bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECT OF REIMBURSEMENT POLICY ON VISUAL OUTCOMES IN PATIENTS WITH DIABETIC MACULAR EDEMA TREATED WITH RANIBIZUMAB
Authors: Lai Tso-Ting , Hsieh Yi-Ting , Yang Chung-May , Ho Tzyy-Chang , Yang Chang-Hao
Published: December 2019

Purpose:

To evaluate effects of reimbursement policy change on visual outcomes of patients with diabetic macular edema treated with ranibizumab.

Methods:

In this retrospective comparative cohort study, we included 78 treatment-naïve patients with diabetic macular edema (107 eyes) insured under Taiwan's National Health Insurance from July 2013 to January 2015 (Group A) and April 2016 to June 2017 (Group B), or before and after the major reimbursement policy change, respectively. Best-corrected visual acuity (BCVA), optical coherence tomography findings, and injection numbers at baseline and postinjection Months 3, 6, and 12 were collected. Mean BCVA change and predictive factors for enhanced BCVA improvement at Month 12 were analyzed.

Results:

The mean improvement in BCVA at 1 year was 5.8 ETDRS letters (Group A) before and 14.8 letters (Group B) after the policy change (P = 0.009), and the mean numbers of injections were 4.6 ± 2.0 and 6.5 ± 2.3 in Group A and B (P < 0.001), respectively. Linear regression revealed that greater visual improvement at Month 12 was significantly associated with worse baseline BCVA, greater visual gain at Month 3, new reimbursement policy (Group B), and the presence of subretinal fluid in baseline optical coherence tomography, but not with total injection number. Compared with Group A, Group B had enhanced BCVA improvement when baseline subretinal fluid was present (P = 0.001), but not when subretinal fluid was absent (P = 0.656).

Conclusion:

Health care policy change significantly affected the visual outcomes of patients with diabetic macular edema in a clinical practice setting, with superior final BCVA and BCVA improvement after increased reimbursement. Presence of subretinal fluid at baseline predicted enhanced post-policy change visual improvement.
Birth Season and Infection Risk Among Children Under 5 Years Old
Authors: Christensen Karina , Christensen Nikolas , Husby Steffen , Kyhl Henriette , Boysen Sandberg Maria , Fisker Niels
Published: December 2019

Background:

The season in which a child is born may affect the immune system development and thereby influence the risk of infections. In this study, we examined the associations between birth season and the risk of hospital admission or symptoms associated with a wide range of infections.

Methods:

This study is a prospective cohort study of 2434 children with an average follow-up of 3.5 years. Admission data were obtained from the Danish National Patient Registry. Via short message service (SMS) questionnaires, 1279 families reported symptoms of infections in a 1-year period.

Results:

Of the 2434 children, 639 (26.3%) were admitted to the hospital, and the children experienced on average 64.4 days with symptoms of infection within 1 year. There was no association between birth season and hospital admissions due to all infectious causes [incidence rate ratio (IRR) = 0.89; 95% confidence interval (CI), 0.65–1.22; P = 0.471]. However, children born in the fall had a higher IRR for admission due to all infectious causes when excluding admissions within the first year of life. Winter- and spring-born children had lower IRRs for admission due to gastrointestinal infections than summer-born children, but this association was alone present when admissions within the first year of life were included. The short message service-survey showed significantly lower IRRs for any symptom of infection among winter-born (IRR = 0.85; 95% CI, 0.75–0.96; P = 0.009) and fall-born children (IRR = 0.88; 95% CI, 0.78–0.99; P = 0.033) in comparison with summer-born children.

Conclusions:

Birth season was not associated with hospital admission due to all infectious causes within the first 5 years of age; however, fall-birth was associated with a higher IRR for admissions due to all infectious causes after the first year of life. The association between birth season and admissions due to gastrointestinal infections was only seen when including children admitted under the age of one. Being born in fall or winter was associated with a decreased IRR for number of days with any symptom of infection registered at home.
Complex regional pain syndrome patient immunoglobulin M has pronociceptive effects in the skin and spinal cord of tibia fracture mice
Authors: Guo Tian-Zhi , Wei Tzuping , Tajerian Maral , Clark J. David , Birklein Frank , Goebel Andreas , Li Wen-Wu , Sahbaie Peyman , Escolano Fabiola L. , Herrnberger Myriam , Kramer Heidrum H. , Kingery Wade S.
Published: December 2019

