Impact of the COVID-19 related border restrictions on influenza and other common respiratory viral infections in New Zealand.

BACKGROUND: New Zealand's (NZ) complete absence of community transmission of influenza and respiratory syncytial virus (RSV) after May 2020, likely due to COVID-19 elimination measures, provided a rare opportunity to assess the impact of border restrictions on common respiratory viral infections over the ensuing 2 years. METHODS: We collected the data from multiple surveillance systems, including hospital-based severe acute respiratory infection surveillance, SHIVERS-II, -III and -IV community cohorts for acute respiratory infection (ARI) surveillance, HealthStat sentinel general practice (GP) based influenza-like illness surveillance and SHIVERS-V sentinel GP-based ARI surveillance, SHIVERS-V traveller ARI surveillance and laboratory-based surveillance. We described the data on influenza, RSV and other respiratory viral infections in NZ before, during and after various stages of the COVID related border restrictions. RESULTS: We observed that border closure to most people, and mandatory government-managed isolation and quarantine on arrival for those allowed to enter, appeared to be effective in keeping influenza and RSV infections out of the NZ community. Border restrictions did not affect community transmission of other respiratory viruses such as rhinovirus and parainfluenza virus type-1. Partial border relaxations through quarantine-free travel with Australia and other countries were quickly followed by importation of RSV in 2021 and influenza in 2022. CONCLUSION: Our findings inform future pandemic preparedness and strategies to model and manage the impact of influenza and other respiratory viral threats.

Low-affinity CD8+ T cells provide interclonal help to high-affinity CD8+ T cells to augment alloimmunity.

Following solid organ transplantation, small precursor populations of polyclonal CD8+ T cells specific for any graft-expressed antigen preferentially expand their high-affinity clones. This phenomenon, termed "avidity maturation," results in a larger population of CD8+ T cells with increased sensitivity to alloantigen, posing a greater risk for graft rejection. Using a mouse model of minor-mismatched skin transplantation, coupled with the tracking of 2 skin graft-reactive CD8+ T cell receptor-transgenic tracer populations with high and low affinity for the same peptide-major histocompatibility complex, we explored the conventional paradigm that CD8+ T cell avidity maturation occurs through T cell receptor affinity-based competition for cognate antigen. Our data revealed "interclonal CD8-CD8 help," whereby lower/intermediate affinity clones help drive the preferential expansion of their higher affinity counterparts in an interleukin-2/CD25-dependent manner. Consequently, the CD8-helped high-affinity clones exhibit greater expansion and develop augmented effector functions in the presence of their low-affinity counterparts, correlating with more severe graft damage. Finally, interclonal CD8-CD8 help was suppressed by costimulation blockade treatment. Thus, high-affinity CD8+ T cells can leverage help from low-affinity CD8+ T cells of identical specificity to promote graft rejection. Suppressing provision of interclonal CD8-CD8 help may be important to improve transplant outcomes.

Heterogeneity in allospecific T cell function in transplant-tolerant hosts determines susceptibility to rejection following infection.

Even when successfully induced, immunological tolerance to solid organs remains vulnerable to inflammatory insults, which can trigger rejection. In a mouse model of cardiac allograft tolerance in which infection with Listeria monocytogenes (Lm) precipitates rejection of previously accepted grafts, we showed that recipient CD4+ TCR75 cells reactive to a donor MHC class I-derived peptide become hypofunctional if the allograft is accepted for more than 3 weeks. Paradoxically, infection-induced transplant rejection was not associated with transcriptional or functional reinvigoration of TCR75 cells. We hypothesized that there is heterogeneity in the level of dysfunction of different allospecific T cells, depending on duration of their cognate antigen expression. Unlike CD4+ TCR75 cells, CD4+ TEa cells specific for a peptide derived from donor MHC class II, an alloantigen whose expression declines after transplantation but remains inducible in settings of inflammation, retained function in tolerant mice and expanded during Lm-induced rejection. Repeated injections of alloantigens drove hypofunction in TEa cells and rendered grafts resistant to Lm-dependent rejection. Our results uncover a functional heterogeneity in allospecific T cells of distinct specificities after tolerance induction and reveal a strategy to defunctionalize a greater repertoire of allospecific T cells, thereby mitigating a critical vulnerability of tolerance.

A new national health system: the opportunity to address data quality issues in maternal immunisation coverage.

