bluuebunny/crossref_metadata_2025 huggingface dataset:
346 How Do we Increase Adherence to Home Exercise Programmes? Interviews with Older Adults and Physiotherapists
Authors: Khalijah Siti , Timmons Suzanne
Published: September 2019

Background

Regular exercise and physical activity can maintain function and cardiovascular health, and prevent cognitive decline, in older adults. However, studies show that there is often poor adherence to home exercise programmes (HEP). The purpose of this study was to explore how HEP are perceived by both older adults and physiotherapists.

Methods

A convenience sample of 28 older adults attending outpatient physiotherapy clinics were given an exercise journal to record their adherence to the HEP prescribed by their physiotherapists for six weeks. Subsequently, semi-structured interviews were conducted with a purposive sample, and the corresponding prescribing physiotherapists, to achieve maximal variation in terms of HEP adherence, age and sex. The interviews were audio recorded, transcribed, and simple content analysis performed.

Results

Fourteen participants returned their exercise journal. Median age was 80; half were female; median Berg Balance Score and Timed-up-and-Go-Test were 49 and 16 seconds respectively. Participants exercised a median 79.8% of the prescribed dose, or 5.6 days per week. Seven older adults were interviewed; about half had a positive attitude towards exercise. They were also moderately positive about their HEP (comments ranged from “doable” and “nothing bad about it” to “enjoyable”). Barriers included time, mood, boredom, remembering to do the HEP, and variable health status. Enablers included simple instructions and design, family encouragement, and sense of achievement. Physiotherapists (n=5) perceived that many older adults aren’t compliant with HEPs, but there was some therapeutic nihilism (“you can’t force them”). Their HEP instructions varied from verbal to written instructions/diagrams; one physiotherapist used individualised video content. Notably, participants with good adherence understood their HEP well in terms of content and purpose, although this may be cause or effect.

Conclusion

To improve compliance with HEP, healthcare professionals need to take time to motivate the recipient, simplify their instructions, and trouble-shoot potential barriers at the time of prescription.
70 Can a Wholefood Plant-based Diet Affect Healthy Ageing?
Authors: O'Mullan Ailin
Published: September 2019

Background

This study sought to examine existing evidence regards the effects of a wholefood plant-based diet on healthy ageing. As of March 2018 the average life expectancy in Ireland was 81.4 years, ten years above the global average. However approximately 1 million people suffer from chronic disease with 64.8% of people over 65 living with co-morbidity (TILDA 2014). The prevention and treatment of these diseases is central to the healthy ageing of our population.

Methods

This systematic review of the literature explored diet, health, ageing and disease. A scoping search, with relevant key words, was followed by an in-depth search with reference to a pre-ordained search syntax template. Specific eligibility criteria, determined by a PICOSS system were applied to the results. All included studies underwent quality assessment in line with the critical appraisal checklist for cross sectional studies. Extracted data was displayed in table format initially and then explained through narrative synthesis.

Results

A large body of evidence was found to suggest that cardiovascular disease, metabolic disorders and inflammatory conditions improved with a wholefood plant-based diet. Evidence in relation to certain cancers was present but not conclusive. Breast cancer was the exception to this. Evidentiary support, for reductions in BMI and in the need for polypharmacy were also found.

Conclusion

More research is needed into the benefits of a wholefood plant-based Diet. However as this diet is a low cost, low risk intervention it could be applied beneficially in the interim. Ageing was found to be a life-wide, life–long process so the research concluded that this diet could provide benefit to all.

“The side effects of a plant-based diet could be the elimination of the need to take drugs, and further research is needed to find ways to make Plant-Based Diet the new normal” Tuso, et al (2013).
112 A Critical Evaluation of the VIP Tool in Identifying Frailty in the Older Adult in a Kerry Hospital
Authors: Brolly Amanda , Bergin Liza , McQuinn Paudie , Buckley O’Sullivan Shinann , Naughton Corina
Published: September 2019

Background

The Variable Indicative of Placement risk (VIP) is a tool that was developed in Belgium to identify older people at risk of adverse health outcomes at the time of hospital admission (Vandewoude et al 2008). VIP is a simple 3-item screening tool for the selection of hospitalized patients aged 70 and older who are at increased risk of problems at discharge. It asks three simple questions about frailty factors already existing before admission. This tool has been validated to select patients who would benefit from a geriatric assessment (Vandewoude et al 2008).

As part of the implementation process, it is important to critically review VIP as a frailty screening and selection tool for the Frailty Intervention Therapy Team (FITT) service compared to age criteria alone. There is a risk that patients screening negative on VIP could be inappropriately excluded from the FITT review.

