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Lectins are a class of carbohydrate-binding proteins that may have antiviral activity by binding to the glycans on the virion surface to interfere with viral entry. We have identified a novel lectin (named Shictin) from Shiitake mushroom ( Lentinula edodes )-derived vesicle-like nanoparticles (VLNs, or exosomes) that exhibits strong activity against the SARS-CoV-2 Omicron variant with an IC 50 value of 87 nM. Shictin contains 298 amino acids and consists of two unique domains (N-terminal and C-terminal domain). The N-terminal domain is the carbohydrate-binding domain (CBD) that is homologous with CBDs of other lectins, suggesting that Shictin inhibits SARS-CoV-2 infection by binding to the glycans on the virion surface to prevent viral entry. This finding demonstrates that exosomes of vegetables are a valuable source for the identification of antiviral lectins. Therefore, it is believed that lectins from vegetable VLNs have potential as antiviral therapeutic agents.

Aims: Cutaneous follicular (infundibular-tricholemmal) squamous cell carcinoma (FSCC) is a new World Health Organization entity. We present the largest series of published cases, summarizing clinical data, diagnostic criteria, differential diagnosis, and implications for patient management., Methods: Cases were identified from 2004 to 2011. Inclusion criteria included discrete attachment(s) of the tumor to the overlying epidermis via follicular infundibula, tricholemmal keratinization, and cellular pleomorphism. Keratoacanthoma and lesions with adjacent bowenoid epidermal dysplasia were excluded., Results: One hundred three cases of FSCC identified. 48.5% demonstrated completely circumscript borders ( in situ for practical purposes), 12.6% uncertain for invasion (overwhelmingly pushing borders), and only 38.8% as clearly invasive. Follicular mucin in acantholytic spaces within tumor epithelium was a distinctive finding in 57.2% of cases. Clinical data indicated predominance in elderly (median 78.5 years) men (70.4%), with preferential head and neck location (81.6%). Many were clinically suspected as squamous cell carcinoma (48.5%). However, a significant minority were clinically diagnosed as basal cell carcinoma (40.8%). This may reflect that FSCC commonly presented as a papule or nodule (51.3%). By contrast, keratoacanthoma was less frequently suggested (17.2%) and still fewer lesions were suspected to be actinic keratosis/Bowen's disease (13.6%). Follow-up in 82 cases (median 26.5 months, range 3-144) identified 5 (6.1%) local recurrences. There was no instance of metastasis in the subgroup of lesions with completely circumscript borders. Three of 45 (6.7%) patients, with follow-up, considered to have tumors with invasive pushing, and/or infiltrative borders developed lymph node metastases., Conclusions: FSCC is identified as a common skin cancer, incorporating historical entities, such as infundibular carcinoma and tricholemmal carcinoma, with readily identifiable histologic features. Correct diagnosis has implications for patient management; a significant subgroup of lesions show completely circumscript borders that are considered in situ for practical purposes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Difficulty in appropriately responding to threats is a key feature of psychiatric disorders, especially fear-related conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD). Most prior work on threat and fear regulation involves exposure to external threatful cues. However, fear can also be triggered by aversive, within-the-body, sensations. This interoceptive signaling of fear is highly relevant to PD and PTSD but is not well understood, especially in the context of sex. Using female and male mice, the current study investigated fear-associated spontaneous and conditioned behaviors to carbon dioxide (CO 2 ) inhalation, a potent interoceptive threat that induces fear and panic. We also investigated whether behavioral sensitivity to CO 2 is associated with delayed PTSD-relevant behaviors. CO 2 evoked heterogenous freezing behaviors in both male and female animals. However, active, rearing behavior was significantly reduced in CO 2 -exposed male but not female mice. Interestingly, behavioral sensitivity to CO 2 was associated with compromised fear extinction, independent of sex. However, in comparison to CO 2 -exposed males, females elicited less freezing and higher rearing during extinction suggesting an engagement of active versus passive defensive coping. Persistent neuronal activation marker ΔFosB immuno-mapping revealed attenuated engagement of infralimbic-prefrontal areas in both sexes but higher activation of brain stem locus coeruleus (LC) area in females. Inter-regional co-activation mapping revealed sex-independent disruptions in the infralimbic-amygdala associations but altered LC associations only in CO 2 -exposed female mice. Lastly, dopamine β hydroxylase positive (DβH  + ve ) noradrenergic neuronal cell counts in the LC correlated with freezing and rearing behaviors during CO 2 inhalation and extinction only in female but not male mice. Collectively, these data provide evidence for higher active defensive responding to interoceptive threat CO 2 -associated fear in females that may stem from increased recruitment of the brainstem noradrenergic system. Our findings reveal distinct contributory mechanisms that may promote sex differences in fear and panic associated pathologies., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 Published by Elsevier Inc.)

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of LDL-C. LDL-C-lowering drugs, such as statins or monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9), are known to reduce the risk of cardiovascular diseases; however, statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a "high-risk" patient population or those who have failed other therapies. Based on the proven efficacy and safety profile of existing monoclonal antibodies, we have developed a peptide-based vaccine against PCSK9, VXX-401, as an alternative option to treat hypercholesterolemia and prevent ASCVD. VXX-401 is designed to trigger a safe humoral immune response against PCSK9, resulting in the production of endogenous antibodies and a subsequent 30-40% reduction in blood LDL-C. In this article, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C-lowering effects in nonhuman primates. In addition, antibodies induced by VXX-401 bind to human PCSK9 with high affinity and block the inhibitory effect of PCSK9 on LDL-C uptake in a hepatic cell model. A repeat-dose toxicity study conducted in nonhuman primates under good laboratory practices toxicity indicated a suitable safety and tolerability profile, with injection site reactions being the main findings. As a promising safe and effective LDL-C-lowering therapy, VXX-401 may represent a broadly accessible and convenient option to treat hypercholesterolemia and prevent ASCVD., Competing Interests: Conflict of interest All studies described herein were funded by Vaxxinity, Inc All authors are past or current Vaxxinity employees and hold company stock/stock options., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Testing for germline pathogenic variants (GPVs) in cancer predisposition genes is increasingly offered as part of routine care for patients with cancer. This is often urgent in oncology clinics due to potential implications on treatment and surgical decisions. This also allows identification of family members who should be offered predictive genetic testing. In the UK, it is common practice for healthcare professionals to provide a patient information leaflet (PIL) at point of care for diagnostic genetic testing in patients with cancer, after results disclosure when a GPV is identified, and for predictive testing of at-risk relatives. Services usually create their own PIL, resulting in duplication of effort and wide variability regarding format, content, signposting and patient input in co-design and evaluation., Methods: Representatives from UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar programme and Association of Genetic Nurse Counsellors (AGNC) held a 2-day meeting with the aim of making recommendations for clinical practice regarding co-design of PIL for germline cancer susceptibility genetic testing. Lynch syndrome and haematological malignancies were chosen as exemplar conditions., Results: Meeting participants included patient representatives including as co-chair, multidisciplinary clinicians and other experts from across the UK. High-level consensus for UK recommendations for clinical practice was reached on several aspects of PIL using digital polling, including that PIL should be offered, accessible, co-designed and evaluated with patients., Conclusions: Recommendations from the meeting are likely to be applicable for PIL co-design for a wide range of germline genetic testing scenarios., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Antibodies provide critical protective immunity against COVID-19, and the Fc-mediated effector functions and mucosal antibodies also contribute to the protection. To expand the characterization of humoral immunity stimulated by subunit protein-peptide COVID-19 vaccine UB-612, preclinical studies in non-human primates were undertaken to investigate mucosal secretion and the effector functionality of vaccine-induced antibodies in antibody-dependent monocyte phagocytosis (ADMP) and antibody-dependent NK cell activation (ADNKA) assays. In cynomolgus macaques, UB-612 induced potent serum-neutralizing, RBD-specific IgG binding, ACE2 binding-inhibition antibodies, and antibodies with Fc-mediated effector functions in ADMP and ADNKA assays. Additionally, immunized animals developed mucosal antibodies in bronchoalveolar lavage fluids (BAL). The level of mucosal or serum ADMP and ADNKA antibodies was found to be UB-612 dose-dependent. Our results highlight that the novel subunit UB-612 vaccine is a potent B-cell immunogen inducing polyfunctional antibody responses contributing to anti-viral immunity and vaccine efficacy.

