Ventilatory and chronotropic incompetence during incremental and constant load exercise in end-stage renal disease: a comparative physiology study.

Maximal O2 uptake is impaired in end-stage renal disease (ESRD), reducing quality of life and longevity. While determinants of maximal exercise intolerance are well defined, little is known of limitation during submaximal constant load exercise. By comparing individuals with ESRD and healthy controls, the aim of this exploratory study was to characterize mechanisms of exercise intolerance in participants with ESRD by assessing cardiopulmonary physiology at rest and during exercise. Resting spirometry and echocardiography were performed in 20 dialysis-dependent participants with ESRD (age: 59 ± 12 yr, 14 men and 6 women) and 20 healthy age- and sex-matched controls. Exercise tolerance was assessed with ventilatory gas exchange and central hemodynamics during a maximal cardiopulmonary exercise test and 30 min of submaximal constant load exercise. Left ventricular mass (292 ± 102 vs. 185 ± 83 g, P = 0.01) and filling pressure (E/e': 6.48 ± 3.57 vs. 12.09 ± 6.50 m/s, P = 0.02) were higher in participants with ESRD; forced vital capacity (3.44 ± 1 vs. 4.29 ± 0.95 L/min, P = 0.03) and peak O2 uptake (13.3 ± 2.7 vs. 24.6 ± 7.3 mL·kg-1·min-1, P < 0.001) were lower. During constant load exercise, the relative increase in the arterial-venous O2 difference (13 ± 18% vs. 74 ± 18%) and heart rate (32 ± 18 vs. 75 ± 29%) were less in participants with ESRD despite exercise being performed at a higher percentage of maximum minute ventilation (48 ± 3% vs. 39 ± 3%) and heart rate (82 ± 2 vs. 64 ± 2%). Ventilatory and chronotropic incompetence contribute to exercise intolerance in individuals with ESRD. Both are potential targets for medical and lifestyle interventions.

The Incorporation of an Advanced Donation Program Into Kidney Paired Exchange: Initial Experience of the National Kidney Registry.

The continued growth of kidney paired donation (KPD) to facilitate transplantation for otherwise incompatible or suboptimal living kidney donors and recipients has depended on a balance between the logistics required for patients and the collaborating transplant centers. The formation of chains for KPD and the shipping of kidneys have permitted networks such as the National Kidney Registry (NKR) to offer KPD to patients over a transcontinental area. However, over the last 3 years, we have encountered patient requests for a more flexible experience in KPD to meet their individual needs often due to rigid time constraints. To accommodate these requests, we have developed an Advanced Donation Program (ADP) in which the donor desires to donate by a specific date, but their paired recipient has not yet been matched to a specific donor or scheduled for surgery. After obtaining careful informed consent from both the donor and paired recipient, 10 KPD chains were constructed using an ADP donor. These 10 ADP donors have facilitated 47 transplants, and thus far eight of their paired recipients have received a kidney within a mean of 178 (range 10-562) days. The ADP is a viable method to support time limited donors in a KPD network.

Consensus conference on best practices in live kidney donation: recommendations to optimize education, access, and care.

Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5-6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation.

The role of a bus network in access to primary health care in Metropolitan Auckland, New Zealand.

UNLABELLED: Background: This study examined the spatial accessibility of the population of metropolitan Auckland, New Zealand to the bus network, to connect them to primary health providers, in this case doctors (GP) and dentists. Analysis of accessibility by ethnic identity and socio-economic status were also carried out, because of existing health inequalities along these dimensions. The underlying hypothesis was that most people would live within easy reach of primary health providers, or easy bus transport to such providers. METHODS: An integrated geographic model of bus transport routes and stops, with population and primary health providers (medical. and dental practices) was developed and analysed. RESULTS: Although the network of buses in metropolitan Auckland is substantial and robust it was evident that many people live more than 150 metres from a stop. CONCLUSION: Improving the access to bus stops, particularly in areas of high primary health care need (doctors and dentists), would certainly be an opportunity to enhance spatial access in a growing metropolitan area.

Collision induced ultraviolet structure in nitrogen radar REMPI spectra.

We present 2 + 2 radar REMPI measurements in molecular nitrogen under atmospheric conditions and observe a strong interference in the (1,0) vibrational band of the a(1)Πg ← X(1)Σg(+) electronic manifold. The interference is suppressed by using circularly polarized light, permitting rotational analysis of the 2 + 2 radar REMPI spectrum. It is observed in pure nitrogen, though the structure varies with gas composition. The structure also varies with temperature and pressure. These results indicate that it is collision induced. We hypothesize that the source of the interference is a 3 + 1 REMPI process through the a(″1)Σg(+) electronic state.

