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There are many different types of berry-producing plants that grow throughout North America. These various species of plants produce berries, known by their common names, such as blueberry, lingonberry, cranberry, crowberry, blackberry, bunchberry, bearberry, and strawberry. The berry fruits are important food sources and can be eaten fresh or preserved. The leaves of several species can also be enjoyed in teas. Contemporary medicine has demonstrated many potential health benefits of berries due to their antioxidant and anti-inflammatory activity. Indigenous Peoples have not only utilized berries as food, likely over many centuries, but have also passed down knowledge on the medicinal uses of various parts of these plants including the fruits, leaves and roots. This short review provides a synopsis of some of the major species of berry-producing plants that are prevalent in Canada, particularly eastern Canada. Current knowledge and traditional uses of important species of berry-producing plants are discussed.

We report our recent development of a conceptually new generation of exceptionally potent non-peptidic HIV-1 protease inhibitors that displayed excellent pharmacological and drug-resistance profiles. Our X-ray structural studies of darunavir and other designed inhibitors from our laboratories led us to create a variety of inhibitors incorporating fused ring polycyclic ethers and aromatic heterocycles to promote hydrogen bonding interactions with the backbone atoms of HIV-1 protease as well as van der Waals interactions with residues in the S2 and S2' subsites. We have also incorporated specific functionalities to enhance van der Waals interactions in the S1 and S1' subsites. The combined effects of these structural templates are critical to the inhibitors' exceptional potency and drug-like properties. We highlight here our molecular design strategies to promote backbone hydrogen bonding interactions to combat drug-resistance and specific design of polycyclic ether templates to mimic peptide-like bonds in the HIV-1 protease active site. Our medicinal chemistry and drug development efforts led to the development of new generation inhibitors significantly improved over darunavir and displaying unprecedented antiviral activity against multidrug-resistant HIV-1 variants.

Background Randomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far. Methods In this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554). Results Most baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable. Conclusions In conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation. Graphical abstract

We demonstrate the tuneablity of the ultrafast energy flow in magnetic/non-magnetic bilayer structures by changing the wavelength of the optical excitation. This is achieved by an advanced description of the temperature based $\mu$T-model that explicitly considers the wavelength- and layer-dependent absorption profile within multilayer structures. For the exemplary case of a Ni/Au bilayer, our simulations predict that the energy flow from Ni to Au is reversed when changing the wavelength of the excitation from the infrared to the ultraviolet spectral range. These predictions are fully supported by characteristic signatures in the magneto-optical Kerr traces of the Ni/Au model system. Our results will open up new avenues to steer and control the energy transport in designed magnetic multilayer for ultrafast spintronic applications., Comment: 6 pages (+3 pages supplemental), 5 figures (+1 figure in supplemental)

Background Previous studies indicated that amyloid scintigraphy in combination with free light chain (FLC) assessment yields an excellent diagnostic accuracy for cardiac transthyretin (ATTR) amyloidosis (1). As a consequence, the diagnosis of ATTR amyloidosis is increasingly made without the actual gold-standard method endomyocardial biopsy (EMB). Whether this leads to misdiagnosis in real-world practice is currently underinvestigated. We aimed to describe the diagnostic accuracy of amyloid scintigraphy in a real world setting. Methods Seven tertiary care centers throughout Austria agreed to participate in the study and performed a systematic retrospective medical records search from 2017 to 2020. Patients were included in case of available results of amyloid scintigraphy, FLC assessment and EMB, respectively. Amyloid scintigraphy was performed using a 99m-technetium-labelled tracer. Histological analysis was performed using immunohistochemistry. The number of submitted subjects with complete data per center ranged from 2 to 46. The patient number increased with years, with 15 patients investigated in 2017 and 32 in 2020. Results We enrolled 101 patients (21% women) with a mean age of 73±9 years and median NT-proBNP (IQR) of 2694 (1601–5239) pg/ml (Table 1). An abnormal Perugini Score (ie. grade II or III) was present in 57 patients (56%) and FLC assessment was overall indicative of monoclonal protein in 60 patients (59%). Among patients with abnormal Perugini Score, 29 had FLC assessment indicative of monoclonal protein. The most common histopathological diagnoses were ATTR in 60 patients (59%) and cardiac light chain (AL) amyloidosis in 20 patients (20%). One further patient was diagnosed with concomitant AL and ATTR amyloidosis. Further diagnoses included ApoA4 (n=2) and AA amyloidosis (n=1), while cardiac amyloidosis was ruled out in 17 patients (17%). ATTR was diagnosed in 54 patients with Perugini Score II or III compared with 6 patients with Perugini < II, yielding a sensitivity of abnormal Perugini score for ATTR amyloidosis of 90%. Among patients with abnormal Perugini Score (n=57), ATTR was diagnosed in 55 patients, and AL amyloidosis in 3 (one had concomitant ATTR and AL), yielding a positive predictive value (PPV) of abnormal Perugini Score of 97% (Table 2). Two AL patients had Perugini Score of II and one had Perugini Score of III. When excluding patients with monoclonal gammopathy, the PPV of abnormal Perugini Score was 100%. Conclusion Our data confirm a PPV of abnormal amyloid scintigraphy of 100% for cardiac ATTR amyloidosis when monoclonal gammopathy was excluded. mong patients with monoclonal gammopathy, one of ten patients with abnormal scintigraphy had AL amyloidosis as the underlying condition. Our data underscore that tissue biopsy and histopathological analysis should be performed in every patient with suspected amyloidosis and monoclonal gammopathy even in case of Perugini Score II or III. Funding Acknowledgement Type of funding sources: None.