Scytovirin (SVN) is a lectin from cyanobacteria which has a strong inhibitory activity against Ebola virus infection. We engineered scytovirin as the inhibitor for surface display of lactic acid bacteria to block Ebola virus infection. Two different bacterial strains ( Lactobacillus casei and Lactococcus lactis ) were successfully engineered for scytovirin expression on the bacterial surface. These bacteria were found to be effective at neutralizing pseudotyped Ebolavirus in a cell-based assay. This approach can be utilized for prophylactic prevention, as well as for treatment. Since lactic acid bacteria can colonize the human body, a long-term efficacy could be achieved. Furthermore, this approach is also simple and cost-effective and can be easily applied in the regions of Ebola outbreaks in the developing countries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wiggins, Nguyen, Wei, Wang, Hollingsead Olson and Xiang.)

Keratoacanthoma (KA) is widely considered a benign, usually self-resolving, neoplasm distinct from cutaneous squamous cell carcinoma (cSCC), while some consider KA to be indistinguishable from cSCC. Published studies indicate utility for p16, p53, Ki-67 immunostaining and elastic van Gieson (EVG) in the assessment of KA and cSCC. We compared clinical features and staining patterns for p16, p53, Ki-67 and EVG in fully excised KA, cSCC with KA-like features (cSCC-KAL) and other cSCC (cSCC-OTHER). Significant differences between KA, cSCC-KAL and cSCC-OTHER were found for head and neck location (20%, 86%, 84%), and duration <5 months (95%, 63%, 36%). KA shows both a mosaic pattern for p16 (>25-90% of neoplasm area) and peripheral graded pattern for p53 (up to 50% moderate and strong nuclear staining) in 92% compared with 0% of cSCC-KAL and 0% of cSCC-OTHER. In contrast, a highly aberrant pattern (usually null) for one or both p16 and p53, was present in 0% of KA, 83.8% of cSCC-KAL and 90.9% of cSCC-OTHER. Abnormal distribution of Ki-67 beyond the peripheral 1-3 cells was uncommon in KA (4.2%) and common in cSCC-KAL (67.6%) and cSCC-OTHER (88.4%). Moderate to striking entrapment of elastic and collagen fibres was present in the majority of KA (84%), cSCC-KAL (81%) and cSCC-OTHER (65%). KA are clinically distinct neoplasms typically of short duration occurring preferentially outside the head and neck and generally lacking aberrations of p16, p53 and Ki-67, compared with cSCC that have high rates of aberrant or highly aberrant p16, p53 and Ki-67, but EVG lacked specificity., (Copyright © 2023. Published by Elsevier B.V.)

Membrane proteins expressed on the surface of enveloped viruses are conformational antigens readily recognized by B cells of the immune system. An effective vaccine would require the synthesis and delivery of these native conformational antigens in lipid membranes that preserve specific epitope structures. We have created an extracellular vesicle-based technology that allows viral membrane antigens to be selectively recruited onto the surface of WW domain-activated extracellular vesicles (WAEVs). Budding of WAEVs requires secretory carrier-associated membrane protein 3, which through its proline-proline-alanine-tyrosine motif interacts with WW domains to recruit fused viral membrane antigens onto WAEVs. Immunization with influenza and HIV viral membrane proteins displayed on WAEVs elicits production of virus-specific neutralizing antibodies and, in the case of influenza antigens, protects mice from the lethal viral infection. WAEVs thus represent a versatile platform for presenting and delivering membrane antigens as vaccines against influenza, HIV, and potentially many other viral pathogens.

Background: Germline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing., Methods: We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway)., Results: Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with <5% of patients contacting the genetics specialist hotline. All progression criteria established for continuation of the study were met., Conclusion: Pilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses., Trial Registration Number: ISRCTN87845055., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Filoviruses enter cells through macropinocytosis and trafficking into the endosomes in which they bind to the receptor Niemann-Pick C1 protein (NPC1) for membrane fusion and entry into the cytoplasm. The endosomal receptor-binding is critical step for filovirus entry. Designing inhibitors to block receptor binding will prevent viral entry. Using available binding structural information from the co-crystal structures of the viral GP with the receptor NPC1 or with monoclonal antibodies, we have conducted structure-based design of peptide inhibitors to target the receptor binding site (RBS). The designed peptides were tested for their inhibition activity against pseudo-typed or replication-competent viruses in a cell-based assay. The results indicate that these peptides exhibited strong activities against both Ebola and Marburg virus infection. It is expected that these peptides can be further developed for therapeutic use to treat filovirus infection and combat the outbreaks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Genetic testing for cancer predisposition has been curtailed by the cost of sequencing, and testing has been restricted by eligibility criteria. As the cost of sequencing decreases, the question of expanding multi-gene cancer panels to a broader population arises. We evaluated how many additional actionable genetic variants are returned by unrestricted panel testing in the private sector compared to those which would be returned by adhering to current NHS eligibility criteria. We reviewed 152 patients referred for multi-gene cancer panels in the private sector between 2014 and 2016. Genetic counselling and disclosure of all results was standard of care provided by the Consultant. Every panel conducted was compared to current eligibility criteria. A germline pathogenic / likely pathogenic variant (P/LP), in a gene relevant to the personal or family history of cancer, was detected in 15 patients (detection rate of 10%). 46.7% of those found to have the P/LP variants (7 of 15), or 4.6% of the entire set (7 of 152), did not fulfil NHS eligibility criteria. 46.7% of P/LP variants in this study would have been missed by national testing guidelines, all of which were actionable. However, patients who do not fulfil eligibility criteria have a higher Variant of Uncertain Significance (VUS) burden. We demonstrated that the current England NHS threshold for genetic testing is missing pathogenic variants which would alter management in 4.6%, nearly 1 in 20 individuals. However, the clinical service burden that would ensue is a detection of VUS of 34%., (© 2022. The Author(s).)