Methods

All patients over 75 were screened using the VIP tool over a 6 week period by nursing staff in triage The “Think Frail” tool was also used to screen all patients reviewed by FITT- both positive & negative VIP Data was retrospectively gathered and VIP positive/negative patients reviewed by FITT were analysed

Results

55% were VIP positive 45% were VIP negative 16.5% of VIP negative patients were screened positive for frailty using the “Think Frail” tool We found VIP under-recognised patients presenting with reduced mobility (5.5%, n=20), acute confusion (2.7%, n=10) and polypharmacy (8.1%, n=29), all potentially modifiable frailty

Conclusion

The VIP tool is not sensitive to identifying the presence of pre-frailty markers including falls, polypharmacy and acute confusion. Further research is needed into the use of the VIP tool in Ireland. It is recommended that this tool is not used independently to identify frailty in the ED.
146 The Lived Experience of Carer Resilience Told by Carer Advocates
Authors: Reid Laura , Harmon Aisling
Published: September 2019

Background

Established in 2013 this network of volunteer family carers is a national advocacy group that presents a vital opportunity for carers to use their voice to raise awareness of issues affecting families living with dementia in Ireland. The network is facilitated by a dementia specific service provider.

These carer advocates wish to present on a piece of qualitative research they have recently conducted on the topic of carer resilience at the advanced stages of caring for a loved one with dementia.

Methods

There are 43 family carer advocates on the network, all of whom were invited to participate in this research.

The piece of qualitative research conducted by the network with its members took the form of a questionnaire.

The research sought to ascertain how informed and supported carers felt as their loved ones transitioned to long term residential care and the stage thereafter.

This research did not discuss the level of professional care given to their loved one but what supports and services were offered to the carer at that time and how this affected their resilience.

The aspect of caring for a loved one availing of hospice care naturally emerged during the research process and this topic was also explored in relation to carer resilience.

Completed questionnaires were analysed to show findings and draw conclusions.

Results

The research gives insight into the lived experience of carer resilience told by carer advocates. The results show that carer advocates feel ill-informed and badly supported as their loved one transitions to or resided in long term residential care.

The research also showed that carers feel more informed and supported if their loved one availed of hospice care rather than long term residential care.

Conclusion

Carers are not properly informed or supported when their loved one transitions to or resides in long term residential care and this negatively affects their resilience.
APOE genotype, hypertension severity and outcomes after intracerebral haemorrhage
Authors: Biffi Alessandro , Murphy Meredith P , Kubiszewski Patryk , Kourkoulis Christina , Schwab Kristin , Gurol Mahmut Edip , Greenberg Steven M , Viswanathan Anand , Anderson Christopher D , Rosand Jonathan
Published: September 2019

Intracerebral haemorrhage in the elderly is a severe manifestation of common forms of cerebral small vessel disease. Nearly 60% of intracerebral haemorrhage survivors will develop clinical manifestations of small vessel disease progression including recurrent haemorrhage, ischaemic stroke, dementia, late-life depression and gait impairment within 5 years. Blood pressure measurements following intracerebral haemorrhage are strongly associated with this risk. However, aggressive blood pressure lowering in the elderly carries substantial risks. In order to determine whether there might be an opportunity to select individuals at the highest risk for small vessel disease progression for aggressive blood pressure reduction, we investigated whether APOE gene variants ɛ2/ɛ4 modify the association between blood pressure and small vessel disease clinical progression after intracerebral haemorrhage. We conducted a single-centre longitudinal study at a tertiary care referral centre (Massachusetts General Hospital in Boston, MA, USA), analysing 716 consecutive survivors of acute intracerebral haemorrhage, enrolled from January 2006 to December 2016. We conducted research interviews at the time of enrolment and obtained APOE genotypes from peripheral venous blood samples. We followed patients longitudinally by means of validated phone-based research encounters, aimed at gathering measurements of systolic and diastolic blood pressure, as well as information on small vessel disease clinical outcomes (including recurrent haemorrhage, incident ischaemic stroke, incident dementia, incident depression and incident gait impairment). APOE ε4 and systolic blood pressure were associated with the risk of recurrent haemorrhage, ischaemic stroke and post-haemorrhage dementia, depression and gait impairment (all P < 0.05). APOE ε4 and systolic blood pressure interacted to increase the risk of recurrent haemorrhage, ischaemic stroke, dementia and gait impairment (all interaction P < 0.05). Among patients with elevated blood pressure following intracerebral haemorrhage (average systolic blood pressure 120–129 mmHg and diastolic blood pressure <80 mmHg) only those with one or more APOE ε4 copies were at increased risk for one or more small vessel disease outcomes (hazard ratio = 1.97, 95% confidence interval 1.17–3.31). Among haemorrhage survivors with hypertension (stage 1 and beyond) APOE genotype also stratified risk for all small vessel disease outcomes. In conclusion, APOE genotype modifies the already strong association of hypertension with multiple small vessel disease clinical outcomes among intracerebral haemorrhage survivors. These data raise the possibility that genetic screening could inform blood pressure treatment goals in this patient population.
Evaluating stably expressed genes in single cells
Authors: Lin Yingxin , Ghazanfar Shila , Strbenac Dario , Wang Andy , Patrick Ellis , Lin David M , Speed Terence , Yang Jean Y H , Yang Pengyi
Published: September 2019

Background

Single-cell RNA-seq (scRNA-seq) profiling has revealed remarkable variation in transcription, suggesting that expression of many genes at the single-cell level is intrinsically stochastic and noisy. Yet, on the cell population level, a subset of genes traditionally referred to as housekeeping genes (HKGs) are found to be stably expressed in different cell and tissue types. It is therefore critical to question whether stably expressed genes (SEGs) can be identified on the single-cell level, and if so, how can their expression stability be assessed? We have previously proposed a computational framework for ranking expression stability of genes in single cells for scRNA-seq data normalization and integration. In this study, we perform detailed evaluation and characterization of SEGs derived from this framework.