The emergence of multidrug resistant (MDR) HIV strains severely reduces the effectiveness of antiretroviral therapy. Clinical inhibitor darunavir (1) has picomolar binding affinity for HIV-1 protease (PR), however, drug resistant variants like PR(S17) show poor inhibition by 1, despite the presence of only two mutated residues in the inhibitor-binding site. Antiviral inhibitors that target MDR proteases like PR(S17) would be valuable as therapeutic agents. Inhibitors 2 and 3 derived from 1 through substitutions at P1, P2 and P2ʹ positions exhibit 3.4- to 500-fold better inhibition than clinical inhibitors for PR(S17) with the exception of amprenavir. Crystal structures of PR(S17)/2 and PR(S17)/3 reveal how these inhibitors target the two active site mutations of PR(S17). The substituted methoxy P2 group of 2 forms new interactions with G48V mutation, while the modified bis-fluoro-benzyl P1 group of 3 forms a halogen interaction with V82S mutation, contributing to improved inhibition of PR(S17).

Intraoperative neurophysiological information could increase accuracy of surgical deep brain stimulation (DBS) lead placement. Subsequently, DBS therapy could be optimized by specifically targeting pathological activity. In Parkinson’s disease, local field potentials (LFPs) excessively synchronized in the beta band (13–35 Hz) correlate with akinetic-rigid symptoms and their response to DBS therapy, particularly low beta band suppression (13–20 Hz) and high frequency gamma facilitation (35–250 Hz). In dystonia, LFPs abnormally synchronize in the theta/alpha (4–13 Hz), beta and gamma (60–90 Hz) bands. Phasic dystonic symptoms and their response to DBS correlate with changes in theta/alpha synchronization. In essential tremor, LFPs excessively synchronize in the theta/alpha and beta bands. Adaptive DBS systems will individualize pathological characteristics of neurophysiological signals to automatically deliver therapeutic DBS pulses of specific spatial and temporal parameters.

There has been a proliferation of studies demonstrating important sex differences in cognitive aging and dementia, and with this an increased interest in the role of menopause and sex steroid hormones in women's brain health. Foundational longitudinal studies of cognitive changes from the premenopause to perimenopause stage have shown reliable declines in verbal memory, with variable findings in processing speed, attention/working memory and verbal fluency. Continued research is needed to advance understanding of the range of cognitive domains affected, the duration of cognitive changes, the generalizability of these changes across cultures, the factors that account for such changes and the factors that can improve cognition at this time. In this article, we briefly review and draw on findings from large longitudinal studies of cognitive changes across the menopause transition to inform the design of future studies on this topic. We focus on key issues such as objective versus subjective cognitive measures; cognitive domains and tests; staging menopause; study design; mediators of cognitive effects (including hormones and menopause symptoms); and consideration of key covariates. We suggest that a more uniform and evidence-based approach to the investigation of these issues can advance the quality of the science in menopause and cognition.