Background: With increasing complexity of our aging inpatient population, we implemented an interprofessional geriatric and palliative care intervention on a hospitalist service. This study aimed to measure the intervention's impact on length of stay (LOS), 30-day readmission, and the daily intensity of inpatient services utilization., Methods: Using a nonrandomized controlled intervention at a 1000-bed U.S. academic quaternary medical center, we studied 13,941 individuals admitted to a general medicine hospitalist service (of which 5644 were age > =65 years); 1483 were on intervention teams (576 age > =65 years), 5413 concurrent controls, and 7045 historical controls. On 2 of 11 hospitalist teams, a geriatrician, palliative care physician and social worker attended multidisciplinary discharge rounds twice weekly, to recommend inpatient geriatric or palliative care consult (GPCC), postacute nursing or home care, versus postdischarge outpatient consultation. We measured the difference in improvement over time between intervention and control team patients for the following: (1) LOS adjusted for case-mix index, (2) 30-day readmissions, and (3) intensity of hospital service utilization (mean services provided per patient per day)., Results: Adjusted LOS (in hospital days) was decreased by 0.36 days (p = 0.039) for the 1483 patients in the intervention teams, with greater LOS reduction of 0.55 days per admission (p = 0.022) on average among the subset of 576 older patient admissions. Readmissions were unchanged (-1.17%, p = 0.48 for all patients; 1.91%, p = 0.46 for older patients). However, the daily relative value unit (RVU) utilization was modestly increased for both the overall and older subgroup, 0.35 RVUs (p = 0.041) and 0.74 RVUs (p < 0.001) per patient-day on average across the intervention teams, respectively., Conclusion: An interprofessional intervention of geriatric and palliative care consultation in collaboration with a hospitalist service may reduce LOS, especially for geriatric patients, without an increase in readmissions. This model may have broader implications for hospital care and should be further studied., (© 2021 The American Geriatrics Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Neurodevelopmental disorders such as epilepsy and autism have been linked to an imbalance of excitation and inhibition (E/I) in the central nervous system. The simplicity and tractability of C. elegans allows our electroconvulsive seizure (ES) assay to be used as a behavioral readout of the locomotor circuit and neuronal function. C. elegans possess conserved nervous system features such as gamma-aminobutyric acid (GABA) and GABA receptors in inhibitory neurotransmission, and acetylcholine (Ach) and acetylcholine receptors in excitatory neurotransmission. Our previously published data has shown that decreasing inhibition in the motor circuit, via GABAergic manipulation, will extend the time of locomotor recovery following electroshock. Similarly, mutations in a HECT E3 ubiquitin ligase called EEL-1 leads to impaired GABAergic transmission, E/I imbalance and altered sensitivity to electroshock. Mutations in the human ortholog of EEL-1, called HUWE1, are associated with both syndromic and non-syndromic intellectual disability. Both EEL-1 and its previously established binding protein, OGT-1, are expressed in GABAergic motor neurons, localize to GABAergic presynaptic terminals, and function in parallel to regulate GABA neuron function. In this study, we tested behavioral responses to electroshock in wildtype, ogt-1, eel-1 and ogt-1; eel-1 double mutants. Both ogt-1 and eel-1 null mutants have decreased inhibitory GABAergic neuron function and increased electroshock sensitivity. Consistent with EEL-1 and OGT-1 functioning in parallel pathways, ogt-1; eel-1 double mutants showed enhanced electroshock susceptibility. Expression of OGT-1 in the C. elegans nervous system rescued enhanced electroshock defects in ogt-1; eel-1 double mutants. Application of a GABA agonist, Baclofen, decreased electroshock susceptibility in all animals. Our C. elegans electroconvulsive seizure assay was the first to model a human X-linked Intellectual Disability (XLID) associated with epilepsy and suggests a potential novel role for the OGT-1/EEL-1 complex in seizure susceptibility., Competing Interests: The authors have declared that no competing interests exist.