AIM: Maternal immunisation coverage is suboptimal in Aotearoa New Zealand. Our objective was to highlight discrepancies resulting from how maternal immunisation coverage for pertussis and influenza is measured in Aotearoa New Zealand. METHOD: A retrospective cohort study of pregnant people was undertaken using administrative datasets. Maternity and immunisation data from three sources (National Immunisation Register [NIR], general practice [GP], and pharmaceutical claims) were linked to determine the proportion of immunisation records not recorded in the NIR but captured in claims data, and to compare this with coverage data available from Te Whatu Ora - Health New Zealand. RESULTS: We found that while increasing numbers of maternal immunisations are being captured in the NIR, around 10% remain unrecorded on the NIR, but within claims datasets. CONCLUSION: Accurate maternal immunisation coverage data is important for public health action. Implementation of the whole-of-life Aotearoa Immunisation Register (AIR) is an important opportunity to improve completeness and consistency of maternal immunisation coverage reporting.

Oral administration of the commensal Alistipes onderdonkii prolongs allograft survival.

Intestinal commensals can exert immunomodulatory effects on the host, with beneficial or detrimental consequences depending on underlying diseases. We have previously correlated longer survival of minor mismatched skin grafts in mice with the presence of an intestinal commensal bacterium, Alistipes onderdonkii. In this study, we investigated its sufficiency and mechanism of action. Oral administration of A onderdonkii strain DSM19147 but not DSM108265 was sufficient to prolong minor mismatched skin graft survival through inhibition of tumor necrosis factor production. Through metabolomic and metagenomic comparisons between DSM19147 and DSM108265, we identified candidate gene products associated with the anti-inflammatory effect of DSM19147. A onderdonkii DSM19147 can lower inflammation both at a steady state and after transplantation and may serve as an anti-inflammatory probiotic beneficial for transplant recipients.

Falls of newborn infants in a New Zealand hospital: A case series.

AIM: The fall of a newborn baby to the hospital floor is a devastating experience for the family and staff caring for the mother and baby. The aim of this study was to report our experience in an ethnically diverse and socioeconomically disadvantaged community. METHODS: The study was a retrospective case series of all baby falls in the Counties Manukau Health (New Zealand) post-natal care wards, birthing suites and birthing units from 2015 to 2018. Information from the incident reporting system was used to identify the circumstances surrounding the fall. In addition, medical records of the mother and the baby were examined for the admission during which the fall occurred. RESULTS: There were 32 cases (rate 12.1/10 000 live births). Mothers of babies who fell were more likely to present late for antenatal care, to smoke and be obese. They were more likely to have delivered by caesarean. Falls were more likely to occur at night and around weekends. In most instances (84%) the mother fell asleep with baby on the bed while breastfeeding. There were no major injuries. CONCLUSIONS: The rate of baby falls is considerably greater than previous reports. Recommendations are made to reduce this occurrence. These can be incorporated into safe sleep education.

Reduced Satb1 expression predisposes CD4+ T conventional cells to Treg suppression and promotes transplant survival.

Limiting CD4+ T cell responses is important to prevent solid organ transplant rejection. In a mouse model of costimulation blockade-dependent cardiac allograft tolerance, we previously reported that alloreactive CD4+ conventional T cells (Tconvs) develop dysfunction, losing proliferative capacity. In parallel, induction of transplantation tolerance is dependent on the presence of regulatory T cells (Tregs). Whether susceptibility of CD4+ Tconvs to Treg suppression is modulated during tolerance induction is unknown. We found that alloreactive Tconvs from transplant tolerant mice had augmented sensitivity to Treg suppression when compared with memory T cells from rejector mice and expressed a transcriptional profile distinct from these memory T cells, including down-regulated expression of the transcription factor Special AT-rich sequence-binding protein 1 (Satb1). Mechanistically, Satb1 deficiency in CD4+ T cells limited their expression of CD25 and IL-2, and addition of Tregs, which express higher levels of CD25 than Satb1-deficient Tconvs and successfully competed for IL-2, resulted in greater suppression of Satb1-deficient than wild-type Tconvs in vitro. In vivo, Satb1-deficient Tconvs were more susceptible to Treg suppression, resulting in significantly prolonged skin allograft survival. Overall, our study reveals that transplantation tolerance is associated with Tconvs' susceptibility to Treg suppression, via modulated expression of Tconv-intrinsic Satb1. Targeting Satb1 in the context of Treg-sparing immunosuppressive therapies might be exploited to improve transplant outcomes.