Results

Here, we show that gene expression stability indices derived from the early human and mouse development scRNA-seq datasets and the "Mouse Atlas" dataset are reproducible and conserved across species. We demonstrate that SEGs identified from single cells based on their stability indices are considerably more stable than HKGs defined previously from cell populations across diverse biological systems. Our analyses indicate that SEGs are inherently more stable at the single-cell level and their characteristics reminiscent of HKGs, suggesting their potential role in sustaining essential functions in individual cells.

Conclusions

SEGs identified in this study have immediate utility both for understanding variation and stability of single-cell transcriptomes and for practical applications such as scRNA-seq data normalization. Our framework for calculating gene stability index, "scSEGIndex," is incorporated into the scMerge Bioconductor R package (https://sydneybiox.github.io/scMerge/reference/scSEGIndex.html) and can be used for identifying genes with stable expression in scRNA-seq datasets.
Toward a precision behavioral medicine approach to addressing high-risk sun exposure: a qualitative analysis
Authors: Stump Tammy K , Spring Bonnie , Marchese Sara Hoffman , Alshurafa Nabil , Robinson June K
Published: September 2019

Objectives

Precision behavioral medicine techniques integrating wearable ultraviolet radiation (UVR) sensors may help individuals avoid sun exposure that places them at-risk for skin cancer. As a preliminary step in our patient-centered process of developing a just-in-time adaptive intervention, this study evaluated reactions and preferences to UVR sensors among melanoma survivors.

Materials and Methods

Early stage adult melanoma survivors were recruited for a focus group (n = 11) or 10-day observational study, which included daily wearing a UVR sensor and sun exposure surveys (n = 39). Both the focus group moderator guide and observational study exit interviews included questions on UVR sensing as a potential intervention strategy. These responses were transcribed and coded using an inductive strategy.

Results

Most observational study participants (84.6%) said they would find information provided by UVR sensors to be useful to help them learn about how specific conditions (eg, clouds, location) impact sun exposure and provide in-the-moment alerts. Focus group participants expressed enthusiasm for UVR information and identified preferred qualities of a UVR sensor, such as small size and integration with other devices. Participants in both studies indicated concern that UVR feedback may be difficult to interpret and some expressed that a UVR sensor may not be convenient or desirable to wear in daily life.

Discussion

Melanoma survivors believe that personalized UVR exposure information could improve their sun protection and want this information delivered in a method that is meaningful and actionable.

Conclusion

UVR sensing is a promising component of a precision behavioral medicine strategy to reduce skin cancer risk.
Creative Destruction and Uncertainty
Authors: Sedláček Petr
Published: September 2019

Uncertainty rises in recessions. But does uncertainty cause downturns or vice versa? This paper argues that counter-cyclical uncertainty fluctuations are a by-product of technology growth. In a firm dynamics model with endogenous technology adoption, faster technology growth widens the dispersion of firm-level productivity shocks, a benchmark uncertainty measure. Moreover, faster technology growth spurs a creative destruction process, generates a temporary downturn, and renders uncertainty counter-cyclical. Estimates from structural vector autoregressions (VARs) on U.S. data confirm the model’s predictions. On average, 1/4 of the cyclical variation in uncertainty is driven by technology shocks. This fraction rises to 2/3 around the “dot-com” bubble.
Ramelteon for Prevention of Postoperative Delirium: A Randomized Controlled Trial in Patients Undergoing Elective Pulmonary Thromboendarterectomy*
Authors: Jaiswal Stuti J. , Vyas Anuja D. , Heisel Andrew J. , Ackula Haritha , Aggarwal Ashna , Kim Nick H. , Kerr Kim M. , Madani Michael , Pretorius Victor , Auger William R. , Fernandes Timothy M. , Malhotra Atul , Owens Robert L.
Published: September 2019

Objectives:

To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting.

Design:

Parallel-arm, randomized, double-blinded, placebo-controlled trial.

Setting:

Academic medical center in La Jolla, California.

Patients:

Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy.

Interventions:

Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU.

Measurements and Main Results:

Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5–1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2–3 d] vs ramelteon 3 d [2–5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1–3 d] vs ramelteon 3 d [2–4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3–5 d] vs 4 d [3–6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2–3.2; p = 0.717), all placebo versus ramelteon, respectively.