Memorializes Eugene A. Shapiro (1919-2021). A trailblazer in professional psychology, Shapiro played key roles institutionally in establishing psychology as a major health profession. He won a scholarship to Rutgers to complete his BS in psychology, and later won acceptance into the doctoral program in clinical psychology at New York University (NYU). He earned his PhD from NYU in 1953. Gene, along with Jack Wiggins, was instrumental in increasing the availability of psychological services to military personnel and their families under programs such as the Civilian Health and Medical Program of the Uniformed Services. Gene helped foreground the interests of practicing psychologists in American Psychological Association (APA), upgrading the Office for Professional Practice to the Practice Directorate. He also helped found the Graduate School of Applied and Professional Psychology at Rutgers University, the first university-based professional school in the country, and was a pioneer in the prescribing psychologist movement. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Objective: To test the hypothesis that in syndromes associated with frontotemporal lobar degeneration, behavioural impairment predicts loss of functional independence and motor clinical features predict mortality, irrespective of diagnostic group., Methods: We used a transdiagnostic approach to survival in an epidemiological cohort in the UK, testing the association between clinical features, independence and survival in patients with clinical diagnoses of behavioural variant frontotemporal dementia (bvFTD n=64), non-fluent variant primary progressive aphasia (nfvPPA n=36), semantic variant primary progressive aphasia (svPPA n=25), progressive supranuclear palsy (PSP n=101) and corticobasal syndrome (CBS n=68). A principal components analysis identified six dimensions of clinical features. Using Cox proportional hazards and logistic regression, we identified the association between each of these dimensions and both functionally independent survival (time from clinical assessment to care home admission) and absolute survival (time to death). Analyses adjusted for the covariates of age, gender and diagnostic group. Secondary analysis excluded specific diagnostic groups., Results: Behavioural disturbance, including impulsivity and apathy, was associated with reduced functionally independent survival (OR 2.46, p<0.001), even if patients with bvFTD were removed from the analysis. Motor impairments were associated with reduced absolute survival, even if patients with PSP and CBS were removed from the analysis., Conclusion: Our results can assist individualised prognostication and planning of disease-modifying trials, and they support a transdiagnostic approach to symptomatic treatment trials in patients with clinical syndromes associated with frontotemporal lobar degeneration., Competing Interests: Competing interests: JBR serves as an associate editor to Brain, and is a non-remunerated trustee of the Guarantors of Brain and the PSP Association (UK). He provides consultancy to Asceneuron, Biogen, UCB and has research grants from AZ-Medimmune, Janssen and Lilly as industry partners in the Dementias Platform UK., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Total DNA (intracellular, iDNA and extracellular, eDNA) from ancient permafrost records the mixed genetic repository of the past and present microbial populations through geological time. Given the exceptional preservation of eDNA under perennial frozen conditions, typical metagenomic sequencing of total DNA precludes the discrimination between fossil and living microorganisms in ancient cryogenic environments. DNA repair protocols were combined with high throughput sequencing (HTS) of separate iDNA and eDNA fraction to reconstruct metagenome-assembled genomes (MAGs) from ancient microbial DNA entrapped in Siberian coastal permafrost., Results: Despite the severe DNA damage in ancient permafrost, the coupling of DNA repair and HTS resulted in a total of 52 MAGs from sediments across a chronosequence (26-120 kyr). These MAGs were compared with those derived from the same samples but without utilizing DNA repair protocols. The MAGs from the youngest stratum showed minimal DNA damage and thus likely originated from viable, active microbial species. Many MAGs from the older and deeper sediment appear related to past aerobic microbial populations that had died upon freezing. MAGs from anaerobic lineages, including Asgard archaea, however exhibited minimal DNA damage and likely represent extant living microorganisms that have become adapted to the cryogenic and anoxic environments. The integration of aspartic acid racemization modeling and metaproteomics further constrained the metabolic status of the living microbial populations. Collectively, combining DNA repair protocols with HTS unveiled the adaptive strategies of microbes to long-term survivability in ancient permafrost., Conclusions: Our results indicated that coupling of DNA repair protocols with simultaneous sequencing of iDNA and eDNA fractions enabled the assembly of MAGs from past and living microorganisms in ancient permafrost. The genomic reconstruction from the past and extant microbial populations expanded our understanding about the microbial successions and biogeochemical alterations from the past paleoenvironment to the present-day frozen state. Furthermore, we provided genomic insights into long-term survival mechanisms of microorganisms under cryogenic conditions through geological time. The combined strategies in this study can be extrapolated to examine other ancient non-permafrost environments and constrain the search for past and extant extraterrestrial life in permafrost and ice deposits on Mars. Video abstract.

Background/objectives: In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, a multifactorial intervention was associated with a nonsignificant 8% reduction in time to first serious fall injury but a significant 10% reduction in time to first self-reported fall injury relative to enhanced usual care. The effect of the intervention on other outcomes important to patients has not yet been reported. We aimed to evaluate the effect of the intervention on patient well-being including concern about falling, anxiety, depression, physical function, and disability., Design: Pragmatic cluster-randomized trial of 5,451 community-living persons at high risk for serious fall injuries., Setting: A total of 86 primary care practices within 10 U.S. healthcare systems., Participants: A random subsample of 743 persons aged 75 and older., Measurements: The well-being measures, assessed at baseline, 12 months, and 24 months, included a modified version of the Fall Efficacy Scale, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scales, and Late-Life Function and Disability Instrument., Results: Participants in the intervention (n = 384) and control groups (n = 359) were comparable in age: mean (standard deviation) of 81.9 (4.7) versus 81.8 (5.0) years. Mean scores were similar between groups at 12 and 24 months for concern about falling, physical function, and disability, whereas the intervention group's mean scores on anxiety and depression were .7 points lower (i.e., better) at 12 months and .6 to .8 points lower at 24 months. For each of these outcomes, differences between the groups' adjusted least square mean changes from baseline to 12 and 24 months, respectively, were quantitatively small. The overall difference in means between groups over 2 years was statistically significant only for depression, favoring the intervention: -1.19 (99% confidence interval, -2.36 to -.02), with 3.5 points representing a minimally important difference., Conclusions: STRIDE's multifactorial intervention to reduce fall injuries was not associated with clinically meaningful improvements in patient well-being., (© 2020 The American Geriatrics Society.)

Objective: Widespread metabolic changes are seen in neurodegenerative disease and could be used as biomarkers for diagnosis and disease monitoring. They may also reveal disease mechanisms that could be a target for therapy. In this study we looked for blood-based biomarkers in syndromes associated with frontotemporal lobar degeneration., Methods: Plasma metabolomic profiles were measured from 134 patients with a syndrome associated with frontotemporal lobar degeneration (behavioural variant frontotemporal dementia n = 30, non fluent variant primary progressive aphasia n = 26, progressive supranuclear palsy n = 45, corticobasal syndrome n = 33) and 32 healthy controls., Results: Forty-nine of 842 metabolites were significantly altered in frontotemporal lobar degeneration syndromes (after false-discovery rate correction for multiple comparisons). These were distributed across a wide range of metabolic pathways including amino acids, energy and carbohydrate, cofactor and vitamin, lipid and nucleotide pathways. The metabolomic profile supported classification between frontotemporal lobar degeneration syndromes and controls with high accuracy (88.1-96.6%) while classification accuracy was lower between the frontotemporal lobar degeneration syndromes (72.1-83.3%). One metabolic profile, comprising a range of different pathways, was consistently identified as a feature of each disease versus controls: the degree to which a patient expressed this metabolomic profile was associated with their subsequent survival (hazard ratio 0.74 [0.59-0.93], p = 0.0018)., Conclusions: The metabolic changes in FTLD are promising diagnostic and prognostic biomarkers. Further work is required to replicate these findings, examine longitudinal change, and test their utility in differentiating between FTLD syndromes that are pathologically distinct but phenotypically similar.

