENT FINDINGS: Review of data over the last 5 years have identified certain risk predictors and outcomes that might be helpful in evaluation of the elderly transplant recipient, which we aim to summarize in this review. SUMMARY: Identifying predictors to risk stratify elderly patients and promote transplantation is much needed. Modifiable risks should be addressed to ensure more candidates become transplantable. A combination of physical, medical, and immunological markers to better identify recipients is imperative for future research gearing towards precision medicine.

Expression and purification of tau protein and its frontotemporal dementia variants using a cleavable histidine tag.

Recombinant tau protein is widely used to study the biochemical, cellular and pathological aspects of tauopathies, including Alzheimer's disease and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTPD-17). Pure tau in high yield is a requirement for in vitro evaluation of the protein's physiological and toxic functions. However, the preparation of recombinant tau is complicated by the protein's propensity to aggregate and form truncation products, necessitating the use of multiple, time-consuming purification methods. In this study, we investigated parameters that influence the expression of wild type and FTPD-17 pathogenic tau, in an attempt to identify ways to maximise expression yield. Here, we report on the influence of the choice of host strain, induction temperature, duration of induction, and media supplementation with glucose on tau expression in Escherichia coli. We also describe a straightforward process to purify the expressed tau proteins using immobilised metal affinity chromatography, with favourable yields over previous reports. An advantage of the described method is that it enables high yield production of functional oligomeric and monomeric tau, both of which can be used to study the biochemical, physiological and toxic properties of the protein.

Extended distal pancreatectomy for pancreatic adenocarcinoma with splenic vein thrombosis and/or adjacent organ invasion.

BACKGROUND: Patients with adenocarcinoma of the pancreatic body/tail and associated vascular thrombosis or adjacent organ invasion are suboptimal candidates for resection. We hypothesized that extended distal pancreatectomy (EDP) for locally advanced adenocarcinoma is associated with a survival benefit. METHODS: We retrospectively reviewed a prospectively collected database of patients who underwent distal pancreatectomy (DP) for adenocarcinoma at a single academic institution (1996 to 2011) with greater than or equal to 2 years of follow-up. RESULTS: Among 680 DP patients, 93 were indicated for pancreatic adenocarcinoma. Splenic vein thrombosis (n = 26) did not significantly affect morbidity, mortality, or survival. Standard DP was performed in 70 patients and 23 underwent EDP with no difference in morbidity/mortality. Patients with EDP had a survival comparable with patients with standard DP (disease-free survival 18 vs 12 months = .8; overall survival 23 vs 17 months, P =.6). There was no difference in survival between EDP patients with versus without pathologic invasion of adjacent organs, but a trend favored those without. CONCLUSION: EDP is safe and should be considered in fit patients with locally advanced adenocarcinoma.

Satisfaction following immediate breast reconstruction: Experiences in the early post-operative stage.

OBJECTIVES: This qualitative study aimed to achieve an understanding of women's experiences of immediate breast reconstruction following mastectomy, to better understand the factors influencing patient satisfaction. DESIGN: Nine women were recruited from a breast unit in the North West of England. Participants were 3-9 months post-reconstruction, had received either an implant-based or Latissimus Dorsi-based immediate reconstruction and were not receiving any adjuvant therapies. An inductive qualitative and phenomenological approach was adopted to data collection and analysis. METHODS: Women took part in semi-structured interviews. All interviews were transcribed and analysed using thematic analysis. RESULTS: Four themes were generated: Seeking and receiving information; coping with the outcome of reconstruction; the need for on-going support and a new life after surgery. CONCLUSION: The study highlights difficulties surrounding receiving information and decision-making, how women make sense of recovery, how they solicit and receive support, and the process by which they begin to make sense of their futures. More focus on these areas in service provision may aid positive psychological outcomes in the recovery process following immediate breast reconstruction.

Induction immunosuppression in liver transplantation: a review.