Conclusions:

Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.
Evidence map of ductal carcinoma in situ management options
Authors: Bouskill Kathryn , Hempel Susanne , Richardson Andrea , Ganz Patricia A. , Baxi Sangita , Zutshi Rushil , Larkin Jody , Motala Aneesa , Miles Jeremy N. V. , Crandall Carolyn J.
Published: September 2019

Objective:

Ductal carcinoma in situ (DCIS) has the potential to progress to invasive carcinoma. The optimal management of DCIS and methods for individualizing treatment of DCIS are still being determined. This evidence map depicts the robustness and topical span of research on DCIS management choice on patient-centered and clinical outcomes.

Methods:

We searched PubMed, EMBASE, PsycINFO, PubMed Health, PROSPERO, and clinical practice guideline sites to identify systematic reviews of DCIS management options and consulted with topic experts. A bubble plot visualizes the literature volume and research content for patient-centered outcomes. An online decision tree facilitates discussions with patients and guides through the available evidence.

Results:

In total, 40 systematic reviews met inclusion criteria. The research syntheses addressed DCIS management options, including the role of magnetic resonance imaging, axillary surgery/sentinel lymph node biopsy, and excisional biopsy. The map shows existing evidence for mutually exclusive treatment options including active surveillance, breast-conserving surgery, nipple sparing mastectomy, and simple mastectomy. Research findings for intraoperative radiation, adjuvant radiation therapy, adjuvant hormone therapy, hypofractionation radiotherapy, accelerated partial breast irradiation, radiation therapy plus boost, and combined radiation and hormone therapy, as well as for breast reconstruction after mastectomy and surveillance mammography postsurgery are also displayed. The evidence map highlights a scarcity of robust evidence on patient-centered outcomes.

Conclusions:

The evidence map provides an overview of DCIS research showing the range of management options and remaining decisional dilemmas that follow a diagnosis of DCIS. It maps the evidence in accessible tools to guide practice and future research.

Video Summary:

http://links.lww.com/MENO/A448.
Extraluminal Sigmoid Sinus Angioplasty: A Pertinent Reconstructive Surgical Method Targeting Dural Sinus Hemodynamics to Resolve Pulsatile Tinnitus
Authors: Hsieh Yue-Lin , Wang Wuqing
Published: September 2019

Objectives:

1) To provide information on the treatment of pulsatile tinnitus (PT) with transtemporal extraluminal sigmoid sinus angioplasty (ESSA); and 2) to discuss the current clinical management of PT.

Study Design:

This was a retrospective study.

Settings:

Multi-institutional tertiary university medical centers.

Patients:

Fifty-four PT patients with transverse–sigmoid sinus enlargement and prominent transverse–sigmoid junction with or without sigmoid sinus wall anomalies or transverse sinus anomalies.

Intervention:

All patients underwent ESSA under local anesthesia.

Main Outcome Measures:

Intraoperative discoveries and surgical resolution of PT, morphology, and computational fluid dynamics.

Results:

Fifty-three of the 54 (98%) patients experienced a significant reduction in, or complete resolution of, PT after ESSA. No major surgical complications occurred, except for one case where we observed a full collapse of the sinus wall. On average, this surgery reduced the cross-sectional area at the transverse–sigmoid junction by 61.5%. Our intraoperative discoveries suggest that sigmoid sinus wall anomalies may not be a definitive cause of PT. The transverse–sigmoid sinus system was significantly larger (in term of both cross-sectional area and volume) on the ipsilesional side compared with the contralesional side. Following ESSA, the vascular wall pressure and vortex flow at the transverse–sigmoid junction decreased considerably, and the flow velocity and wall shear stress increased significantly.

Conclusion:

ESSA is a highly effective surgical technique for PT patients with transverse–sigmoid sinus enlargement and prominent transverse–sigmoid junction, regardless of whether they also have sigmoid sinus wall or transverse sinus anomalies. A large transverse–sigmoid system with prominent transverse–sigmoid junction is a predisposing factor for PT, and only by improving patients’ intrasinus hemodynamics could PT be resolved efficiently. In cases without complete obstruction of venous return, ESSA is safe. No postoperative complications related to neurological disorders were observed.
Understanding pretreatment loss to follow-up of tuberculosis patients: an explanatory qualitative study in Chennai, India
Authors: Thomas Beena E. , Suresh Chandra , Lavanya J. , Lindsley Mika M. , Galivanche Amith T. , Sellappan Senthil , Ovung Senthanro , Aravind Amritha , Lincy Savari , Raja Agnes Lawrence , Kokila S. , Javeed B. , Arumugam S. , Mayer Kenneth H. , Swaminathan Soumya , Subbaraman Ramnath
Published: September 2019

Introduction

Pretreatment loss to follow-up (PTLFU)—dropout of patients after diagnosis but before registration in treatment—is a major gap in TB care delivery in India and globally. Patient and healthcare worker (HCW) perspectives are critical for developing interventions to address this problem.