Background For patients with early breast cancer, knowledge of germline BRCA1 / 2 status increasingly influences management as well as informing future cancer risk for patients and their families. As access to germline testing expands, it is important that this benefit is extended to survivors as well as to the newly diagnosed. Methods In collaboration with our breast unit colleagues and by embedding a Senior Genetic Counsellor in the virtual multidisciplinary meeting, we identified patients suitable for genetics review 5 years after their breast cancer diagnosis. Results Between May 2015 and December 2018, 2044 patients were discussed, of whom 769 patients were identified for notes review by Genetics. Of these, 275 had already undergone testing and 47 had confirmed germline pathogenic variants in BRCA1 / 2 A further 463 were recommended for referral. One hundred and eighty patients were subsequently offered testing with 161 accepting (161/180, 89%). Nine patients were found to harbour pathogenic variants in either BRCA1 or BRCA2 (9/161, 6%). Of the initial 2044 patients reviewed, 2.7% (56/2044) are now known to carry germline pathogenic variants. Conclusion The survivorship setting provides an opportunity for genetic review underpinned by collaborative working between cancer specialists and the genetics team., Competing Interests: Competing interests: AG received honoraria from Astra Zeneca and Roche paid to the institution and personal fees from Tesaro. ZK received honoraria for education talks from Astra Zeneca and Tesaro (paid to institution) and Lilly (personal fees)., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Injuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined., Methods: We conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention that included risk assessment and individualized plans, administered by specially trained nurses, to prevent fall injuries. A total of 86 primary care practices across 10 health care systems were randomly assigned to the intervention or to enhanced usual care (the control) (43 practices each). The participants were community-dwelling adults, 70 years of age or older, who were at increased risk for fall injuries. The primary outcome, assessed in a time-to-event analysis, was the first serious fall injury, adjudicated with the use of participant report, electronic health records, and claims data. We hypothesized that the event rate would be lower by 20% in the intervention group than in the control group., Results: The demographic and baseline characteristics of the participants were similar in the intervention group (2802 participants) and the control group (2649 participants); the mean age was 80 years, and 62.0% of the participants were women. The rate of a first adjudicated serious fall injury did not differ significantly between the groups, as assessed in a time-to-first-event analysis (events per 100 person-years of follow-up, 4.9 in the intervention group and 5.3 in the control group; hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.25). The rate of a first participant-reported fall injury was 25.6 events per 100 person-years of follow-up in the intervention group and 28.6 events per 100 person-years of follow-up in the control group (hazard ratio, 0.90; 95% CI, 0.83 to 0.99; P = 0.004). The rates of hospitalization or death were similar in the two groups., Conclusions: A multifactorial intervention, administered by nurses, did not result in a significantly lower rate of a first adjudicated serious fall injury than enhanced usual care. (Funded by the Patient-Centered Outcomes Research Institute and others; STRIDE ClinicalTrials.gov number, NCT02475850.)., (Copyright © 2020 Massachusetts Medical Society.)

The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. We included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype. To date, 49 patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two per cent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four per cent of patients with corticobasal syndrome had progressive supranuclear palsy-like features and 30% of patients with progressive supranuclear palsy had corticobasal syndrome-like features. Many patients with progressive supranuclear palsy and corticobasal syndrome had language impairments consistent with non-fluent variant PPA while patients with behavioural variant frontotemporal dementia often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n = 133), we identified patterns of covarying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships, with a continuous spectrum across the cohort rather than discrete diagnostic entities. In the 46 patients with follow-up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

A comprehensive phylogeny of species, i.e., a tree of life, has potential uses in a variety of contexts, including research, education, and public policy. Yet, accessing the tree of life typically requires special knowledge, complex software, or long periods of training. The Phylotastic project aims make it as easy to get a phylogeny of species as it is to get driving directions from mapping software. In prior work, we presented a design for an open system to validate and manage taxon names, find phylogeny resources, extract subtrees matching a user's taxon list, scale trees to time, and integrate related resources such as species images. Here, we report the implementation of a set of tools that together represent a robust, accessible system for on-the-fly delivery of phylogenetic knowledge. This set of tools includes a web portal to execute several customizable workflows to obtain species phylogenies (scaled by geologic time and decorated with thumbnail images); more than 30 underlying web services (accessible via a common registry); and code toolkits in R and Python (allowing others to develop custom applications using Phylotastic services). The Phylotastic system, accessible via http://www.phylotastic.org, provides a unique resource to access the current state of phylogenetic knowledge, useful for a variety of cases in which a tree extracted quickly from online resources (as distinct from a tree custom-made from character data) is sufficient, as it is for many casual uses of trees identified here., Competing Interests: Declaration of conflicting interest:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background/aims: To validate the use of the Test Your Memory (TYM) test in dementias other than Alzheimer's disease, and to compare the TYM test to two other short cognitive tests., Methods: One hundred and fifty-seven patients with dementia other than typical Alzheimer's disease were recruited from a specialist memory clinic. Patients completed the TYM test, the revised Addenbrooke's Cognitive Examination (ACE-R) and Mini-Mental State Examination (MMSE), plus neurological examination, clinical diagnostics and multi-disciplinary team review. Their TYM scores were compared to age-matched controls and an Alzheimer's disease cohort., Results: Patients scored an average of 34.4/50 on the TYM test compared to 46.0/50 in age-matched controls. Using the threshold of 42/50, the TYM test detected 80% of non-Alzheimer dementias. The area under the ROC curve was 0.89 with a PPV of 0.80 and a NPV of 0.84. The TYM test performed better than the ACE-R (using the threshold of 83) which detected 69% of cases and the MMSE (using a threshold of 24) which detected only 27%., Conclusions: The TYM test is a useful test in the detection of non-Alzheimer dementia. The TYM test performs much better than the MMSE at detecting non-Alzheimer dementias.

This paper summarises the current status of two novel short cognitive tests (SCT), known as Test Your Memory (TYM) and Test Your Memory for Mild Cognitive Impairment (TYM-MCI). The history of and recent research on the TYM and TYM-MCI are summarised in applications for Alzheimer's and non-Alzheimer's dementia and mild cognitive impairment. The TYM test can be used in a general neurology clinic and can help distinguish patients with Alzheimer's disease (AD) from those with no neurological cause for their memory complaints. An adapted tele-TYM test administered by telephone to patients produces scores which correlate strongly with the clinic-administered Addenbrookes Cognitive Examination revised (ACE-R) test and can identify patients with dementia. Patients with AD decline on the TYM test at a rate of 3.6-4.1 points/year., Competing Interests: The authors declare no conflict of interest

The Karabo distributed control system has been developed to address the challenging requirements of the European X-ray Free Electron Laser facility, including complex and custom-made hardware, high data rates and volumes, and close integration of data analysis for distributed processing and rapid feedback. Karabo is a pluggable, distributed application management system forming a supervisory control and data acquisition environment as part of a distributed control system. Karabo provides integrated control of hardware, monitoring, data acquisition and data analysis on distributed hardware, allowing rapid control feedback based on complex algorithms. Services exist for access control, data logging, configuration management and situational awareness through alarm indicators. The flexible framework enables quick response to the changing requirements in control and analysis, and provides an efficient environment for development, and a single interface to make all changes immediately available to operators and experimentalists.

