Coupled myovascular expansion directs cardiac growth and regeneration.

Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here, we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled. We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encoding Vegfa enhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting that Vegfa can stimulate human cardiac growth. Our work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.

The Excess Costs of Hospitalization for Acute Stroke in People With Communication Impairment: A Stroke123 Data Linkage Substudy.

OBJECTIVE: To describe the costs of hospital care for acute stroke for patients with aphasia or dysarthria. DESIGN: Observational study from the Stroke123 project. SETTING: Data from patients admitted with stroke (2009-2013) from 22 hospitals in Queensland participating in the Australian Stroke Clinical Registry (AuSCR) were linked to administrative datasets. PARTICIPANTS: Communication impairments were identified using International Classification of Diseases, 10th Revision, Australian Modification codes. Overall, 1043 of 4195 (25%) patients were identified with aphasia (49% were women; median age 78 years; 83% with ischemic stroke), and 1005 (24%) with dysarthria (42% were women; median age 76 years; 85% with ischemic stroke). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Linked patient-level, hospital clinical costing related to the stroke, were adjusted to 2013/2014 Australian dollars (AU$, US$ conversion x 0.691) using recommended national price indices and multivariable regression analysis with clustering by hospital performed. RESULTS: Compared with patients without aphasia, the median hospital costs/patient were greater for those with aphasia for medical (aphasia AU$2273 vs AU$1727, P<.001), nursing (aphasia AU$3829 vs AU$2748, P<.001) and allied health services (aphasia AU$1138 vs AU$720, P<.001). Similarly, costs were greater for patients with dysarthria compared with those without dysarthria. Adjusted median total costs were AU$2882 greater for patients with aphasia compared with patients without aphasia (95% confidence interval, AU$1880-3884), and AU$843 greater for patients with dysarthria compared with those without dysarthria (95% confidence interval, AU$-301 to 1987). CONCLUSIONS: People with communication impairment after stroke incur greater hospital costs, in particular for medical, allied health, and nursing resources.

Sequence Evaluation and Comparative Analysis of Novel Assays for Intact Proviral HIV-1 DNA.

The HIV proviral reservoir is the major barrier to cure. The predominantly replication-defective proviral landscape makes the measurement of virus that is likely to cause rebound upon antiretroviral therapy (ART)-cessation challenging. To address this issue, novel assays to measure intact HIV proviruses have been developed. The intact proviral DNA assay (IPDA) is a high-throughput assay that uses two probes to exclude the majority of defective proviruses and determine the frequency of intact proviruses, albeit without sequence confirmation. Quadruplex PCR with four probes (Q4PCR) is a lower-throughput assay that uses limiting dilution long-distance PCR amplification followed by quantitative PCR (qPCR) and near-full-length genome sequencing (nFGS) to estimate the frequency of sequence-confirmed intact proviruses and provide insight into their clonal composition. To explore the advantages and limitations of these assays, we compared IPDA and Q4PCR measurements from 39 ART-suppressed people living with HIV. We found that IPDA and Q4PCR measurements correlated with one another, but frequencies of intact proviral DNA differed by approximately 19-fold. This difference may be in part due to inefficiencies in long-distance PCR amplification of proviruses in Q4PCR, leading to underestimates of intact proviral frequencies. In addition, nFGS analysis within Q4PCR explained that some of this difference is explained by proviruses that are classified as intact by IPDA but carry defects elsewhere in the genome. Taken together, this head-to-head comparison of novel intact proviral DNA assays provides important context for their interpretation in studies to deplete the HIV reservoir and shows that together the assays bracket true reservoir size.IMPORTANCE The intact proviral DNA assay (IPDA) and quadruplex PCR (Q4PCR) represent major advances in accurately quantifying and characterizing the replication-competent HIV reservoir. This study compares the two novel approaches for measuring intact HIV proviral DNA in samples from 39 antiretroviral therapy (ART)-suppressed people living with HIV, thereby informing ongoing efforts to deplete the HIV reservoir in cure-related trials.

Longitudinal Dynamics of Intact HIV Proviral DNA and Outgrowth Virus Frequencies in a Cohort of Individuals Receiving Antiretroviral Therapy.