Methods

We prospectively tracked newly diagnosed smear-positive TB patients from 22 TB diagnostic centers in Chennai, one of India’s largest cities. Patients who did not start therapy within 14 days, or who died or were lost to follow-up before official registration in treatment, were classified as PTLFU cases. We conducted qualitative interviews with all trackable PTLFU patients, or family members of patients who had died. We conducted focus group discussions (FGDs) with three types of HCWs involved in TB care. Interview and FGD recordings were transcribed, coded, and analyzed with the support of Dedoose 8.0.35 software to identify key themes. We created categories into which these themes clustered, identified relationships among thematic categories, and assembled findings into a broader explanatory model for PTLFU.

Results

We conducted six FGDs comprising 53 HCWs and 33 individual patient or family member interviews. Themes clustered into five categories. Examining relationships among these categories revealed two pathways leading to PTLFU as part of a broader explanatory model. In the first pathway, administrative and organizational health system barriers—including the complexity of navigating the system, healthcare worker absenteeism, and infrastructure failures—resulted in patients feeling frustration or resignation, leading to disengagement from care. Health system barriers experienced by patients were in turn shaped by constraints that made it difficult for HCWs to do their jobs effectively. In the second pathway, negative or judgmental HCW attitudes and behaviors towards patients contributed to patient distrust of the health system, resulting in refusal of further care.

Conclusion

Health system barriers contribute substantially to PTLFU directly and by amplifying patient-related challenges to engaging in care. Interventions should focus on removing administrative hurdles patients face in the health system, improving the quality of the HCW-patient interaction, and alleviating constraints HCWs face in being able to provide optimal patient-centered care.
De novo EIF2AK1andEIF2AK2variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation
Authors: Mao Dongxue , Reuter Chloe M. , Ruzhnikov Maura R.Z. , Beck Anita E. , Farrow Emily G. , Emrick Lisa T. , Rosenfeld Jill A. , Mackenzie Katherine M. , Robak Laurie , Wheeler Matthew T. , Burrage Lindsay C. , Jain Mahim , Liu Pengfei , Calame Daniel , Küry Sebastien , Sillesen Martin , Schmitz-Abe Klaus , Tonduti Davide , Spaccini Luigina , Iascone Maria , Genetti Casie A. , Graf Madeline , Tran Alyssa , Alejandro Mercedes ,   Undiagnosed Diseases Network, Lee Brendan H. , Thiffault Isabelle , Agrawal Pankaj B. , Bernstein Jonathan A. , Bellen Hugo J. , Chao Hsiao-Tuan
Published: September 2019

EIF2AK1andEIF2AK2encode members of the Eukaryotic Translation Initiation Factor 2 Alpha Kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants inEIF2AK1andEIF2AK2have not been reported. Here, we describe the identification of eight unrelated individuals with heterozygousde novomissense variants inEIF2AK1(1/8) orEIF2AK2(7/8). Features seen in these eight individuals include white matter alterations (8/8), developmental delay (8/8), impaired language (8/8), cognitive impairment (7/8), ataxia (6/8), dysarthria in probands with verbal ability (6/6), hypotonia (6/8), hypertonia (5/8), and involuntary movements (3/8). Individuals withEIF2AK2variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and patient-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate Eukaryotic Translation Initiation Factor 2 Subunit 1, (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM), a leukoencephalopathy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate thatEIF2AK2missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.
Exploring the Links between Specific Depression Symptoms and Brain Structure: A Network Study
Authors: Hilland Eva , Landrø Nils Inge , Kraft Brage , Tamnes Christian K. , Fried Eiko I. , Maglanoc Luigi A. , Jonassen Rune
Published: September 2019

The network approach to psychopathology has recently received considerable attention, and is as a novel way of conceptualizing mental disorders as causally interacting symptoms. In this study, we modeled a joint network of depression symptoms and depression-related brain structures, using 21 symptoms and five regional brain measures. We used a mixed sample of 268 individuals previously treated for one or more major depressive episodes and never depressed individuals. The network revealed associations between brain structure and unique depressive symptoms, which may clarify relationships regarding symptomatic and biological heterogeneity in depression.
Dendritic GABAB receptors control nonlinear information transfer along the dendro-somatic axis in layer 5 pyramidal neurons
Authors: Schulz Jan M. , Larkum Matthew E.
Published: September 2019

Dendritic GABAB receptors (GABABRs) mediate a slow form of interhemispheric inhibition. Surprisingly, this inhibition has no detectable effect on the somatic membrane potential of layer 5 pyramidal neurons, whereas the action potential (AP) output is robustly decreased even when the input is proximal to the cell body. To elucidate the underlying mechanisms, we systematically mapped the AP frequency-current (F-I) relationship during dual patch-clamp recordings from soma and apical dendrite. The AP output function was governed by the synergistic interaction between dendritic and somatic compartments as the local input and transfer resistance from dendrite to soma (Kds) depended on the dendritic membrane potential. Thus, Kds doubled at an estimated rate of once per 28.7 mV depolarization due to HCN channel deactivation. In addition, dendritic L-type Ca2+ channels converted individual APs into dendritic Ca2+ spikes causing high-frequency bursts of APs (HFB) during large dendritic depolarization. Activation of dendritic GABABRs greatly reduced both nonlinear mechanisms. While direct block of L-type Ca2+ channels reduced the number of HFBs, K+ channel activation decreased voltage-dependent input and transfer resistances and decreased the AP rate under all conditions. These results highlight the powerful modulation of the input integration in pyramidal neurons by metabotropic receptor-activated K+ channels.
Timing and duration of phenological subsidies: toward a mechanistic understanding of impacts on community structure and ecosystem processes in stream food chains
Authors: Takimoto Gaku , Sato Takuya
Published: September 2019