The prevalence of microbial life in permafrost up to several million years (Ma) old has been well documented. However, the long-term survivability, evolution, and metabolic activity of the entombed microbes over this time span remain underexplored. We integrated aspartic acid (Asp) racemization assays with metagenomic sequencing to characterize the microbial activity, phylogenetic diversity, and metabolic functions of indigenous microbial communities across a ∼0.01- to 1.1-Ma chronosequence of continuously frozen permafrost from northeastern Siberia. Although Asp in the older bulk sediments (0.8 to 1.1 Ma) underwent severe racemization relative to that in the youngest sediment (∼0.01 Ma), the much lower d-Asp/l-Asp ratio (0.05 to 0.14) in the separated cells from all samples suggested that indigenous microbial communities were viable and metabolically active in ancient permafrost up to 1.1 Ma. The microbial community in the youngest sediment was the most diverse and was dominated by the phyla Actinobacteria and Proteobacteria In contrast, microbial diversity decreased dramatically in the older sediments, and anaerobic, spore-forming bacteria within Firmicutes became overwhelmingly dominant. In addition to the enrichment of sporulation-related genes, functional genes involved in anaerobic metabolic pathways such as fermentation, sulfate reduction, and methanogenesis were more abundant in the older sediments. Taken together, the predominance of spore-forming bacteria and associated anaerobic metabolism in the older sediments suggest that a subset of the original indigenous microbial community entrapped in the permafrost survived burial over geological time. IMPORTANCE Understanding the long-term survivability and associated metabolic traits of microorganisms in ancient permafrost frozen millions of years ago provides a unique window into the burial and preservation processes experienced in general by subsurface microorganisms in sedimentary deposits because of permafrost's hydrological isolation and exceptional DNA preservation. We employed aspartic acid racemization modeling and metagenomics to determine which microbial communities were metabolically active in the 1.1-Ma permafrost from northeastern Siberia. The simultaneous sequencing of extracellular and intracellular genomic DNA provided insight into the metabolic potential distinguishing extinct from extant microorganisms under frozen conditions over this time interval. This in-depth metagenomic sequencing advances our understanding of the microbial diversity and metabolic functions of extant microbiomes from early Pleistocene permafrost. Therefore, these findings extend our knowledge of the survivability of microbes in permafrost from 33,000 years to 1.1 Ma., (Copyright © 2019 American Society for Microbiology.)

Lactobacillus bacteria are potential delivery vehicles for biopharmaceutical molecules because they are well-recognized as safe microorganisms that naturally inhabit the human body. The goal of this study was to employ these lactobacilli to combat human immunodeficiency virus type 1 (HIV-1) infection and transmission. By using a chromosomal integration method, we engineered Lactobacillus acidophilus ATCC 4356 to display human CD4, the HIV-1 receptor, on the cell surface. Since human CD4 can bind to any infectious HIV-1 particles, the engineered lactobacilli can potentially capture HIV-1 of different subtypes and prevent infection. Our data demonstrate that the CD4-carrying bacteria are able to adsorb HIV-1 particles and reduce infection significantly in vitro and also block intrarectal HIV-1 infection in a humanized mouse model in preliminary tests in vivo Our results support the potential of this approach to decrease the efficiency of HIV-1 sexual transmission. IMPORTANCE In the absence of an effective vaccine, alternative approaches to block HIV-1 infection and transmission with commensal bacteria expressing antiviral proteins are being considered. This report provides a proof-of-concept by using Lactobacillus bacteria stably expressing the HIV-1 receptor CD4 to capture and neutralize HIV-1 in vitro and in a humanized mouse model. The stable expression of antiviral proteins, such as CD4, following genomic integration of the corresponding genes into this Lactobacillus strain may contribute to the prevention of HIV-1 sexual transmission., (Copyright © 2019 American Society for Microbiology.)

HIV-1 enters cells through binding between viral envelope glycoprotein (Env) and cellular receptors to initiate virus and cell fusion. HIV-1 Env precursor (gp160) is cleaved into two units noncovalently bound to form a trimer on virions, including a surface unit (gp120) and a transmembrane unit (gp41) responsible for virus binding and membrane fusion, respectively. The polar region (PR) at the N terminus of gp41 comprises 17 residues, including 7 polar amino acids. Previous studies suggested that the PR contributes to HIV-1 membrane fusion and infectivity; however, the precise role of the PR in Env-mediated viral entry and the underlying mechanisms remain unknown. Here, we show that the PR is critical for HIV-1 fusion and infectivity by stabilizing Env trimers. Through analyzing the PR sequences of 57,645 HIV-1 isolates, we performed targeted mutagenesis and functional studies of three highly conserved polar residues in the PR (S532P, T534A, and T536A) which have not been characterized previously. We found that single or combined mutations of these three residues abolished or significantly decreased HIV-1 infectivity without affecting viral production. These PR mutations abolished or significantly reduced HIV-1 fusion with target cells and also Env-mediated cell-cell fusion. Three PR mutations containing S532P substantially reduced gp120 and gp41 association, Env trimer stability, and increased gp120 shedding. Furthermore, S532A mutation significantly reduced HIV-1 infectivity and fusogenicity but not Env expression and cleavage. Our findings suggest that the PR of gp41, particularly the key residue S532, is structurally essential for maintaining HIV-1 Env trimer, viral fusogenicity, and infectivity. IMPORTANCE Although extensive studies of the transmembrane unit (gp41) of HIV-1 Env have led to a fusion inhibitor clinically used to block viral entry, the functions of different domains of gp41 in HIV-1 fusion and infectivity are not fully elucidated. The polar region (PR) of gp41 has been proposed to participate in HIV-1 membrane fusion in biochemical analyses, but its role in viral entry and infectivity remain unclear. In our effort to characterize three nucleotide mutations of an HIV-1 RNA element that partially overlaps the PR coding sequence, we identified a novel function of the PR that determines viral fusion and infectivity. We further demonstrated the structural and functional impact of six PR mutations on HIV-1 Env stability, viral fusion, and infectivity. Our findings reveal the previously unappreciated function of the PR and the underlying mechanisms, highlighting the important role of the PR in regulating HIV-1 fusion and infectivity., (Copyright © 2019 American Society for Microbiology.)