Relationship between fractional anisotropy of cerebral white matter and metabolite concentrations measured using (1)H magnetic resonance spectroscopy in healthy adults.

Fractional anisotropy (FA) of water diffusion in cerebral white matter (WM), derived from diffusion tensor imaging (DTI), is a sensitive index of microscopic WM integrity. Physiological and metabolic factors that explain intersubject variability in FA values were evaluated in two cohorts of healthy adults of different age spans (N=65, range: 28-50years; and N=25, age=66.6±6.2, range: 57-80years). Single voxel magnetic resonance spectroscopy (MRS) was used to measure N-acetylaspartate (NAA), total choline-containing compounds, and total creatine, bilaterally in an associative WM tract: anterior corona radiata (ACR). FA values were calculated for the underlying, proximal and two distal WM regions. Two-stage regression analysis was used to calculate the proportion of variability in FA values explained by spectroscopy measurements, at the first stage, and subject's age, at the second stage. WM NAA concentration explained 23% and 66% of intersubject variability (p<0.001) in the FA of the underlying WM in the younger and older cohorts, respectively. WM NAA concentration also explained a significant proportion of variability in FA of the genu of corpus callosum (CC), a proximal WM tract where some of the fibers contained within the spectroscopic voxel decussate. NAA concentrations also explained a significant proportion of variability in the FA values in the splenium of CC, a distal WM tract that also carries associative fibers, in both cohorts. These results suggest that MRS measurements explained a significant proportion of variability in FA values in both proximal and distal WM tracts that carry similar fiber-types.

The geographic distribution of patients seeking emergency dental care at the Royal Dental Hospital of Melbourne, Australia.

BACKGROUND: Little detail is known about the geographical catchment areas covered by dental hospitals, with no previous Australian studies of this kind. The aim of this study was to assess the geographical distribution of public dental emergency patients and their socioeconomic status to define catchment zones for a dental hospital. METHODS: All patients requesting emergency dental care at the Royal Dental Hospital Melbourne, meeting the inclusion criteria, in calendar years 2006 and 2010 were included in the sample. Geographic information systems tools were used to locate and link each patient address to the socioeconomic data. RESULTS: For both 2006 and 2010 95% of the patients were living within 50km of the hospital. In 2006, most of the patients seeking care lived within a 15km radius of the dental hospital whilst in 2010 that distance increased somewhat. Patients from areas with similar socioeconomic status living more than 10km away from the hospital had poorer access to dental emergency treatment. CONCLUSIONS: The hospital had a surprisingly large catchment zone that overlapped those of smaller community-based clinics.

Opioid analgesia in necrotizing pancreatitis: Incidence and timing of a hidden crisis.

BACKGROUND: Rates of opioid usage during necrotizing pancreatitis (NP) disease course are unknown. We hypothesized that a significant number of NP patients were prescribed opioid analgesics chronically. METHODS: Single institution IRB-approved retrospective study of 230 NP patients treated between 2015 and 2019. RESULTS: Data were available for 198/230 (86%) patients. 166/198 (84%) were discharged from their index hospitalization with a prescription for an opioid. At the first clinic visit following hospitalization, 110/182 (60%) were using opioids. Six months after disease onset, 72/163 (44%) continued to require opioids. At disease resolution, 38/144 (26%) patients remained on opioid medications. The rate of active opioid prescriptions at six months after disease onset declined throughout the period studied from 68% in 2015 to 39% in 2019. CONCLUSIONS: Opioid prescriptions are common in NP. Despite decline over time, 1 in 4 patients remain on opioids at disease resolution. These data identify an opportunity to adjust analgesic prescription practice in NP patients.

Apoptosis-modulatory miR-361-3p as a novel treatment target in endocrine-responsive and endocrine-resistant breast cancer.