Antibody therapy for induction is seldom used in liver transplantation in the United States, but continues to be used in approximately 10% of patients. The most commonly used antibody at the current time is basiliximab (Simulect, Novartis) and is used in adults with renal dysfunction at the time of liver transplantation with the intention of delaying introduction of calcineurin-inhibitors. In children, the same antibody is commonly used in order to reduce rates of acute rejection. Most patients, adult and pediatric, are treated with initially higher levels of tacrolimus rather than antibody induction.

LFA-1-specific therapy prolongs allograft survival in rhesus macaques.

Outcomes in transplantation have been limited by suboptimal long-term graft survival and toxicities associated with current immunosuppressive approaches. T cell costimulation blockade has shown promise as an alternative strategy to avoid the side effects of conventional immunosuppressive therapies, but targeting CD28-mediated costimulation alone has proven insufficient to prevent graft rejection in primates. Donor-specific memory T (TM) cells have been implicated in costimulation blockade-resistant transplant rejection, due to their enhanced effector function and decreased reliance on costimulatory signaling. Thus, we have tested a potential strategy to overcome TM cell-driven rejection by targeting molecules preferentially expressed on these cells, such as the adhesion molecule lymphocyte function-associated antigen 1 (LFA-1). Here, we show that short-term treatment (i.e., induction therapy) with the LFA-1-specific antibody TS-1/22 in combination with either basiliximab (an IL-2Rα-specific mAb) and sirolimus (a mammalian target of rapamycin inhibitor) or belatacept (a high-affinity variant of the CD28 costimulation-blocker CTLA4Ig) prolonged islet allograft survival in nonhuman primates relative to control treatments. Moreover, TS-1/22 masked LFA-1 on TM cells in vivo and inhibited the generation of alloproliferative and cytokine-producing effector T cells that expressed high levels of LFA-1 in vitro. These results support the use of LFA-1-specific induction therapy to neutralize costimulation blockade-resistant populations of T cells and further evaluation of LFA-1-specific therapeutics for use in transplantation.

Can the outcome of open carpal tunnel release be predicted?: a review of the literature.

Carpal tunnel syndrome is a common condition affecting 1% of the population. Open carpal tunnel release is the most commonly performed procedure for this condition. About 70-90% of patients have good to excellent long-term outcomes with open carpal tunnel release. The remainder have poor outcomes. An understanding of factors which predict a poor outcome following open carpal tunnel release would be of benefit during preoperative counselling, and provides more accurate expectations of outcomes after surgery. We reviewed the published literature in the English language over the last 20 years in an attempt to ascertain predictors of poor outcomes following open carpal tunnel release. Patient factors such as age, sex and weight were not found to be predictors of a poor outcome following open carpal tunnel release. Similarly, physical examination had little usefulness, save for abductor pollicis wasting, for predicting post-surgical functional limitations, symptoms or satisfaction. Co-morbid conditions such as diabetes, poor health status, thoracic outlet syndrome, double crush, alcohol and smoking have a worse prognosis. Normal nerve conduction studies preoperatively, direct nerve surgery such as neurolysis, abductor pollicis brevis muscle wasting and workers' compensation cases which involve lawyers preoperatively are all associated with worse outcomes. Postoperative physiotherapy may accelerate recovery but neither modifies functional recovery or reduces symptom occurrence.

Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates.

Memory T cells promote allograft rejection particularly in co-stimulation blockade-based immunosuppressive regimens. Here we show that the CD2-specific fusion protein alefacept (lymphocyte function-associated antigen-3-Ig; LFA -3-Ig) selectively eliminates memory T cells and, when combined with a co-stimulation blockade-based regimen using cytotoxic T lymphocyte antigen-4 (CTLA-4)-Ig, a CD80- and CD86-specific fusion protein, prevents renal allograft rejection and alloantibody formation in nonhuman primates. These results support the immediate translation of a regimen for the prevention of allograft rejection without the use of calcineurin inhibitors, steroids or pan-T cell depletion.

mTOR regulates memory CD8 T-cell differentiation.

Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.