Objectives: To determine whether an interprofessional intervention would improve the use and timing of a geriatric consultation on a hospitalist service., Design: Difference-in-differences (DID), which measures the difference in improvement over time between intervention and control team patients attributable to the intervention., Setting: 1,000-bed U.S. academic medical center., Participants: Individuals aged 60 and older admitted to a general medicine hospitalist service (N=7,038; n = 718 on intervention teams, n = 686 historical controls, n = 5,634 on control teams (concurrent and historic)., Intervention: On 2 of 11 hospitalist teams, a geriatrician attended multidisciplinary discharge rounds twice weekly and advised on the benefits of a geriatric consultation for individuals aged 60 and older., Measurements: Primary outcome was percentage of hospitalizations resulting in a geriatric consultation. Secondary outcome was days to geriatric consultation. Both outcomes were controlled for age, sex, comorbidity, mean daily intensity of inpatient care utilization, and admission in the prior 30 days. In the primary analysis, length of stay was controlled., Results: Intervention participants were more likely to have a geriatric consultation (DID = 2.35% absolute percentage points, 95% confidence interval (CI) = 0.59-4.39%) and to have a consultation sooner (DID = 3.61 fewer days, 95% CI = -1 to -7)., Conclusion: An interprofessional intervention that focused on hospitalist ordering practices increased use of appropriate geriatric consultation and decreased time to consultation. This model of interprofessional effort is effective. Future adaptations are needed to target scarce geriatric resources without increasing overall use. J Am Geriatr Soc 66:2372-2376, 2018., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Background: Since April 2013, the UK's National Health Service Breast Screening Programme (NHSBSP) centers have been obliged to provide services for women at the highest risk of breast cancer, including those carrying highly penetrant single gene mutations (BRCA1, BRCA2, TP53). Since then, such individuals previously undergoing surveillance in the Royal Marsden Hospital were referred to their local NHSBSP centers. We aimed to assess patient experience of surveillance provided by local NHSBSP services at 1 and 3 years after repatriation., Patients and Methods: High-risk gene mutation carriers referred to the NHSBSP for breast cancer surveillance were identified from a departmental database in the Cancer Genetics Unit and invited to complete questionnaires about their experience of surveillance under this new pathway, first in 2014 and again in 2016., Results: Three hundred forty-six individuals were invited to participate in 2014, of whom 182 responded (53%). A total of 464 patients were invited in 2016, of whom 246 (53%) completed the second questionnaire. Ninety-four percent of patients with residual breast tissue received some screening at the first (n = 161) and second (n = 185) time points. Ninety-one percent of patients (n = 146) received at least recommended surveillance in the year preceding the initial survey, a proportion decreasing slightly by the second time point (n = 164, 87%). Seventeen percent of individuals required additional diagnostic investigations, with cancers detected in 2%. These proportions remained stable between surveys., Conclusion: Repatriation of high-risk individuals from Royal Marsden Hospital to NHSBSP centers has been successfully accomplished. Most individuals received appropriate recommended annual surveillance. Further improvements are required to ensure equal and timely provision of recommended surveillance., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The V3 loop of the human immunodeficiency virus type 1 (HIV-1) gp120 exterior envelope glycoprotein (Env) becomes exposed after CD4 binding and contacts the coreceptor to mediate viral entry. Prior to CD4 engagement, a hydrophobic patch located at the tip of the V3 loop stabilizes the non-covalent association of gp120 with the Env trimer of HIV-1 subtype B strains. Here, we show that this conserved hydrophobic patch (amino acid residues 307, 309 and 317) contributes to gp120-trimer association in HIV-1 subtype C, HIV-2 and SIV. Changes that reduced the hydrophobicity of these V3 residues resulted in increased gp120 shedding and decreased Env-mediated cell-cell fusion and virus entry in the different primate immunodeficiency viruses tested. Thus, the hydrophobic patch is an evolutionarily conserved element in the tip of the gp120 V3 loop that plays an essential role in maintaining the stability of the pre-triggered Env trimer in diverse primate immunodeficiency viruses., (Copyright © 2018. Published by Elsevier Inc.)

Background: Fall injuries are a major cause of morbidity and mortality among older adults. We describe the design of a pragmatic trial to compare the effectiveness of an evidence-based, patient-centered multifactorial fall injury prevention strategy to an enhanced usual care., Methods: Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) is a 40-month cluster-randomized, parallel-group, superiority, pragmatic trial being conducted at 86 primary care practices in 10 health care systems across United States. The 86 practices were randomized to intervention or control group using covariate-based constrained randomization, stratified by health care system. Participants are community-living persons, ≥70 years, at increased risk for serious fall injuries. The intervention is a comanagement model in which a nurse Falls Care Manager performs multifactorial risk assessments, develops individualized care plans, which include surveillance, follow-up evaluation, and intervention strategies. Control group receives enhanced usual care, with clinicians and patients receiving evidence-based information on falls prevention. Primary outcome is serious fall injuries, operationalized as those leading to medical attention (nonvertebral fractures, joint dislocation, head injury, lacerations, and other major sequelae). Secondary outcomes include all fall injuries, all falls, and well-being (concern for falling; anxiety and depressive symptoms; physical function and disability). Target sample size was 5,322 participants to provide 90% power to detect 20% reduction in primary outcome rate relative to control., Results: Trial enrolled 5,451 subjects in 20 months. Intervention and follow-up are ongoing., Conclusions: The findings of the STRIDE study will have important clinical and policy implications for the prevention of fall injuries in older adults.

Background: Pre-exposure prophylaxis (PrEP) is the use of HIV anti-retroviral therapy to prevent HIV transmission in people at high risk of HIV acquisition. PrEP is highly efficacious when taken either daily, or in an on-demand schedule. In Australia co-formulated tenofovir-emtricitabine is registered for daily use for PrEP, however, this co-formulation is not listed yet on the national subsidized medicines list. We describe a study protocol that aims to demonstrate if the provision of PrEP to up to 3800 individuals at risk of HIV in Victoria, Australia reduces HIV incidence locally by 25% generally and 30% among GBM. Methods: PrEPX is a population level intervention study in Victoria, Australia in which generic PrEP will be delivered to 3800 individuals for up to 36 months. Study eligibility is consistent with the recently updated 2017 Australian PrEP guidelines. Participants will attend study clinics, shared care clinics, or outreach clinics for quarterly HIV/STI screening, biannual renal function tests and other clinical care as required. Study visits and STI diagnoses will be recorded electronically through the ACCESS surveillance system. At each study visit participants will be invited to complete behavioral surveys that collect demographics and sexual risk data. Diagnosis and behavioral data will be compared between PrEPX participants and other individuals testing within the ACCESS surveillance system. A subset of participants will complete in depth surveys and interviews to collect attitudes, beliefs and acceptability data. Participating clinics will provide clinic level data on implementation and management of PrEPX participants. The population level impact on HIV incidence will be assessed using Victorian HIV notification data. Discussion: This study will collect evidence on the real world impact of delivery of PrEP to 3800 individuals at risk of acquiring HIV in Victoria. This study will provide important information for the broader implementation of PrEP planning upon listing of the tenofovir-emtricitabine on the national subsidized list of medicines. The study is registered on the Australian New Zealand Clinical Trials Registry (ACTRN12616001215415).

Competing Interests: Competing interests: None declared.