Phenological resources are common across many ecological communities, and can strongly affect community dynamics. Recent field manipulation experiments in stream food chains found that seasonal timing and duration of terrestrial prey inputs affected the feeding behavior, growth, and maturation of fish predators, caused predator-mediated indirect effects on aquatic prey, and modified trophic-cascading effects on litter processing. These experiments described impacts of resource phenological changes over a few month period, and long-term impacts of continued changes in resource phenology are unknown. Here we develop a mathematical model to extrapolate long-term predictions about the effects of changes in resource phenology from the results of field manipulation experiments. The model predicts that advanced timing generally decreases aquatic prey and litter processing and prolonged duration will either increase or decrease aquatic prey and litter processing depending on the total amount and pre-disturbed timing and duration of terrestrial prey inputs. Importantly, our modeling approach clarifies the mechanisms by which stage-specific responses of life history processes in fish, such as growth, maturation, and reproduction, respond to phenological changes in terrestrial prey inputs and mediate indirect effects on aquatic prey and litter processing. Stage-specific responses of life history processes are an integral part of the mechanisms with which to predict the consequences of phenological species interactions at the community and ecosystem levels.
Vaginal microbiota of adolescents and their mothers: A preliminary study of vertical transmission and persistence
Authors: Bassis Christine M. , Bullock Kaylie A. , Sack Daniel E. , Saund Katie , Pirani Ali , Snitkin Evan S. , Alaniz Veronica I. , Quint Elisabeth H. , Young Vincent B. , Bell Jason D.
Published: September 2019

Background

Factors that influence vaginal microbiota composition, including its source, are not well understood. To determine if vaginal microbiota transmission from mother to daughter at birth influences the human vaginal microbiota composition in adolescence, we investigated the relationship between the vaginal microbiota of 13 mother/daughter pairs and the daughter’s birth mode.

Results

Based on analysis of bacterial 16S rRNA gene sequences, the vaginal microbiotas of mother/daughter pairs were more similar to each other if the daughter was born by vaginal delivery rather than by C-section. Additionally, genome sequences from an important member of the vaginal microbiota, Lactobacillus crispatus, isolated from one mother/daughter pair in which the daughter was born by vaginal delivery, were highly similar.

Conclusions

Both community-level analysis and isolate genome sequence analysis are consistent with birth-mode dependent transmission and persistence of at least some members of the vaginal microbiota.

Importance

The composition of the human vaginal microbiota is related to many aspects of health from infection susceptibility to preterm birth. Our study provides evidence that transmission of vaginal bacteria from mother to daughter at birth may be an important factor influencing vaginal microbiota composition into adolescence.
Integrative analysis of multi-platform reverse-phase protein array data for the pharmacodynamic assessment of response to targeted therapies
Authors: Byron Adam , Bernhardt Stephan , Ouine Bérèngere , Cartier Aurélie , Macleod Kenneth G. , Carragher Neil O. , Sibut Vonick , Korf Ulrike , Serrels Bryan , de Koning Leanne
Published: September 2019

Reverse-phase protein array (RPPA) technology uses panels of high-specificity antibodies to measure proteins and protein post-translational modifications in cells and tissues. The approach offers sensitive and precise quantification of large numbers of samples and has thus found applications in the analysis of clinical and pre-clinical samples. For effective integration into drug development and clinical practice, robust assays with consistent results are essential. Leveraging a collaborative RPPA model, we set out to assess the variability between three different RPPA platforms using distinct instrument set-ups and workflows. Employing multiple RPPA-based approaches operated across distinct laboratories, we characterised a range of human breast cancer cells and their protein-level responses to two clinically relevant cancer drugs. We integrated multi-platform RPPA data and used unsupervised learning to identify protein expression and phosphorylation signatures that were not dependent on RPPA platform and analysis workflow. Our findings indicate that proteomic analyses of cancer cell lines using different RPPA platforms can identify concordant profiles of response to pharmacological inhibition, including when using different antibodies to measure the same target antigens. These results highlight the robustness and the reproducibility of RPPA technology and its capacity to identify protein markers of disease or response to therapy.
Bacteria control cell volume by coupling cell-surface expansion to dry-mass growth
Authors: Oldewurtel Enno R. , Kitahara Yuki , Cordier Baptiste , Özbaykal Gizem , van Teeffelen Sven
Published: September 2019