Breast cancer (BC) is the most diagnosed cancer in women worldwide. In estrogen receptor (ER)-positive disease, anti-estrogens and aromatase inhibitors (AI) improve patient survival; however, many patients develop resistance. Dysregulation of apoptosis is a common resistance mechanism; thus, agents that can reinstate the activity of apoptotic pathways represent promising therapeutics for advanced drug-resistant disease. Emerging targets in this scenario include microRNAs (miRs). To identify miRs modulating apoptosis in drug-responsive and -resistant BC, a high-throughput miR inhibitor screen was performed, followed by high-content screening microscopy for apoptotic markers. Validation demonstrated that miR-361-3p inhibitor significantly increases early apoptosis and reduces proliferation of drug-responsive (MCF7), plus AI-/antiestrogen-resistant derivatives (LTED, TamR, FulvR), and ER- cells (MDA-MB-231). Importantly, proliferation-inhibitory effects were observed in vivo in a xenograft model, indicating the potential clinical application of miR-361-3p inhibition. RNA-seq of tumour xenografts identified FANCA as a direct miR-361-3p target, and validation suggested miR-361-3p inhibitor effects might be mediated in part through FANCA modulation. Moreover, miR-361-3p inhibition resulted in p53-mediated G1 cell cycle arrest through activation of p21 and reduced BC invasion. Analysis of publicly available datasets showed miR-361-3p expression is significantly higher in primary breast tumours vspaired normal tissue and is associated with decreased overall survival. In addition, miR-361-3p inhibitor treatment of BC patient explants decreased levels of miR-361-3p and proliferation marker, Ki67. Finally, miR-361-3p inhibitor showed synergistic effects on BC growth when combined with PARP inhibitor, Olaparib. Together, these studies identify miR-361-3p inhibitor as a potential new treatment for drug-responsive and -resistant advanced BC.

Addition of short-term androgen deprivation therapy to dose-escalated radiation therapy improves failure-free survival for select men with intermediate-risk prostate cancer.

BACKGROUND: Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain. PATIENTS AND METHODS: We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. RESULTS: Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P = 0.004). Recursive partitioning analysis of men without ADT classified Gleason 4 + 3 = 7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P = 0.009) but did not improve FFS for men with favorable disease (96.3% versus 97.4%; P = 0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (P = 0.006) but did not improve FFS for men with unfavorable disease and moderate or severe comorbidity (P = 0.380). CONCLUSION: The addition of ADT to DE-RT improves FFS for men with unfavorable IR-PrCa, especially those with no or minimal comorbidity.

Cardiopulmonary and metabolic physiology during hemodialysis and inter/intradialytic exercise.

Hemodialysis is associated with numerous symptoms and side effects that, in part, may be due to subclinical hypoxia. However, acute cardiopulmonary and metabolic physiology during hemodialysis is not well defined. Intradialytic and interdialytic exercise appear to be beneficial and may alleviate these side effects. To better understand these potential benefits, the acute physiological response to exercise should be evaluated. The aim of this study was to compare and characterize the acute physiological response during hemodialysis, intradialytic exercise, and interdialytic exercise. Cardiopulmonary physiology was evaluated during three conditions: 1) hemodialysis without exercise (HD), 2) intradialytic exercise (IDEx), and 3) interdialytic exercise (Ex). Exercise consisted of 30-min constant load cycle ergometry at 90% V̇O2AT (anaerobic threshold). Central hemodynamics (via noninvasive bioreactance) and ventilatory gas exchange were recorded during each experimental condition. Twenty participants (59 ± 12 yr, 16/20 male) completed the protocol. Cardiac output (Δ = -0.7 L/min), O2 uptake (Δ = -1.4 mL/kg/min), and arterial-venous O2 difference (Δ = -2.0 mL/O2/100 mL) decreased significantly during HD. Respiratory exchange ratio exceeded 1.0 throughout HD and IDEx. Minute ventilation was lower (P = 0.001) during IDEx (16.5 ± 1.1 L/min) compared with Ex (19.8 ± 1.0 L/min). Arterial-venous O2 difference was partially restored further to IDEx (4.6 ± 1.9 mL/O2/100 mL) compared with HD (3.5 ± 1.2 mL/O2/100 mL). Hemodialysis altered cardiopulmonary and metabolic physiology, suggestive of hypoxia. This dysregulated physiology contributed to a greater physiological demand during intradialytic exercise compared with interdialytic exercise. Despite this, intradialytic exercise partly normalized cardiopulmonary physiology during treatment, which may translate to a reduction in the symptoms and side effects of hemodialysis.NEW & NOTEWORTHY This study is the first, to our knowledge, to directly compare cardiopulmonary and metabolic physiology during hemodialysis, intradialytic exercise, and interdialytic exercise. Hemodialysis was associated with increased respiratory exchange ratio, blunted minute ventilation, and impaired O2 uptake and extraction. We also identified a reduced ventilatory response during intradialytic exercise compared with interdialytic exercise. Impaired arterial-venous O2 difference during hemodialysis was partly restored by intradialytic exercise. Despite dysregulated cardiopulmonary and metabolic physiology during hemodialysis, intradialytic exercise was well tolerated.