BACKGROUND: The replication-competent human immunodeficiency virus (HIV) reservoir is the major barrier to cure. The quantitative viral outgrowth assay (QVOA), the gold-standard method to quantify replication-competent HIV, is resource intensive, which limits its application in large clinical trials. The intact proviral DNA assay (IPDA) requires minimal cell input relative to QVOA and quantifies both defective and intact proviral HIV DNA, the latter potentially serving as a surrogate marker for replication-competent provirus. However, there are limited cross-sectional and longitudinal data on the relationship between IPDA and QVOA measurements. METHODS: QVOA and IPDA measurements were performed on 156 resting CD4 T-cell (rCD4) samples from 83 antiretroviral therapy-suppressed HIV-positive participants. Longitudinal QVOA and IPDA measurements were performed on rCD4 from 29 of these participants. RESULTS: Frequencies of intact, defective, and total proviruses were positively associated with frequencies of replication-competent HIV. Longitudinally, decreases in intact proviral frequencies were strikingly similar to that of replication-competent virus in most participants. In contrast, defective proviral DNA frequencies appeared relatively stable over time in most individuals. CONCLUSIONS: Changes in frequencies of IPDA-derived intact proviral DNA and replication-competent HIV measured by QVOA are similar. IPDA is a promising high-throughput approach to estimate changes in the frequency of the replication-competent reservoir.

Impact of Biological Sex on Immune Activation and Frequency of the Latent HIV Reservoir During Suppressive Antiretroviral Therapy.

BACKGROUND: Persistent HIV infection of long-lived resting CD4 T cells, despite antiretroviral therapy (ART), remains a barrier to HIV cure. Women have a more robust type 1 interferon response during HIV infection relative to men, contributing to lower initial plasma viremia. As lower viremia during acute infection is associated with reduced frequency of latent HIV infection, we hypothesized that women on ART would have a lower frequency of latent HIV compared to men. METHODS: ART-suppressed, HIV seropositive women (n = 22) were matched 1:1 to 22 of 39 ART-suppressed men. We also compared the 22 women to all 39 men, adjusting for age and race as covariates. We measured the frequency of latent HIV using the quantitative viral outgrowth assay, the intact proviral DNA assay, and total HIV gag DNA. We also performed activation/exhaustion immunophenotyping on peripheral blood mononuclear cells and quantified interferon-stimulated gene (ISG) expression in CD4 T cells. RESULTS: We did not observe evident sex differences in the frequency of persistent HIV in resting CD4 T cells. Immunophenotyping and CD4 T-cell ISG expression analysis revealed marginal differences across the sexes. CONCLUSIONS: Differences in HIV reservoir frequency and immune activation appear to be small across sexes during long-term suppressive therapy.

Y-Peg-in-a-Round-Hole Closure for Immediate Periareolar Mastectomy Expander Reconstruction.

INTRODUCTION: Mastectomies closed with a linear scar can distort the resulting shape of the breast. We present our novel Y-peg-in-a-round-hole closure method of the mastectomy scar, which improves the shape of the reconstructed breast while maintaining reliable healing, implant coverage, and minimum scar size for covering by tattoo. MATERIALS AND METHODS: A retrospective review of all breast reconstruction cases performed by the senior surgeon during the period from January 2010 to January 2017 was undertaken. Data were analyzed for wound healing problems, infection rates and mastectomy skin flap necrosis. RESULTS: Data were extracted for 126 consecutive patients with 154 breast reconstructions. Twelve breasts (7.7%) experienced wound healing problems, for which 7 (4.5%) required revisionary surgery. Eighteen breasts (11.7%) developed an infection requiring antibiotics, of which 8 (5.2%) needed a further operation. Four breasts (2.6%) needed removal of the implant. No patients were lost to follow-up. CONCLUSION: After nipple resecting mastectomy, the Y-peg-in-a-round-hole scar minimizes radial size and contour deformity but allows for reliable wound healing.

APOBEC3G and APOBEC3F Act in Concert To Extinguish HIV-1 Replication.