Oral alloantigen exposure promotes donor-specific tolerance in a mouse model of minor-mismatched skin transplantation.

Oral antigen exposure is a powerful, non-invasive route to induce immune tolerance to dietary antigens, and has been modestly successful at prolonging graft survival in rodent models of transplantation. To harness the mechanisms of oral tolerance for promoting long-term graft acceptance, we developed a mouse model where the antigen ovalbumin (OVA) was introduced orally prior to transplantation with skin grafts expressing OVA. Oral OVA treatment pre-transplantation promoted permanent graft acceptance and linked tolerance to skin grafts expressing OVA fused to the additional antigen 2W. Tolerance was donor-specific, as secondary donor-matched, but not third-party allografts were spontaneously accepted. Oral OVA treatment promoted an anergic phenotype in OVA-reactive CD4+ and CD8+ conventional T cells (Tconvs) and expanded OVA-reactive Tregs pre-transplantation. However, skin graft acceptance following oral OVA resisted partial depletion of Tregs and blockade of PD-L1. Mechanistically, we revealed a role for the proximal gut draining lymph nodes (gdLNs) in mediating this effect, as an intestinal infection that drains to the proximal gdLNs prevented tolerance induction. Our study extends previous work applying oral antigen exposure to transplantation and serves as proof of concept that the systemic immune mechanisms supporting oral tolerance are sufficient to promote long-term graft acceptance.

Health Promotion, Health Literacy and Vaccine Hesitancy: The Role of Humanoid Robots.

The use of humanoid robot technologies within global healthcare settings is rapidly evolving; however, the potential of robots in health promotion and health education is not established. The aim of this study was to explore the impact of a social humanoid robot on individuals' knowledge of influenza (flu) prevention and attitudes towards influenza vaccination. A multi-methods approach involving pre and post-test questions and interviews was used. The study was undertaken in a publicly funded tertiary level hospital in northern Queensland, Australia. Of the 995 participants, the majority were visitors (53.07%). The mean age of the participants was 42.25 (SD=19.54) years. Based on the three knowledge questions that were posed at the two-point interactions of participants with the humanoid robot 'Pepper', the results showed that there was a significant difference in the correct responses pre- and post-test regarding the best way to avoid getting the flu (Exact McNemar significance probability <.0001), how long the flu virus can live outside the human body (p <.0001) and the length of time for handwashing to be effective against spreading germs (p <.0001). The results also showed that there was a significant difference in attitudes associated with influenza vaccination when pre-test was compared to post-test (p=.0019). Interaction of the participants with the humanoid robot demonstrated immediate knowledge gains and attitudinal change that suggests that humanoid robots may be an important intervention for health promotion in prevention of influenza and other respiratory viruses.

Prospective community programme versus parent-driven care to prevent respiratory morbidity in children following hospitalisation with severe bronchiolitis or pneumonia.

BACKGROUND: Hospitalisation with severe lower respiratory tract infection (LRTI) in early childhood is associated with ongoing respiratory symptoms and possible later development of bronchiectasis. We aimed to reduce this intermediate respiratory morbidity with a community intervention programme at time of discharge. METHODS: This randomised, controlled, single-blind trial enrolled children aged <2 years hospitalised for severe LRTI to 'intervention' or 'control'. Intervention was three monthly community clinics treating wet cough with prolonged antibiotics referring non-responders. All other health issues were addressed, and health resilience behaviours were encouraged, with referrals for housing or smoking concerns. Controls followed the usual pathway of parent-initiated healthcare access. After 24 months, all children were assessed by a paediatrician blinded to randomisation for primary outcomes of wet cough, abnormal examination (crackles or clubbing) or chest X-ray Brasfield score ≤22. FINDINGS: 400 children (203 intervention, 197 control) were enrolled in 2011-2012; mean age 6.9 months, 230 boys, 87% Maori/Pasifika ethnicity and 83% from the most deprived quintile. Final assessment of 321/400 (80.3%) showed no differences in presence of wet cough (33.9% intervention, 36.5% controls, relative risk (RR) 0.93, 95% CI 0.69 to 1.25), abnormal examination (21.7% intervention, 23.9% controls, RR 0.92, 95% CI 0.61 to 1.38) or Brasfield score ≤22 (32.4% intervention, 37.9% control, RR 0.85, 95% CI 0.63 to 1.17). Twelve (all intervention) were diagnosed with bronchiectasis within this timeframe. INTERPRETATION: We have identified children at high risk of ongoing respiratory disease following hospital admission with severe LRTI in whom this intervention programme did not change outcomes over 2 years. TRIAL REGISTRATION NUMBER: ACTRN12610001095055.