The high-pressure, high-temperature phase diagram of cerium.

We present an experimental study of the high-pressure, high-temperature behaviour of cerium up to ∼22 GPa and 820 K using angle-dispersive x-ray diffraction and external resistive heating. Studies above 820 K were prevented by chemical reactions between the samples and the diamond anvils of the pressure cells. We unambiguously measure the stability region of the orthorhombic oC4 phase and find it reaches its apex at 7.1 GPa and 650 K. We locate the α-cF4-oC4-tI2 triple point at 6.1 GPa and 640 K, 1 GPa below the location of the apex of the oC4 phase, and 1-2 GPa lower than previously reported. We find the α-cF4 → tI2 phase boundary to have a positive gradient of 280 K (GPa)-1, less steep than the 670 K (GPa)-1 reported previously, and find the oC4 → tI2 phase boundary to lie at higher temperatures than previously found. We also find variations as large as 2-3 GPa in the transition pressures at which the oC4 → tI2 transition takes place at a given temperature, the reasons for which remain unclear. Finally, we find no evidence that the α-cF4 → tI2 is not second order at all temperatures up to 820 K.

Asynchronous, out-of-sequence, transcontinental chain kidney transplantation: a novel concept.

The organ donor shortage has been the most important hindrance in getting listed patients transplanted. Living kidney donors who are incompatible with their intended recipients are an untapped resource for expanding the donor pool through participation in transplant exchanges. Chain transplantation takes this concept further, with the potential to benefit even more recipients. We describe the first asynchronous, out of sequence transplant chain that was initiated by transcontinental shipment of an altruistic donor kidney 1 week after that recipient's incompatible donor had already donated his kidney to the next recipient in the chain. The altruistic donor kidney was transported from New York to Los Angeles and functioned immediately after transplantation. Our modified-sequence asynchronous transplant chain (MATCH) enabled eight recipients, at four different institutions, to benefit from the generosity of one altruistic donor and warrants further exploration as a promising step toward addressing the organ donor shortage.

Genetic and environmental contributions to body mass index: comparative analysis of monozygotic twins, dizygotic twins and same-age unrelated siblings.

BACKGROUND: Earlier studies have established that a substantial percentage of variance in obesity-related phenotypes is explained by genetic components. However, only one study has used both virtual twins (VTs) and biological twins and was able to simultaneously estimate additive genetic, non-additive genetic, shared environmental and unshared environmental components in body mass index (BMI). Our current goal was to re-estimate four components of variance in BMI, applying a more rigorous model to biological and virtual multiples with additional data. Virtual multiples share the same family environment, offering unique opportunities to estimate common environmental influence on phenotypes that cannot be separated from the non-additive genetic component using only biological multiples. METHODS: Data included 929 individuals from 164 monozygotic twin pairs, 156 dizygotic twin pairs, five triplet sets, one quadruplet set, 128 VT pairs, two virtual triplet sets and two virtual quadruplet sets. Virtual multiples consist of one biological child (or twins or triplets) plus one same-aged adoptee who are all raised together since infancy. We estimated the additive genetic, non-additive genetic, shared environmental and unshared random components in BMI using a linear mixed model. The analysis was adjusted for age, age(2), age(3), height, height(2), height(3), gender and race. RESULTS: Both non-additive genetic and common environmental contributions were significant in our model (P-values<0.0001). No significant additive genetic contribution was found. In all, 63.6% (95% confidence interval (CI) 51.8-75.3%) of the total variance of BMI was explained by a non-additive genetic component, 25.7% (95% CI 13.8-37.5%) by a common environmental component and the remaining 10.7% by an unshared component. CONCLUSION: Our results suggest that genetic components play an essential role in BMI and that common environmental factors such as diet or exercise also affect BMI. This conclusion is consistent with our earlier study using a smaller sample and shows the utility of virtual multiples for separating non-additive genetic variance from common environmental variance.

The role of Drosophila mushroom body signaling in olfactory memory.

The mushroom bodies of the Drosophila brain are important for olfactory learning and memory. To investigate the requirement for mushroom body signaling during the different phases of memory processing, we transiently inactivated neurotransmission through this region of the brain by expressing a temperature-sensitive allele of the shibire dynamin guanosine triphosphatase, which is required for synaptic transmission. Inactivation of mushroom body signaling through alpha/beta neurons during different phases of memory processing revealed a requirement for mushroom body signaling during memory retrieval, but not during acquisition or consolidation.