UNLABELLED: The multifunctional HIV-1 accessory protein Vif counters the antiviral activities of APOBEC3G (A3G) and APOBEC3F (A3F), and some Vifs counter stable alleles of APOBEC3H (A3H). Studies in humanized mice have shown that HIV-1 lacking Vif expression is not viable. Here, we look at the relative contributions of the three APOBEC3s to viral extinction. Inoculation of bone marrow/liver/thymus (BLT) mice with CCR5-tropic HIV-1JRCSF(JRCSF) expressing a vif gene inactive for A3G but not A3F degradation activity (JRCSFvifH42/43D) displayed either no or delayed replication. JRCSF expressing a vif gene mutated to inactivate A3F degradation but not A3G degradation (JRCSFvifW79S) always replicated to high viral loads with variable delays. JRCSF with vif mutated to lack both A3G and A3F degradation activities (JRCSFvifH42/43DW79S) failed to replicate, mimicking JRCSF without Vif expression (JRCSFΔvif). JRCSF and JRCSFvifH42/43D, but not JRCSFvifW79S or JRCSFvifH42/43DW79S, degraded APOBEC3D. With one exception, JRCSFs expressing mutant Vifs that replicated acquired enforced vif mutations. These mutations partially restored A3G or A3F degradation activity and fully replaced JRCSFvifH42/43D or JRCSFvifW79S by 10 weeks. Surprisingly, induced mutations temporally lagged behind high levels of virus in blood. In the exceptional case, JRCSFvifH42/43D replicated after a prolonged delay with no mutations in vif but instead a V27I mutation in the RNase H coding sequence. JRCSFvifH42/43D infections exhibited massive GG/AG mutations in pol viral DNA, but in viral RNA, there were no fixed mutations in the Gag or reverse transcriptase coding sequence. A3H did not contribute to viral extinction but, in combination with A3F, could delay JRCSF replication. A3H was also found to hypermutate viral DNA. IMPORTANCE: Vif degradation of A3G and A3F enhances viral fitness, as virus with even a partially restored capacity for degradation outgrows JRCSFvifH42/43D and JRCSFvifW79S. Unexpectedly, fixation of mutations that replaced H42/43D or W79S in viral RNA lagged behind the appearance of high viral loads. In one exceptional JRCSFvifH42/43D infection, vif was unchanged but replication proceeded after a long delay. These results suggest that Vif binds and inhibits the non-cytosine deaminase activities of intact A3G and intact A3F, allowing JRCSFvifH42/43D and JRCSFvifW79S to replicate with reduced fitness. Subsequently, enhanced Vif function is acquired by enforced mutations. In infected cells, JRCSFΔvif and JRCSFvifH42/43DW79S are exposed to active A3F and A3G and fail to replicate. JRCSFvifH42/43D Vif degrades A3F and, in some cases, overcomes A3G mutagenic activity to replicate. Vif may have evolved to inhibit A3F and A3G by stoichiometric binding and subsequently acquired the ability to target these proteins to proteasomes.

Nanoformulations of Rilpivirine for Topical Pericoital and Systemic Coitus-Independent Administration Efficiently Prevent HIV Transmission.

Vaginal HIV transmission accounts for the majority of new infections worldwide. Currently, multiple efforts to prevent HIV transmission are based on pre-exposure prophylaxis with various antiretroviral drugs. Here, we describe two novel nanoformulations of the reverse transcriptase inhibitor rilpivirine for pericoital and coitus-independent HIV prevention. Topically applied rilpivirine, encapsulated in PLGA nanoparticles, was delivered in a thermosensitive gel, which becomes solid at body temperature. PLGA nanoparticles with encapsulated rilpivirine coated the reproductive tract and offered significant protection to BLT humanized mice from a vaginal high-dose HIV-1 challenge. A different nanosuspension of crystalline rilpivirine (RPV LA), administered intramuscularly, protected BLT mice from a single vaginal high-dose HIV-1 challenge one week after drug administration. Using transmitted/founder viruses, which were previously shown to establish de novo infection in humans, we demonstrated that RPV LA offers significant protection from two consecutive high-dose HIV-1 challenges one and four weeks after drug administration. In this experiment, we also showed that, in certain cases, even in the presence of drug, HIV infection could occur without overt or detectable systemic replication until levels of drug were reduced. We also showed that infection in the presence of drug can result in acquisition of multiple viruses after subsequent exposures. These observations have important implications for the implementation of long-acting antiretroviral formulations for HIV prevention. They provide first evidence that occult infections can occur, despite the presence of sustained levels of antiretroviral drugs. Together, our results demonstrate that topically- or systemically administered rilpivirine offers significant coitus-dependent or coitus-independent protection from HIV infection.