Background This paper examines a methamphetamine treatment and peer support program for gay men and other men who have sex with men (MSM) who use methamphetamine. Australian MSM use illicit drugs including methamphetamine at significantly higher rates than the broader community.1,2 Methamphetamine rates are higher again amongst HIV positive MSM. Methamphetamine in the MSM community is associated with sexual activity and may be associated with psychosocial harms including risk of the transmission of HIV and sexually transmissible infections.3,4,7,8 Methods: This paper presents the formal evaluation of Re-Wired, Australia's first structured methamphetamine treatment and support program for MSM, consisting of a free, six week therapeutic group and Re-Wired 2.0, a follow up peer support group. Data collection included baseline and post intervention administration of the Kessler Scale of Psychological Distress (K10) and the Drug Use Disorders Identification Test (DUDIT), the Personal Wellbeing Index (PWI) and the Readiness to Change Questionnaire (RCQ). This was complemented with qualitative session feedback and a small number of post intervention participant interviews., Results: Program evaluation demonstrated modest improvements in participant psychological distress, personal well-being and stage of change and reductions in methamphetamine use post intervention. Qualitative data revealed benefits of a specialised harm reduction intervention for this population through addressing fear of discrimination and stigma., Conclusions: The presented harm reduction program for MSM who use methamphetamine demonstrates the potential for a specialist peer-based approach to reduce harm in this vulnerable population. This approach may be suitable for adaptation with MSM populations in similar high-income settings.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.

Background: To validate a short cognitive test: the Test Your Memory for Mild Cognitive Impairment (TYM-MCI) in the diagnosis of patients with amnestic mild cognitive impairment or mild Alzheimer's disease (aMCI/AD)., Methods: Two hundred and two patients with mild memory problems were recruited. All had 'passed' the Mini-Mental State Examination (MMSE). Patients completed the TYM-MCI, the Test Your Memory test (TYM), MMSE and revised Addenbrooke's Cognitive Examination (ACE-R), had a neurological examination, clinical diagnostics and multidisciplinary team review., Results: As a single test, the TYM-MCI performed as well as the ACE-R in the distinction of patients with aMCI/AD from patients with subjective memory impairment with a sensitivity of 0.79 and specificity of 0.91. Used in combination with the ACE-R, it provided additional value and identified almost all cases of aMCI/AD. The TYM-MCI correctly classified most patients who had equivocal ACE-R scores. Integrated discriminant improvement analysis showed that the TYM-MCI added value to the conventional memory assessment. Patients initially diagnosed as unknown or with subjective memory impairment who were later rediagnosed with aMCI/AD scored poorly on their original TYM-MCI., Conclusion: The TYM-MCI is a powerful short cognitive test that examines verbal and visual recall and is a valuable addition to the assessment of patients with aMCI/AD. It is simple and cheap to administer and requires minimal staff time and training., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function., (Copyright © 2017 by the American Society of Nephrology.)

Historically, the medical subspecialties have not focused on the needs of older adults. This has changed with the implementation of initiatives to integrate geriatrics and aging research into the medical and surgical subspecialties and with the establishment of a home for internal medicine specialists within the annual American Geriatrics Society (AGS) meeting. With the support of AGS, other professional societies, philanthropies, and federal agencies, efforts to integrate geriatrics into the medical and surgical subspecialties have focused largely on training the next generation of physicians and researchers. They have engaged several subspecialties, which have followed parallel paths in integrating geriatrics and aging research. As a result of these combined efforts, there has been enormous progress in the integration of geriatrics and aging research into the medical and surgical subspecialties, and topics once considered to be geriatric concerns are becoming mainstream in medicine, but this integration remains a work in progress and will need to adapt to changes associated with healthcare reform., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Objectives: To estimate the lifetime risk, prevalence, incidence, and mortality of the principal clinical syndromes associated with frontotemporal lobar degeneration (FTLD) using revised diagnostic criteria and including intermediate clinical phenotypes., Methods: Multisource referral over 2 years to identify all diagnosed or suspected cases of frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) in 2 UK counties (population 1.69 million). Diagnostic confirmation used current consensus diagnostic criteria after interview and reexamination. Results were adjusted to the 2013 European standard population., Results: The prevalence of FTD, PSP, and CBS was 10.8/100,000. The incidence and mortality were very similar, at 1.61/100,000 and 1.56/100,000 person-years, respectively. The estimated lifetime risk is 1 in 742. Survival following diagnosis varied widely: from PSP 2.9 years to semantic variant FTD 9.1 years. Age-adjusted prevalence peaked between 65 and 69 years at 42.6/100,000: the age-adjusted prevalence for persons older than 65 years is double the prevalence for those between 40 and 64 years. Fifteen percent of those screened had a relevant genetic mutation., Conclusions: Key features of this study include the revised diagnostic criteria with improved specificity and sensitivity, an unrestricted age range, and simultaneous assessment of multiple FTLD syndromes. The prevalence of FTD, PSP, and CBS increases beyond 65 years, with frequent genetic causes. The time from onset to diagnosis and from diagnosis to death varies widely among syndromes, emphasizing the challenge and importance of accurate and timely diagnosis. A high index of suspicion for FTLD syndromes is required by clinicians, even for older patients., (© 2016 American Academy of Neurology.)

The notion that kidney function declines with age in the general population is well known in the Nephrology community and the average loss of glomerular filtration rate (GFR) about 1ml per year in most longitudinal studies. There is much debate within the community about whether this represents "normal aging" or whether this constitutes a form of renal disease. However this debate turns out, the real question is whether this decline is preventable - can it be modified or slowed? Efforts to find drivers of this decline are still in the very earliest stages, but have shown some promise at elucidating some of the pathologies involved. This article will address both the wider issue of the biology of aging as well as the specific pathologies of the aging kidney., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The American College of Medical Genetics and Genomics released recommendations for reporting incidental findings (IFs) in clinical exome and genome sequencing. These suggest 'opportunistic genomic screening' should be available to both adults and children each time a sequence is done and would be undertaken without seeking preferences from the patient first. Should opportunistic genomic screening be implemented in the United Kingdom, the Association of Genetic Nurses and Counsellors (AGNC), which represents British and Irish genetic counsellors and nurses, feels strongly that the following must be considered (see article for complete list): (1) Following appropriate genetic counselling, patients should be allowed to consent to or opt out of opportunistic genomic screening. (2) If true IFs are discovered the AGNC are guided by the report from the Joint Committee on Medical Genetics about the sharing of genetic testing results. (3) Children should not be routinely tested for adult-onset conditions. (4) The formation of a list of variants should involve a representative from the AGNC as well as a patient support group. (5) The variants should be for serious or life-threatening conditions for which there are treatments or preventative strategies available. (6) There needs to be robust evidence that the benefits of opportunistic screening outweigh the potential harms. (7) The clinical validity and utility of variants should be known. (8) There must be a quality assurance framework that operates to International standards for laboratory testing. (9) Psychosocial research is urgently needed in this area to understand the impact on patients.