Presenilin-1 and memories of the forebrain.

In this issue of Neuron, report that forebrain-specific Presenilin-1 conditional knockout mice show defects in enrichment-induced neurogenesis in the dentate gyrus. This defect in neurogenesis is associated with enhanced fear memory of contextual cues when animals are subjected to enrichment between training and testing. The authors suggest that neurogenesis in the adult dentate gyrus may serve to clear out old memory traces from the hippocampus, thus leaving the hippocampus available for new memory processing.

The synaptic impact of the host immune response in a parkinsonian allograft rat model: Influence on graft-derived aberrant behaviors.

Graft-induced dyskinesias (GIDs), side-effects found in clinical grafting trials for Parkinson's disease (PD), may be associated with the withdrawal of immunosuppression. The goal of this study was to determine the role of the immune response in GIDs. We examined levodopa-induced dyskinesias (LIDs), GID-like behaviors, and synaptic ultrastructure in levodopa-treated, grafted, parkinsonian rats with mild (sham), moderate (allografts) or high (allografts plus peripheral spleen cell injections) immune activation. Grafts attenuated amphetamine-induced rotations and LIDs, but two abnormal motor syndromes (tapping stereotypy, litter retrieval/chewing) emerged and increased with escalating immune activation. Immunohistochemical analyses confirmed immune activation and graft survival. Ultrastructural analyses showed increases in tyrosine hydroxylase-positive (TH+) axo-dendritic synapses, TH+ asymmetric specializations, and non-TH+ perforated synapses in grafted, compared to intact, striata. These features were exacerbated in rats with the highest immune activation and correlated statistically with GID-like behaviors, suggesting that immune-mediated aberrant synaptology may contribute to graft-induced aberrant behaviors.

Residual specimen cellularity after neoadjuvant chemotherapy for breast cancer.

BACKGROUND: Neoadjuvant chemotherapy for breast cancer reduces tumour cellularity, the percentage of the primary tumour area that is composed of invasive tumour cells. Minimal residual tumour cellularity (5 per cent or less of tumour area composed of invasive tumour cells) may be associated with an increased risk of false-negative intraoperative margins. The aim of this study was to evaluate the incidence of minimal residual tumour cellularity after neoadjuvant chemotherapy and its impact on the frequency of false-negative margins and conversion from breast-conserving surgery to mastectomy. METHODS: The final pathology slides of 510 patients who had surgery after neoadjuvant chemotherapy were reviewed. RESULTS: Of 396 patients with residual invasive breast cancer after neoadjuvant chemotherapy, 100 specimens (25.3 per cent) had minimal residual cellularity; this was more frequent in patients with invasive lobular carcinoma (17.0 versus 5.1 per cent; P < 0.001) or well and moderately differentiated carcinoma (68.0 versus 52.4 per cent; P = 0.007). Among 149 patients who had initial breast-conserving surgery, false-negative intraoperative margin rates were 23 per cent in specimens with minimal and 13.8 per cent in those with higher residual cellularity (P = 0.210). There was no significant difference in the rate of conversion to mastectomy between the groups. CONCLUSION: Minimal residual cellularity after neoadjuvant chemotherapy occurred in about 25 per cent of specimens, but did not alter the rate of false-negative intraoperative margins.

The presenting complaints of low income adults for emergency dental care: an analysis of 35,000 episodes in Victoria, Australia.

OBJECTIVE: This study examined the mix of presenting problems faced by a large diverse dental service treating low-income Australian adults and provides a basis for communities to understand and manage demand for dental services. DESIGN: A retrospective analysis in a state-wide multi-centre dental health service. Data for all patients (in all public adult dental clinics in the state of Victoria during May-Aug 2005) who used the emergency services in a 12 week period were recorded and analysed. A triage question tree was developed and embedded into a neural network based computer triage tool. RESULTS: Approximately 52% of low income adults presenting for emergency treatment required treatment on the day of triage. The main problem was with natural teeth (89.6%). Of those with natural teeth problems, 41.3% had pain disturbing their sleep patterns and 14.7% had experienced a swelling. Metropolitan patients accessed the services 2.3 times more than rural patients. CONCLUSION: These data clearly highlight that there is significant opportunity to reduce nearly 48% of on-day demand for emergency dental care through the application of appropriately clinical based triage.