In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection.

BACKGROUND: The latent reservoir in resting CD4(+) T cells presents a major barrier to HIV cure. Latency-reversing agents are therefore being developed with the ultimate goal of disrupting the latent state, resulting in induction of HIV expression and clearance of infected cells. Histone deacetylase inhibitors (HDACi) have received a significant amount of attention for their potential as latency-reversing agents. RESULTS: Here, we have investigated the in vitro and systemic in vivo effect of panobinostat, a clinically relevant HDACi, on HIV latency. We showed that panobinostat induces histone acetylation in human PBMCs. Further, we showed that panobinostat induced HIV RNA expression and allowed the outgrowth of replication-competent virus ex vivo from resting CD4(+) T cells of HIV-infected patients on suppressive antiretroviral therapy (ART). Next, we demonstrated that panobinostat induced systemic histone acetylation in vivo in the tissues of BLT humanized mice. Finally, in HIV-infected, ART-suppressed BLT mice, we evaluated the effect of panobinostat on systemic cell-associated HIV RNA and DNA levels and the total frequency of latently infected resting CD4(+) T cells. Our data indicate that panobinostat treatment resulted in systemic increases in cellular levels of histone acetylation, a key biomarker for in vivo activity. However, panobinostat did not affect the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4(+) T cells. CONCLUSION: We have demonstrated robust levels of systemic histone acetylation after panobinostat treatment of BLT humanized mice; and we did not observe a detectable change in the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4(+) T cells in HIV-infected, ART-suppressed BLT mice. These results are consistent with the modest effects noted in vitro and suggest that combination therapies may be necessary to reverse latency and enable clearance. Animal models will contribute to the progress towards an HIV cure.

A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges.

OBJECTIVES: Pre-exposure prophylaxis (PrEP) using antiretroviral drugs (ARVs) has been shown to reduce HIV transmission in people at high risk of HIV infection. Adherence to PrEP strongly correlates with the level of HIV protection. Long-acting injectable ARVs provide sustained systemic drug exposures over many weeks and can improve adherence due to infrequent parenteral administration. Here, we evaluated a new long-acting formulation of raltegravir for prevention of vaginal HIV transmission. METHODS: Long-acting raltegravir was administered subcutaneously to BALB/c, NSG (NOD-scid-gamma) and humanized BLT (bone marrow-liver-thymus) mice and rhesus macaques. Raltegravir concentration in peripheral blood and tissue was analysed. Suppression of HIV replication was assessed in infected BLT mice. Two high-dose HIV vaginal challenges were used to evaluate protection from HIV transmission in BLT mice. RESULTS: Two weeks after a single subcutaneous injection of long-acting raltegravir in BLT mice (7.5 mg) and rhesus macaques (160 mg), the plasma concentration of raltegravir was comparable to 400 mg orally, twice daily in humans. Serum collected from mice 3 weeks post-administration of long-acting raltegravir efficiently blocked HIV infection of TZM-bl indicator cells in vitro. Administration of long-acting raltegravir suppressed viral RNA in plasma and cervico-vaginal fluids of infected BLT mice, demonstrating penetration of active raltegravir into the female reproductive tract. Using transmitted/founder HIV we observed that BLT mice administered a single subcutaneous dose of long-acting raltegravir were protected from two high-dose HIV vaginal challenges 1 week and 4 weeks after drug administration. CONCLUSIONS: These preclinical results demonstrated the efficacy of long-acting raltegravir in preventing vaginal HIV transmission.