Resilience of T cell-intrinsic dysfunction in transplantation tolerance.

Following antigen stimulation, naïve T cells differentiate into memory cells that mediate antigen clearance more efficiently upon repeat encounter. Donor-specific tolerance can be achieved in a subset of transplant recipients, but some of these grafts are rejected after years of stability, often following infections. Whether T cell memory can develop from a tolerant state and whether these formerly tolerant patients develop antidonor memory is not known. Using a mouse model of cardiac transplantation in which donor-specific tolerance is induced with costimulation blockade (CoB) plus donor-specific transfusion (DST), we have previously shown that systemic infection with Listeria monocytogenes (Lm) months after transplantation can erode or transiently abrogate established tolerance. In this study, we tracked donor-reactive T cells to investigate whether memory can be induced when alloreactive T cells are activated in the setting of tolerance. We show alloreactive T cells persist after induction of cardiac transplantation tolerance, but fail to acquire a memory phenotype despite becoming antigen experienced. Instead, donor-reactive T cells develop T cell-intrinsic dysfunction evidenced when removed from the tolerant environment. Notably, Lm infection after tolerance did not rescue alloreactive T cell memory differentiation or functionality. CoB and antigen persistence were sufficient together but not separately to achieve alloreactive T cell dysfunction, and conventional immunosuppression could substitute for CoB. Antigen persistence was required, as early but not late surgical allograft removal precluded the acquisition of T cell dysfunction. Our results demonstrate transplant tolerance-associated T cell-intrinsic dysfunction that is resistant to memory development even after Lm-mediated disruption of tolerance.

The pursuit of transplantation tolerance: new mechanistic insights.

Donor-specific transplantation tolerance that enables weaning from immunosuppressive drugs but retains immune competence to non-graft antigens has been a lasting pursuit since the discovery of neonatal tolerance. More recently, efforts have been devoted not only to understanding how transplantation tolerance can be induced but also the mechanisms necessary to maintain it as well as how inflammatory exposure challenges its durability. This review focuses on recent advances regarding key peripheral mechanisms of T cell tolerance, with the underlying hypothesis that a combination of several of these mechanisms may afford a more robust and durable tolerance and that a better understanding of these individual pathways may permit longitudinal tracking of tolerance following clinical transplantation to serve as biomarkers. This review may enable a personalized assessment of the degree of tolerance in individual patients and the opportunity to strengthen the robustness of peripheral tolerance.

Exercise increases skin graft resistance to rejection.

Regular exercise reduces risk of various chronic diseases and can prevent the development and recurrence of cancer, making it a promising nonpharmacological modulator of disease. Yet the effect of regular exercise on solid organ transplant outcome remains uncertain. Using a model of voluntary wheel-running exercise and skin transplantation in mice, we hypothesized that exercise strengthens the alloimmune response, leading to an increased rate of rejection. Instead, we found that regular exercise in mice resulted in prolonged graft survival, with mean allograft survival time increasing by almost 50%. We observed this graft survival extension in exercised mice despite evidence of a slightly enhanced alloimmune response, comprised of increased proliferation of alloreactive CD4+ T cells, as well as increased interferon-γ production by these cells. Exercise was not associated with significant changes in numbers of conventional CD4+ or CD8+ T cells, NK cells, or Foxp3+ regulatory T cells. In conclusion, our study suggests that exercise increases skin graft resistance to a similar or slightly higher level of alloimmunity and supports regular exercise as an important beneficial pursuit for transplant recipients.

Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance.