Cells exhibit a high degree of intracellular crowding. To control the level of crowding during growth cells must increase their volumes in response to the accumulation of biomass. UsingEscherichia colias a model organism, we found that cells control cell volume indirectly, by increasing cell-surface area in proportion to biomass growth. Thus, dry-mass density, a readout of intracellular crowding, varies in proportion to the surface-to-volume ratio, both during the cell cycle and during perturbations such as nutrient shifts. On long time scales after shifts, initial dry-mass density is nearly restored by slow variations of the surface-to-mass ratio. Contrary to a long-standing paradigm, cell-envelope expansion is controlled independently of cell-wall synthesis but responds to the activity of cell-wall cleaving hydrolases. Finally, we observed rapid changes of Turgor pressure after nutrient shifts, which were likely responsible for initial changes of cell diameter and dry-mass-density. Together, our experiments reveal important regulatory relationships for cell volume and shape.
Methylthioadenosine is Not Dramatically Elevated inMTAP-Homozygous Deleted Primary Glioblastomas
Authors: Barekatain Yasaman , Yan Victoria C. , Ackroyd Jeffrey J. , Poral Anton H. , Tran Theresa , Georgiou Dimitra K. , Arthur Kenisha , Lin Yu-Hsi , Satani Nikunj , Ballato Elliot S. , deCarvalho Ana , Verhaak Roel , de Groot John , Huse Jason T. , Asara John M. , Muller Florian L.
Published: September 2019

In Brief

The co-deletion ofMTAPin theCDKN2Alocus is a frequent event in diverse cancers including glioblastoma. Recent publications report that significant accumulations of the MTAP substrate, methylthioadenosine (MTA), can sensitizeMTAP-deleted cancer cells to novel inhibitors of PRMT5 and MAT2A for targeted therapy against tumors with this particular genetic alteration. In this work, using comprehensive metabolomic profiling, we show that MTA is primarily secreted, resulting in exceedingly high levels of extracellular MTAin vitro. We further show that primary human glioblastoma tumors minimally accumulate MTAin vivo, which is likely explained by the metabolism of MTA byMTAP-competent stromal cells. Together, these data challenge whether the metabolic conditions required for therapies to exploit vulnerabilities associatedMTAPdeletions are present in primary human tumors, questioning their translational efficacy in the clinic.

Highlights

Methylthioadenosine (MTA) is elevated inMTAP-deleted cancer cellsin vitro, which provides a selective vulnerability to PRMT5 and MAT2A inhibitors

Accumulation of MTA inMTAP-deleted cancer cells is predominately extracellular, suggesting active secretion of MTA.

MTAP-deleted primary human glioblastoma tumors show minimal intratumoral elevations of MTA, which is likely explained by secretion and metabolism byMTAP-competent stromal cells.

Homozygous deletion of theCDK2NAlocus frequently results in co-deletion of methylthioadenosine phosphorylase (MTAP) in many fatal cancers such as glioblastoma multiforme (GBM), resulting in elevations of the substrate metabolite, methylthioadenosine (MTA). To capitalize on such accumulations, therapeutic targeting of protein arginine methyltransferase 5 (PRMT5) and methionine adenosyl transferase (MAT2A) are ongoing. While extensively corroboratedin vitro, the clinical efficacy of these strategies ultimately relies on equally significant accumulations of MTA in human tumors. Here, we show thatin vitroaccumulation of MTA is a predominately extracellular phenomenon, indicating secretion of MTA fromMTAP-deleted cells. In primary human GBMs, we find that MTA levels are not significantly higher inMTAP-deleted compared toMTAP-intact tumors or normal brain tissue. Together, these findings highlight the metabolic discrepancies betweenin vitromodels and primary human tumors and should thus be carefully considered in the development of the precision therapies targetingMTAP-homozygous deleted GBM.
An Open Source Unsupervised Algorithm for Identification and Fast Prediction of Behaviors
Authors: Hsu Alexander I. , Yttri Eric A.
Published: September 2019

Studying naturalistic behavior remains a prohibitively difficult objective. Recent machine learning advances have enabled limb localization. Extracting behaviors, however, requires ascertaining the spatiotemporal patterns of these positions. To provide the missing bridge from poses to actions and their kinematics, we developed B-SOiD - an open-source, unsupervised algorithm that identifies behavior without user bias. By training a machine classifier on pose pattern statistics clustered using new methods, our approach achieves greatly improved processing speed and the ability to generalize across subjects or labs. Using a frameshift alignment paradigm, B-SOiD overcomes previous temporal resolution barriers that prevent the use of other algorithms with electrophysiological recordings. Using only a single, off-the-shelf camera, B-SOiD provides categories of sub-action for trained behaviors and kinematic measures of individual limb trajectories in an animal model. These behavioral and kinematic measures are difficult but critical to obtain, particularly in the study of pain, OCD, and movement disorders.
Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective
Authors: Oliynyk Roman Teo
Published: September 2019