HIV pre-exposure prophylaxis for women and infants prevents vaginal and oral HIV transmission in a preclinical model of HIV infection.

BACKGROUND: Approximately 1.5 million HIV-positive women become pregnant annually. Without treatment, up to 45% will transmit HIV to their infants, primarily through breastfeeding. These numbers highlight that HIV acquisition is a major health concern for women and children globally. They also emphasize the urgent need for novel approaches to prevent HIV acquisition that are safe, effective and convenient to use by women and children in places where they are most needed. METHODS: 4'-Ethynyl-2-fluoro-2'-deoxyadenosine, a potent NRTI with low cytotoxicity, was administered orally to NOD/SCID/γc-/- mice and to bone marrow/liver/thymus (BLT) humanized mice, a preclinical model of HIV infection. HIV inhibitory activity in serum, cervicovaginal secretions and saliva was evaluated 4 h after administration. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine's ability to prevent vaginal and oral HIV transmission was evaluated using highly relevant transmitted/founder viruses in BLT mice. RESULTS: Strong HIV inhibitory activity in serum, cervicovaginal secretions and saliva obtained from animals after a single oral dose of 4'-ethynyl-2-fluoro-2'-deoxyadenosine (10 mg/kg) demonstrated efficient drug penetration into relevant mucosal sites. A single daily oral dose of 4'-ethynyl-2-fluoro-2'-deoxyadenosine resulted in efficient prevention of vaginal and oral HIV transmission after multiple high-dose exposures to transmitted/founder viruses in BLT humanized mice. CONCLUSIONS: Our data demonstrated that 4'-ethynyl-2-fluoro-2'-deoxyadenosine efficiently prevents both vaginal and oral HIV transmission. Together with 4'-ethynyl-2-fluoro-2'-deoxyadenosine's relatively low toxicity and high potency against drug-resistant HIV strains, these data support further clinical development of 4'-ethynyl-2-fluoro-2'-deoxyadenosine as a potential pre-exposure prophylaxis agent to prevent HIV transmission in women and their infants.

Breast Milk of HIV-Positive Mothers Has Potent and Species-Specific In Vivo HIV-Inhibitory Activity.

UNLABELLED: Despite the nutritional and health benefits of breast milk, breast milk can serve as a vector for mother-to-child HIV transmission. Most HIV-infected infants acquire HIV through breastfeeding. Paradoxically, most infants breastfed by HIV-positive women do not become infected. This is potentially attributed to anti-HIV factors in breast milk. Breast milk of HIV-negative women can inhibit HIV infection. However, the HIV-inhibitory activity of breast milk from HIV-positive mothers has not been evaluated. In addition, while significant differences in breast milk composition between transmitting and nontransmitting HIV-positive mothers have been correlated with transmission risk, the HIV-inhibitory activity of their breast milk has not been compared. This knowledge may significantly impact the design of prevention approaches in resource-limited settings that do not deny infants of HIV-positive women the health benefits of breast milk. Here, we utilized bone marrow/liver/thymus humanized mice to evaluate the in vivo HIV-inhibitory activity of breast milk obtained from HIV-positive transmitting and nontransmitting mothers. We also assessed the species specificity and biochemical characteristics of milk's in vivo HIV-inhibitory activity and its ability to inhibit other modes of HIV infection. Our results demonstrate that breast milk of HIV-positive mothers has potent HIV-inhibitory activity and indicate that breast milk can prevent multiple routes of infection. Most importantly, this activity is unique to human milk. Our results also suggest multiple factors in breast milk may contribute to its HIV-inhibitory activity. Collectively, our results support current recommendations that HIV-positive mothers in resource-limited settings exclusively breastfeed in combination with antiretroviral therapy. IMPORTANCE: Approximately 240,000 children become infected with HIV annually, the majority via breastfeeding. Despite daily exposure to virus in breast milk, most infants breastfed by HIV-positive women do not acquire HIV. The low risk of breastfeeding-associated HIV transmission is likely due to antiviral factors in breast milk. It is well documented that breast milk of HIV-negative women can inhibit HIV infection. Here, we demonstrate, for the first time, that breast milk of HIV-positive mothers (nontransmitters and transmitters) inhibits HIV transmission. We also demonstrate that breast milk can prevent multiple routes of HIV acquisition and that this activity is unique to human milk. Collectively, our results support current guidelines which recommend that HIV-positive women in resource-limited settings exclusively breastfeed in combination with infant or maternal antiretroviral therapy.