Mechanisms implicated in robust transplantation tolerance at the cellular level can be broadly categorized into those that inhibit alloreactive T cells intrinsically (clonal deletion and dysfunction) or extrinsically through regulation. Here, we investigated whether additional population-level mechanisms control T cells by examining whether therapeutically induced peripheral transplantation tolerance could influence T cell populations' avidity for alloantigens. Whereas T cells with high avidity preferentially accumulated during acute rejection of allografts, the alloreactive T cells in tolerant recipients retained a low-avidity profile, comparable to naive mice despite evidence of activation. These contrasting avidity profiles upon productive versus tolerogenic stimulation were durable and persisted upon alloantigen re-encounter in the absence of any immunosuppression. Thus, peripheral transplantation tolerance involves control of alloreactive T cells at the population level, in addition to the individual cell level. Controlling expansion or eliminating high-affinity, donor-specific T cells long term may be desirable to achieve robust transplantation tolerance in the clinic.

Gut microbes contribute to variation in solid organ transplant outcomes in mice.

BACKGROUND: Solid organ transplant recipients show heterogeneity in the occurrence and timing of acute rejection episodes. Understanding the factors responsible for such variability in patient outcomes may lead to improved diagnostic and therapeutic approaches. Rejection kinetics of transplanted organs mainly depends on the extent of genetic disparities between donor and recipient, but a role for environmental factors is emerging. We have recently shown that major alterations of the microbiota following broad-spectrum antibiotics, or use of germ-free animals, promoted longer skin graft survival in mice. Here, we tested whether spontaneous differences in microbial colonization between genetically similar individuals can contribute to variability in graft rejection kinetics. RESULTS: We compared rejection kinetics of minor mismatched skin grafts in C57BL/6 mice from Jackson Laboratory (Jax) and Taconic Farms (Tac), genetically similar animals colonized by different commensal microbes. Female Tac mice rejected skin grafts from vendor-matched males more quickly than Jax mice. We observed prolonged graft survival in Tac mice when they were exposed to Jax mice microbiome through co-housing or fecal microbiota transplantation (FMT) by gastric gavage. In contrast, exposure to Tac mice did not change graft rejection kinetics in Jax mice, suggesting a dominant suppressive effect of Jax microbiota. High-throughput sequencing of 16S rRNA gene amplicons from Jax and Tac mice fecal samples confirmed a convergence of microbiota composition after cohousing or fecal transfer. Our analysis of amplicon data associated members of a single bacterial genus, Alistipes, with prolonged graft survival. Consistent with this finding, members of the genus Alistipes were absent in a separate Tac cohort, in which fecal transfer from Jax mice failed to prolong graft survival. CONCLUSIONS: These results demonstrate that differences in resident microbiome in healthy individuals may translate into distinct kinetics of graft rejection, and contribute to interpersonal variability in graft outcomes. The association between Alistipes and prolonged skin graft survival in mice suggests that members of this genus might affect host physiology, including at sites distal to the gastrointestinal tract. Overall, these findings allude to a potential therapeutic role for specific gut microbes to promote graft survival through the administration of probiotics, or FMT.

Perceived confidence, competence and training in evidence-based treatments for eating disorders: a survey of clinicians in an Australian regional health service.

OBJECTIVES: Eating disorders (EDs) are challenging to treat and contribute to considerable morbidity and mortality. This study sought to identify the educational preparedness, competence and confidence of clinicians to work with people with EDs; and to identify how services might be improved. METHODS: Clinicians who worked in the emergency department, medical, paediatric wards and mental health services were invited to complete an online survey. RESULTS: From the 136 surveys returned, 73% of respondents reported little or no confidence working with EDs. There was a strong linear correlation between perceived confidence and competence and hours of education. Those with 70 or more hours of self-reported training were 2.7 times more likely to rate themselves as both confident and competent. Improving services for people with eating disorders included the provision of appropriate training, improving access to services including psychotherapy, and facilitating consistency in and continuity of care. CONCLUSIONS: To increase the confidence and competence of the workforce, regular training around EDs should be undertaken. The establishment of a specialist team to provide services across the continuum of care for people with severe or complex EDs appears warranted in a regional health service.

Evaluation of a sudden unexpected death in infancy intervention programme aimed at improving parental awareness of risk factors and protective infant care practices.