With the accumulation of scientific knowledge of the genetic causes of common diseases and continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This study endeavored to assess population genetics consequences of such therapies. Computer simulations were used to evaluate the heterogeneity in causal alleles for polygenic diseases that could exist among geographically distinct populations. The results show that although heterogeneity would not be easily detectable by epidemiological studies following population admixture, even significant heterogeneity would not impede the outcomes of preventive gene therapies. Preventive gene therapies designed to correct causal alleles to a naturally-occurring neutral state of nucleotides would lower the prevalence of polygenic early- to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome would manifest differently for late-onset diseases, for which the therapies would result in a delayed disease onset and decreased lifetime risk, however the lifetime risk would increase again with prolonging population life expectancy, which is a likely consequence of such therapies. If gene therapies that prevent heritable diseases were to be applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even with a fraction of the population receiving such therapies. With ongoing population admixture, all groups would benefit over generations.
A noble TGFβ biogenesis inhibitor exhibits both potent anti-fibrotic and anti-inflammatory capabilities
Authors: Kim Han-Soo , Meang Moon Kee , Kim Saesbyeol , Lee Ji Yong , Seong Baik L. , Kim Ik-Hwan , Youn Byung-Soo
Published: September 2019

Abstracts

Idiopathy pulmonary fibrosis (IPF) is an intractable and fatal human disorder. Our previous study showed that eupatilin exerted a potent anti-fibrotic effect on both in vitro fibrogenesis and bleomycin-induced lung fibrosis model (BLM). Subsequently, an analog called ONG41008 had been identified as a more potent anti-fibrotic than eupatilin and also showed a potent anti-inflammatory capability. Orally administered ONG41008 significantly improved onset of BLM in both prophylactic and therapeutic model and its therapeutic efficacy was similarly compared to or better than pirfenidone by measuring production of collagen and hydroxyproline. Staining collagen or αSMA corroborated these results.

As in vitro fibrogenesis models, DHLF (Diseased Human Lung Fibroblasts from IPF patients) and HSC (hepatic stellate cells) were used for direct effects of ONG41008 on pivotal cellular and molecular functions associated with pathogenic myofibroblasts; ONG41008 dismantled latent TGFb complex (LTC), generating inactive forms of TGFβ, likely limiting TGFβ to TGFβ receptor via depolymerization of F-actin and this blunted SMAD2/SMAD3 phosphorylation, thereby reprogramming EMT. A set of cell imaging studies and transcriptomic analysis were conducted to explore how ONG41008 elicited both anti-fibrotic and anti-inflammatory capabilities. Elastin (ELN) seemed to be a pioneering pharmacodynamic marker. It was also found that NOX4 played an important role in anti- fibrosis because it was functionally connected to major central nod proteins such as lysyl- oxidase (LOX) and numerous collagen family members in an ONG41008-specific fibrogenic interactome. Human NOX4 was significantly induced by TGFβ and completely knocked down by ONG41008. It has been shown that production of reactive oxygen species (ROS) led to activation of inflammasome. ONG41008 may be likely related to anti-inflammation, leading to a key protective effect on fibrogenesis. Concomitant with downregulation of NOX4, expression of macrophages homing chemokines, CCL2 and CCL7 were significantly attenuated by ONG41008. In vitro anti-inflammatory activities of ONG41008 were investigated in RAW264.7 cells, a mouse monocytic cell line stimulated with LPS. ONG41008 substantially attenuated TNFα, CXCL10, CCL2 and CCL7, which are proinflammatory cytokine and important chemokines influencing T cells or macrophages. TNFα was situated at the central nod in LPS-treated macrophages via an ONG41008-specific interactome analysis.

Taken together, ONG41008 is a TGFβ biogenesis inhibitor, being a potent drug for a broad range of fibrotic diseases and could antagonize inflammatory diseases as well.
The Tolman-Eichenbaum Machine: Unifying space and relational memory through generalisation in the hippocampal formation
Authors: Whittington James CR , Muller Timothy H , Mark Shirley , Chen Guifen , Barry Caswell , Burgess Neil , Behrens Timothy EJ
Published: September 2019

The hippocampal-entorhinal system is important for spatial and relational memory tasks. We formally link these domains; provide a mechanistic understanding of the hippocampal role in generalisation; and offer unifying principles underlying many entorhinal and hippocampal cell-types. We propose medial entorhinal cells form a basis describing structural knowledge, and hippocampal cells link this basis with sensory representations. Adopting these principles, we introduce the Tolman-Eichenbaum machine (TEM). After learning, TEM entorhinal cells include grid, band, border and object-vector cells. Hippocampal cells include place and landmark cells, remapping between environments. Crucially, TEM also predicts empirically recorded representations in complex non-spatial tasks. TEM predicts hippocampal remapping is not random as previously believed. Rather structural knowledge is preserved across environments. We confirm this in simultaneously recorded place and grid cells.

One Sentence Summary

Simple principles of representation and generalisation unify spatial and non-spatial accounts of hippocampus and explain many cell representations.