Identifying communication difficulty and context-specific communication supports for patient-provider communication in a sub-acute setting: A prospective mixed methods study.

PURPOSE: To identify the sub-acute rehabilitation inpatients who have communication difficulty and the range of communication supports that can facilitate communicative success. METHOD: A prospective cohort mixed methods study was conducted on two inpatient sub-acute rehabilitation wards. Nurses screened all new admissions for communication difficulty using the Inpatient Functional Communication Interview, Screening Questionnaire (IFCI-SQ). Patients identified as having communication difficulty were interviewed by a speech-language pathologist (SLP) using the Inpatient Functional Communication Interview (IFCI). During the interview, the SLP trialled different communication supports. The number of patients who had communication difficulty on the IFCI-SQ was calculated. The number and type of communication supports that improved communication within the patient-SLP interview were calculated. Deductive-dominant qualitative content analysis was conducted on the communication supports used during the IFCI. RESULT: Seventy patients were screened. Nurses reported communication difficulty in 45/70 (64%) of patients. A total of 15/45 patients were interviewed by an SLP using the IFCI. The provision of communication supports improved communication for all patients within the context of the patient-SLP interview. CONCLUSION: Many sub-acute rehabilitation inpatients have communication difficulty in the hospital setting. A range of communication supports facilitated communication. These insights could inform future communication partner training (CPT) programs.

Aphasia Depression and Psychological Therapy (ADaPT): Perspectives of People with Post-Stroke Aphasia on Participating in a Modified Cognitive Behavioral Therapy.

Aphasia, a communication disability commonly caused by stroke, can profoundly affect a person's mood and identity. We explored the experiences of stroke survivors with aphasia and depression who received a modified cognitive behavioral therapy (CBT)-based psychological intervention. The therapy is manualized with a flexible treatment protocol, including 10 individually based therapy sessions (+2 booster sessions) either via telehealth or in person. Six participants with chronic aphasia (60% of the total sample) participated in in-depth interviews that were analyzed using reflexive thematic analysis. Two core themes were derived from the data: the first theme, helpful elements of therapy-doing enjoyable activities, new ways of thinking, problem solving, working with the experienced therapist, and using telehealth; and the second theme, making progress-mood, communication, acceptance of the 'new me', and improving relationships. All participants found the therapy to be helpful in managing mood problems with various elements being beneficial depending on the individual, highlighting the importance of tailoring the intervention. Therefore, delivering modified CBT to individuals with aphasia is likely to be acceptable both in person and through telehealth. Further evaluation of the intervention and its impact on mood would be beneficial.

Developing consensus-based clinical competencies to guide stroke clinicians in the implementation of psychological care in aphasia rehabilitation.

Background People with aphasia experience depression and anxiety associated with negative outcomes across a range of time post-stroke. Stroke clinicians are well-positioned to facilitate low-intensity psychotherapeutic interventions after aphasia (e.g. mood screening, behavioural activation, problem-solving therapy, relaxation therapy); however, they self-report a lack of knowledge, skills and confidence to do so. The Theoretical Domains Framework (TDF) provides a lens through which to view and target clinician behaviours and training needs in this area of practice. The aim of this study was to develop and gain consensus on items for a rating scale of clinical competencies in facilitating individual-based, low-intensity psychotherapeutic interventions for people with aphasia. Methods An e-Delphi methodology using focus groups and survey rounds was used to gain consensus on clinical competencies considered important. Results Eight stroke clinicians (speech pathologists and psychologists), two people with aphasia and three family members participated in one of four focus groups. Four themes were derived from the data: (1) Communication support, (2) Assessment and therapy structure, (3) Interpersonal skills, and (4) Needs of the significant other (family or friend). Themes informed an initial list of 23 self-rated and observer-rated competency items. Following two rounds of e-Delphi surveys, 11 stroke clinicians (six speech pathologists and five psychologists) reached consensus (80-100%) for 19 competencies. Conclusions The Psychological Care in Aphasia Rehabilitation Competency scale offers a preliminary list of items to guide and train clinicians to implement low-intensity psychotherapeutic interventions for people with aphasia.