AIM: Sudden unexpected death in infancy (SUDI) rates for Maori and Pacific infants remain higher than for other ethnic groups in New Zealand and bed-sharing is a major risk factor when there is smoking exposure in pregnancy. Sleep space programmes of education and Pepi-Pod baby beds require evaluation. METHODS: Two hundred and forty Maori and Pacific women and infants were randomised 1:1, to the Pepi-Pod sleep space programme, or to a control group with 'usual care'. When infants were under 2 weeks of age, baseline interviews occurred, followed up by interviews at 2 and 4 months of age to assess safe sleep knowledge, infant care practices and Pepi-Pod use and acceptability. All participants were offered a New Zealand Standard approved portable cot. RESULTS: At baseline, 25% of babies did not have a baby bed. Knowledge of smoking and bed-sharing as SUDI risks improved at follow-up in both groups. One quarter regularly bed-shared at follow-up in both groups. Intention to bed-share was a strong predictor of subsequent behaviour. Pepi-Pods were regularly used by 46% at 2 months and 16% at 4 months follow-up. CONCLUSIONS: Bed-sharing and knowledge improvement were similar irrespective of group. It is likely that the impact of the intervention was reduced because the control group received better support than 'usual care' and all participants had a baby bed. New Zealand SUDI rates have declined since sleep space programmes have been available. Sleep space programmes should be prioritised for those with modifiable SUDI risk.

The Evolving Understanding of Sudden Unexpected Infant Death.

Sudden unexpected infant death (SUID) is the leading cause for post-neonatal mortality in industrialized nations. Case-control studies have identified risk factors for SUID that have shaped research into studies of causation. Most current hypotheses for the mechanisms for SUID contribute to the "SUID sequence"-hypoxia and/or hypercarbia in sleep to which a vulnerable infant fails to respond adequately and that results in death. Reducing vulnerability in infants and promoting safe sleep for infants is important for prevention and requires knowledge of the prevalence of risk factors within the target population and a culturally sensitive approach. [Pediatr Ann. 2017;46(8):e278-e283.].

Evolving Approaches in the Identification of Allograft-Reactive T and B Cells in Mice and Humans.

Whether a transplanted allograft is stably accepted, rejected, or achieves immunological tolerance is dependent on the frequency and function of alloreactive lymphocytes, making the identification and analysis of alloreactive T and B cells in transplant recipients critical for understanding mechanisms, and the prediction of allograft outcome. In animal models, tracking the fate of graft-reactive T and B cells allows investigators to uncover their biology and develop new therapeutic strategies to protect the graft. In the clinic, identification and quantification of graft-reactive T and B cells allows for the early diagnosis of immune reactivity and therapeutic intervention to prevent graft loss. In addition to rejection, probing of T and B cell fate in vivo provides insights into the underlying mechanisms of alloimmunity or tolerance that may lead to biomarkers predicting graft fate. In this review, we discuss existing and developing approaches to track and analyze alloreactive T and B cells in mice and humans and provide examples of discoveries made utilizing these techniques. These approaches include mixed lymphocyte reactions, trans-vivo delayed-type hypersensitivity, enzyme-linked immunospot assays, the use of antigen receptor transgenic lymphocytes, and utilization of peptide-major histocompatibility multimers, along with imaging techniques for static multiparameter analysis or dynamic in vivo tracking. Such approaches have already refined our understanding of the alloimmune response and are pointing to new ways to improve allograft outcomes in the clinic.

The combination of hypomethylating agents and histone deacetylase inhibitors produce marked synergy in preclinical models of T-cell lymphoma.

T-cell lymphomas (TCL) are aggressive lymphomas usually treated with CHOP (cyclophsophamide, doxorubicin, vincristine, prednisolone)-like regimens upfront. Recent data suggest that TCL are driven by epigenetic defects, potentially rendering them sensitive to epigenetic therapies. We explored the therapeutic merits of a combined epigenetic platform using histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors (DNMT) in in vitro and in vivo models of TCL. The 50% inhibitory concentration (IC50 ) values revealed romidepsin was the most potent HDACI, with an IC50 in the low nanomolar range. The combination with a hypomethylating agent produced synergy across all cell lines, which was confirmed in cytotoxicity and apoptosis assays. An in vivo xenograft study demonstrated inhibition of tumour growth in the combination cohort compared to the single agent. Gene expression array and global methylation profiling revealed differentially expressed genes and modulated pathways for each of the single treatment conditions and the combination. Most of the effects induced by the single agent treatment were maintained in the combination group. In total, 944 unique genes were modulated by the combination treatment, supporting the hypothesis of molecular synergism. These data suggest combinations of hypomethylating agents and HDACIs are synergistic in models of TCL, which is supported at the molecular level.