PURPOSE In metastatic triple-negative breast cancer (mTNBC), consistent biomarkers of immune checkpoint inhibitor (ICI) therapy benefit remain elusive. We evaluated the immune, genomic, and transcriptomic landscape of mTNBC in patients treated with ICIs. METHODS We identified 29 patients with mTNBC treated with pembrolizumab or atezolizumab, either alone (n = 9) or in combination with chemotherapy (n = 14) or targeted therapy (n = 6), who had tumor tissue and/or blood available before ICI therapy for whole-exome sequencing. RNA sequencing and CIBERSORTx-inferred immune population analyses were performed (n = 20). Immune cell populations and programmed death-ligand 1 expression were assessed using multiplexed immunofluorescence (n = 18). Clonal trajectories were evaluated via serial tumor/circulating tumor DNA whole-exome sequencing (n = 4). Association of biomarkers with progression-free survival and overall survival (OS) was assessed. RESULTS Progression-free survival and OS were longer in patients with high programmed death-ligand 1 expression and tumor mutational burden. Patients with longer survival also had a higher relative inferred fraction of CD8+ T cells, activated CD4+ memory T cells, M1 macrophages, and follicular helper T cells and enrichment of inflammatory gene expression pathways. A mutational signature of defective repair of DNA damage by homologous recombination was enriched in patients with both shorter OS and primary resistance. Exploratory analysis of clonal evolution among four patients treated with programmed cell death protein 1 blockade and a tyrosine kinase inhibitor suggested that clonal stability post-treatment was associated with short time to progression. CONCLUSION This study identified potential biomarkers of response to ICIs among patients with mTNBC: high tumor mutational burden; presence of CD8+, CD4 memory T cells, follicular helper T cells, and M1 macrophages; and inflammatory gene expression pathways. Pretreatment deficiencies in the homologous recombination DNA damage repair pathway and the absence of or minimal clonal evolution post-treatment may be associated with worse outcomes.

Antiretroviral drug resistance is a therapeutic obstacle for people with HIV. HIV protease inhibitors darunavir and lopinavir are recommended for resistant infections. We characterized a protease mutant (PR10x) derived from a highly resistant clinical isolate including 10 mutations associated with resistance to lopinavir and darunavir. Compared to the wild-type protease, PR10x exhibits ∼3-fold decrease in catalytic efficiency and K

World Heritage is the pinnacle of the recognition of the natural, aesthetic, and cultural value of a place on the planet. Since its inception in 1972, over 1100 sites have received World Heritage status. Many of these places are being challenged by the effects of climate change. Urgent action is needed to build the resilience and adaptive capacity of World Heritage sites in the face of climate change threats to come. The Wet Tropics of Queensland World Heritage Area (WTWHA) is one of the most effectively regulated and managed protected Areas in the world. This includes the scientific evidence upon which that regulation and management is based. However, there is growing evidence that climate change impacts are a clear and present threat to the Outstanding Universal Value (OUV) upon which the listing is based. This challenges the very concept of OUV and points to the business-as-usual regulation and management not being sufficient to deal with the threat. It also calls for quantum changes in the approaches to protecting natural and cultural heritage and the OUV in World Heritage Areas. This WTWHA case study gives insights into the journey travelled and the pathways that need to be laid out to protect our most cherished internationally recognised natural and cultural landscapes. We demonstrate the importance of evidence in support of advocacy and management action to address the clear impacts of climate change on species, ecosystems, people, and societies living in the WTWHA. The strategic and climate adaptation plans provide the framework upon which these actions take place. Community engagement in the delivery of mitigation, adaptation, and resilience policy is key to the long-term future of the WTWHA.

Introduction Disease-causing mutations in the protocadherin FAT1 have been recently described both in patients with a glomerulotubular nephropathy and in patients with a syndromic nephropathy. Methods We identified 4 patients with FAT1-associated disease, performed clinical and genetic characterization, and compared our findings to the previously published patients. Patient-derived primary urinary epithelial cells were analyzed by quantitative polymerase chain reaction (qPCR) and immunoblotting to identify possible alterations in Hippo signaling. Results Here we expand the spectrum of FAT1-associated disease with the identification of novel FAT1 mutations in 4 patients from 3 families (homozygous truncating variants in 3, compound heterozygous missense variants in 1 patient). All patients show an ophthalmologic phenotype together with heterogeneous renal phenotypes ranging from normal renal function to early-onset end-stage kidney failure. Molecular analysis of primary urine-derived urinary renal epithelial cells revealed alterations in the Hippo signaling cascade with a decreased phosphorylation of both the core kinase MST and the downstream effector YAP. Consistently, we found a transcriptional upregulation of bona fide YAP target genes. Conclusion A comprehensive review of the here identified patients and those previously published indicates a highly diverse phenotype in patients with missense mutations but a more uniform and better recognizable phenotype in the patients with truncating mutations. Altered Hippo signaling and de-repressed YAP activity might be novel contributing factors to the pathomechanism in FAT1-associated renal disease., Graphical abstract