Comprehensive quality assessment for aphasia rehabilitation after stroke: protocol for a multicentre, mixed-methods study.

INTRODUCTION: People with aphasia following stroke experience disproportionally poor outcomes, yet there is no comprehensive approach to measuring the quality of aphasia services. The Meaningful Evaluation of Aphasia SeRvicES (MEASuRES) minimum dataset was developed in partnership with people with lived experience of aphasia, clinicians and researchers to address this gap. It comprises sociodemographic characteristics, quality indicators, treatment descriptors and outcome measurement instruments. We present a protocol to pilot the MEASuRES minimum dataset in clinical practice, describe the factors that hinder or support implementation and determine meaningful thresholds of clinical change for core outcome measurement instruments. METHODS AND ANALYSIS: This research aims to deliver a comprehensive quality assessment toolkit for poststroke aphasia services in four studies. A multicentre pilot study (study 1) will test the administration of the MEASuRES minimum dataset within five Australian health services. An embedded mixed-methods process evaluation (study 2) will evaluate the performance of the minimum dataset and explore its clinical applicability. A consensus study (study 3) will establish consumer-informed thresholds of meaningful change on core aphasia outcome constructs, which will then be used to establish minimal important change values for corresponding core outcome measurement instruments (study 4). ETHICS AND DISSEMINATION: Studies 1 and 2 have been registered with the Australian and New Zealand Clinical Trial Registry (ACTRN12623001313628). Ethics approval has been obtained from the Royal Brisbane and Women's Hospital (HREC/2023/MNHB/95293) and The University of Queensland (2022/HE001946 and 2023/HE001175). Study findings will be disseminated through peer-reviewed publications, conference presentations and engagement with relevant stakeholders including healthcare providers, policy-makers, stroke and rehabilitation audit and clinical quality registry custodians, consumer support organisations, and individuals with aphasia and their families.

The impact of a genomic assay (Oncotype DX) on adjuvant treatment recommendations in early breast cancer.

OBJECTIVES: To assess how the recurrence score of the Oncotype DX breast cancer assay influences adjuvant systemic treatment decisions in the multidisciplinary meeting (MDM) for patients with early breast cancer (EBC) in Australia. DESIGN, SETTING AND PARTICIPANTS: A before-and-after study at three academic medical centres in Melbourne with patients and physicians serving as their own controls. Paired systemic adjuvant treatment recommendations were made in multidisciplinary meetings (MDMs) before and after Oncotype DX testing. Medical oncologists and surgeons, treating patients with unifocal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-negative or node-positive early breast cancer. MAIN OUTCOME MEASURES: Changes in physician treatment recommendations. RESULTS: This study enrolled 151 eligible patients between 1 November 2010 and 30 September 2011. Of these, 101 patients (67%) had node-negative and 50 (33%) had node-positive tumours. Recurrence score information resulted in treatment recommendation changes for 24 patients with node-negative tumours (24%) and for 13 patients with node-positive tumours (26%). The proportional change from chemo-hormonal therapy (CHT) to hormonal therapy (HT) was significantly greater than from HT to CHT for patients with node-negative tumours (23% difference in proportions; P= 0.02), and of similar magnitude for patients with node-positive tumours (25% difference in proportions; P = 0.14). CONCLUSION: The Oncotype DX recurrence score has a major impact on adjuvant treatment decision making in the MDM setting.

Internal mammary node involvement in patients with axilla-negative early breast cancer: a narrative review.

Early breast cancer staging involves radiological and pathological evaluation of the tumour and regional lymph nodes. The internal mammary nodes (IMN) are an important site of possible metastasis and influence disease stage and prognosis. However, the recommendation for routine IMN assessment remains unclear. Internal mammary sentinel lymph node biopsy (SLNB) is associated with increased morbidity and an unknown survival benefit. Furthermore, the IMN are traditionally thought to be involved only synchronous with, or following, axillary node (AXN) metastasis. The aim of this review is to determine the prevalence of IMN metastasis in patients with axilla-negative early breast cancer. A narrative review of studies assessing IMN metastasis was performed. The literature search was completed using the database Medline (Ovid). Twenty-two retrospective studies were identified. The studies included data from SLNB, US, MRI, PET/CT and opportunistic biopsy during free-flap reconstruction (FFR). The prevalence of isolated IMN metastasis ranged from 1.2% to 17.9%.

Mental health support after stroke: A qualitative exploration of lived experience.

PURPOSE: Unmanaged mental health problems following a stroke can be detrimental to recovery. We aimed to explore the lived experience of (a) poststroke mental health difficulties, (b) help-seeking for mental health, including factors that influenced treatment access and utilization, and (c) receiving treatment and support. RESEARCH METHOD: Individual semistructured interviews were conducted in 2022 with 13 participants (62% female, age at stroke 35-76 years) who had experienced mental health difficulties following their stroke. Data were analyzed using reflexive thematic analysis with a critical realist approach. RESULTS: Six themes were identified. Mental health challenges poststroke were diverse in nature. Attitudes and previous experiences relating to mental health influenced the inclination to seek help. Participants valued an individualized approach to the provision and timing of psychoeducation. Accessibility of services was impacted by financial and transportation barriers, as well as availability of services and appropriately trained clinicians. Participation in support groups was a positive experience for most participants. Lived experience of mental health treatment ranged from positive to negative, and participants conveyed helpful and unhelpful aspects. CONCLUSIONS: Findings highlight the importance of early screening and psychoeducation provision for poststroke mental health difficulties, alongside accessible community-based mental health support services throughout the stroke recovery journey. Having varied options for mental health support and treatment may aid stroke survivors in finding an approach that personally works for them. Additionally, it may be helpful to train clinicians to tailor mental health treatment to accommodate stroke-related impairments (e.g., cognitive, sensorimotor). (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Pathologic Complete Response and Oncologic Outcomes in Locally Advanced Breast Cancers Treated With Neoadjuvant Radiation Therapy: An Australian Perspective.

PURPOSE: To assess the degree of pathologic complete response (pCR), postoperative surgical complication rates, and oncological outcomes in women with locally advanced breast cancer or high-risk breast cancers treated with neoadjuvant radiation therapy (NART). METHODS AND MATERIALS: This retrospective, multi-institutional review involved 138 clinically staged patients with 140 breast cancers treated with NART between January 2014 and February 2021. Treatments involved sequential neoadjuvant chemotherapy and NART, followed by mastectomy with or without axillary surgery and immediate autologous breast reconstruction. Descriptive statistics were used to assess patient and disease features, treatment regimens, pathologic response, and factors affecting postoperative complications. Kaplan-Meier curves were performed to assess locoregional recurrence-free, distant metastasis-free, and overall survival outcomes. RESULTS: Median age was 47 years (interquartile range, 42-52). The median follow-up was 35.2 months (interquartile range, 17.1-46.5). pCR was achieved in 36.4% (as defined by Chevallier classification) or 42.1% (as defined by Miller-Payne scores) of patients. Greater pCR rates were achieved for HER2+ (73.8%-85.7%) and triple-negative phenotypes (47.6%-57.1%). There were 21 grade 3 surgical complications including 10 grade 3B breast events and 8 grade 3B donor-site events, where surgical reintervention was required. At 3-years' follow-up, the locoregional recurrence-free survival was 98.1%, distant metastasis-free survival was 83.6%, and overall survival was 95.3%%. CONCLUSIONS: NART is feasible to facilitate a single-stage mastectomy and immediate autologous breast reconstruction. This study demonstrated comparable rates of postoperative complication to standard of care, and high rates of pCR, which translates to high rates of locoregional control, distant metastasis-free survival, and overall survival.