Identification of positive lymph nodes in colon cancer can significantly impact treatment. Few studies have examined the role of lymph node size in staging and prognosis. This study evaluated the relationship between lymph node size and lymph node metastases in right-sided colon cancer.Retrospective chart review was performed for patients undergoing colectomy for right-sided colon cancer from 2015 to 2020 across a single multi-hospital health system. Patients under age 18 or who did not have invasive adenocarcinoma upon pathological examination were excluded. Primary endpoints assessed lymph node size and lymph node metastases. 572 patients were stratified by lymph node size; lymph nodes ≥5 mm (n = 308) were characterized as enlarged.All surgical specimens examined had adequate number of lymph nodes for staging. 33.9% of all specimens examined contained lymph node metastases. Patients with enlarged lymph nodes were significantly more likely to have lymph node metastases than those with normal-sized lymph nodes (p 0.001). Enlarged lymph nodes were associated with advanced nodal staging.Patients with enlarged nodes were significantly more likely to have lymph node metastases than those with normal-sized lymph nodes. Further research to analyze these enlarged lymph nodes on radiologic imaging is warranted to determine the role of radiographic assessment of lymph node size during pre-operative staging.

Asymptomatic hyperuricemia is frequently observed in pediatric kidney transplant recipients; symptomatic hyperuricemia, however, is a rare complication. Only few data are available in this patient population. We, therefore, investigated the prevalence of hyperuricemia and its association with kidney transplant function and blood pressure in a multicenter cohort of pediatric kidney transplant recipients.This is a retrospective, observational multicenter registry study. All pediatric kidney transplant recipients in the CERTAIN database with at least one documented serum uric acid level and a follow-up of 5 years posttransplant were eligible. We identified 151 patients with 395 measurements of serum uric acid. We calculated the prevalence of hyperuricemia, analyzed potential risk factors and clinical consequences such as elevated blood pressure and reduced estimated glomerular filtration rate (eGFR). Statistical analysis was performed using IBM SPSS Statistics 26.One hundred and ten of 395 (27.8%) serum uric acid levels were above 416 µmol/L (7.0 mg/dL), defined as the upper limit of normal. Univariate analysis showed a significant (p = .026) inverse association of serum uric acid with eGFR overtime. There was no significant association of serum uric acid concentrations with body mass index (z-score), blood pressure (z-score), or sex. No episodes of gout were documented.This study shows that hyperuricemia is present in a considerable number of patients sometime after pediatric kidney transplantation and is associated with lower eGFR. Whether hyperuricemia contributes to faster decline of graft function or to the overall cardiovascular risk of these patients remains to be elucidated.

The abundance and size distribution of marine particles control a range of biogeochemical and ecological processes in the ocean, including carbon sequestration. These quantities are the result of complex physical-biological interactions that are difficult to observe, and their spatial and temporal patterns remain uncertain. Here, we present a novel analysis of particle size distributions (PSDs) from a global compilation of in situ Underwater Vision Profiler 5 (UVP5) optical measurements. Using a machine learning algorithm, we extrapolate sparse UVP5 observations to the global ocean from well-sampled oceanographic variables. We reconstruct global maps of PSD parameters (biovolume [BV] and slope) for particles at the base of the euphotic zone. These reconstructions reveal consistent global patterns, with high chlorophyll regions generally characterized by high particle BV and flatter PSD slope, that is, a high relative abundance of large versus small particles. The resulting negative correlations between particle BV and slope further suggests synergistic effects on size-dependent processes such as sinking particle fluxes. Our approach and estimates provide a baseline for an improved understanding of particle cycles in the ocean, and pave the way to global, three-dimensional reconstructions of PSD and sinking particle fluxes from the growing body of UVP5 observations.

BackgroundInfantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder resulting in progressive chronic kidney disease (CKD) and a variety of extrarenal manifestations. This orphan disease remains a challenge for patients, their families and health care providers. There is currently no comprehensive study on patients' clinical course in Germany and Austria.MethodsA retrospective cohort study including 74 patients at eleven centers of care was conducted. Data on time of diagnosis, CKD stage, leukocyte cystine levels (LCL), extrarenal manifestations, and treatment was collected from medical charts and subsequently analyzed using explorative statistics. Age at initiation of kidney replacement therapy (KRT) was evaluated by Kaplan–Meier analyses for different groups of patients.ResultsPatients were diagnosed at a median age of 15 months (IQR: 10–29, range: 0–110), more recent year of birth was not associated with earlier diagnosis. Oral cystine-depleting therapy (i.e., cysteamine) was prescribed at a median dose of 1.26 g/m2 per day (IQR: 1.03–1.48, range: 0.22–1.99). 69.2% of all 198 LCL measurements of 67 patients were within the desired target range (≤ 1 nmol cystine/mg protein). Median time-averaged LCLs per patient (n = 65) amounted to 0.57 nmol cystine/mg protein (IQR: 0.33–0.98, range: 0.07–3.13) when considering only values at least 1 year after initiation of therapy. The overall median height of 242 measurements of 68 patients was at the 7th percentile (IQR: 1–25, range: 1–99). 40.5% of the values were ≤ the 3rd percentile. Patient sex and year of birth were not associated with age at initiation of KRT, but patients diagnosed before the age of 18 months required KRT significantly later than those patients diagnosed at the age of ≥ 18 months (p = 0.033): median renal survival was 21 years (95% CI: 16, -) vs. 13 years (95% CI, 10, -), respectively.ConclusionEarly diagnosis and initiation of cystine depleting therapy is important for renal survival in children with INC. Cysteamine doses and LCL showed that treatment in this cohort met international standards although there is great interindividual variety. Patient growth and other aspects of the disease should be managed more effectively in the future.

Background: Preexistent LUTD are considered a hostile environment, which might negatively impact KTx survival. In such cases, surgical reconstruction of the bladder is required. However, there is still disagreement on the optimal timing of the reconstruction procedure. Methods: This is a multicenter analysis of data from the CERTAIN Registry. Included were 62 children aged 8.18 ± 4.90 years, with LUTD. Study endpoints were the duration of initial posttransplant hospitalization, febrile UTIs, and a composite failure endpoint comprising decline of eGFR, graft loss, or death up to 5 years posttransplant. Outcome was compared to matched controls without bladder dysfunction. Results: Forty-one patients (66.1%) underwent pretransplant and 14 patients (22.6%) posttransplant reconstruction. Bladder augmentation was performed more frequently in the pretransplant (61%) than in the posttransplant group (21%, p =.013). Outcome in the pre- and posttransplant groups and in the subgroups of patients on pretransplant PD with major bladder surgery either pre- (n = 14) or posttransplant (n = 7) was comparable. Outcomes of the main study cohort and the matched control cohort (n = 119) were comparable during the first 4 years posttransplant; at year 5, there were more events of transplant dysfunction in the study cohort with LUTD than in controls (p =.03). Conclusions: This multicenter analysis of the current practice of LUTD reconstruction in pediatric KTx recipients shows that pre- or posttransplant surgical reconstruction of the lower urinary tract is associated with a comparable 5-year outcome. in press

ZUSAMMENFASSUNGOft wird zur Behandlung eines kompliziert verlaufenden nephrotischen Syndroms des Kindesalters eine immunsuppressive Dauertherapie eingesetzt. Als first-line-Therapie beim kompliziert verlaufenden steroidsensiblen nephrotischen Syndrom hat sich in Deutschland in den letzten Jahren Mycophenlatmofetil etabliert. Muss aber ein Calcineurininhibitor eingesetzt werden, kann zwischen Ciclosporin A und Tacrolimus gewählt werden. In dieser Übersichtsarbeit werden die Vor- und Nachteile beider Therapien beleuchtet, die Indikationsstellung bei den unterschiedlichen Verlaufsformen des nephrotischen Syndroms erläutert und mögliche Entscheidungshilfen bei der Wahl des Calcineurininhibitors gegeben.