It has been proposed that complex regional pain syndrome (CRPS) is a post-traumatic autoimmune disease. Previously, we observed that B cells are required for the full expression of CRPS-like changes in a mouse tibia fracture model and that serum immunoglobulin M (IgM) antibodies from fracture mice have pronociceptive effects in muMT fracture mice lacking B cells. The current study evaluated the pronociceptive effects of injecting CRPS patient serum or antibodies into muMT fracture mice by measuring hind paw allodynia and unweighting changes. Complex regional pain syndrome serum binding was measured against autoantigens previously identified in the fracture mouse model. Both CRPS patient serum or IgM antibodies had pronociceptive effects in the fracture limb when injected systemically in muMT fracture mice, but normal subject serum and CRPS patient IgG antibodies had no effect. Furthermore, CRPS serum IgM antibodies had pronociceptive effects when injected into the fracture limb hind paw skin or intrathecally in the muMT fracture mice. Early (1-12 months after injury) CRPS patient (n = 20) sera were always pronociceptive after systemic injection, and chronic (>12 months after injury) CRPS sera were rarely pronociceptive (2/20 patients), while sera from normal subjects (n = 20) and from patients with uncomplicated recoveries from orthopedic surgery and/or fracture (n = 15) were never pronociceptive. Increased CRPS serum IgM binding was observed for keratin 16, histone 3.2, gamma actin, and alpha enolase autoantigens. We postulate that CRPS patient IgM antibodies bind to neoantigens in the fracture mouse skin and spinal cord to initiate a regionally restricted pronociceptive complement response potentially contributing to the CRPS disease process.
Ensuring Organization-Intervention Fit for a Participatory Organizational Intervention to Improve Food Service Workers’ Health and Wellbeing
Authors: Peters Susan E. , Nielsen Karina M. , Nagler Eve M. , Revette Anna C. , Madden Jennifer , Sorensen Glorian
Published: December 2019

Objective:

Food-service workers’ health and wellbeing is impacted by their jobs and work environments. Formative research methods were used to explore working conditions impacting workers’ health to inform intervention planning and implementation and to enhance the intervention's “fit” to the organization.

Methods:

Four qualitative methods (worker focus groups; manager interviews; worksite observations; multi-stakeholder workshop) explored in-depth and then prioritized working conditions impacting workers’ health as targets for an intervention.

Results:

Prioritized working conditions included: ergonomics; work intensity; career development; and job enrichment. Data revealed necessary intervention mechanisms to enhance intervention implementation: worker and management communication infrastructure; employee participation in intervention planning and implementation; tailored worksite strategies; and ensuring leadership commitment.

Conclusions:

These targeted, comprehensive methods move away from a typical focus on generic working conditions, for example, job demands and physical work environment, to explore those conditions unique to an organization. Thereby, enhancing “intervention-fit” at multiple levels within the company context.
Title of review article: admissible daily intake for glutamate
Authors: Tomé Daniel
Published: December 2019

Purpose of review

Total glutamate (Glu) intake is 5–20 g/day in adults and about 40 mg/kg in breast-fed infant. Glu intake is constituted by Glu from protein and free Glu from certain foods and flavor-enhancing additive. The admissible intake of free Glu additive is addressed.

Recent finding

In the gut, Glu is actively metabolized by enterocytes and because of this metabolism, the systemic availability of ingested Glu remains relatively low. Human studies are preferred to assess the transfer in blood of dietary free Glu salts and their possible risks. When human data are not available, experimental animal models provide the basis to assess the risks to humans but toxicity studies in rodents remain for a part controversial. A No Observable Adverse Effect Level (NOAEL) in rodent of 3200 mg/kg/day and an uncertainty factor of 100 lead to an acceptable daily intake (ADI) of 30 mg/kg/day for free Glu salts used as additives, whereas a NOAEL higher than 6000 mg/kg/day and an uncertainty factor of 25 leads to an ADI of 240 mg/kg/day for free Glu salts.

Current discussions indicate an ADI from 30 to 240 mg/kg/day depending on the chosen NOAEL in animal model and compound-specific uncertainty factor (from 25 to 100).
Somatic growth in cystic fibrosis
Authors: Lavi Eran , Gileles-Hillel Alex , Zangen David
Published: December 2019

Purpose of review

Cystic fibrosis (CF) is commonly associated with compromised growth especially in severe cases when the pulmonary function (PFT) deteriorates. As growth optimization is an important aspect of CF management, this review will summarize the current knowledge on the prevalence of growth failure in CF patients, and focus on the mechanisms leading to poor growth, on the association of poor linear growth with reduced PFT and on recombinant human growth hormone (rhGH) therapy in CF patients.

Recent findings

Despite the improvement in CF care in the last 2 decades, compromised linear growth is still quite prevalent. The pathophysiology of growth failure in CF is multifactorial. Malnutrition due to decreased energy intake increased energy expenditure and malabsorption of ingested nutrients secondary to pancreatic insufficiency, all probably play a major role in growth restriction. In addition, chronic inflammation characteristic of CF may contribute to growth failure via alteration in the GH-insulin-like growth factor 1 signaling and other changes in the growth plate. rhGH and new CFTR modulators may improve some growth parameters.

Beyond optimizing nutrition and malabsorption, and controlling chronic inflammation, children with CF may benefit from the anabolic effects of rhGH therapy to improve their anthropometric parameters. Whether this translates into better PFT and improved long-term outcomes is yet to be determined.
Emergency department revisits: a nation-wide database analysis on the same and different hospital revisits
Authors: Lu Tsung-Chien , Ling Dean-An , Tsai Chu-Lin , Shih Fuh-Yuan , Fang Cheng-Chung
Published: December 2019

Objectives

Emergency department (ED) revisits had traditionally been used as a quality indicator, but focused more on the same hospital revisit (SHRV). Our study investigated the 72-hour ED revisits on SHRV and different hospital revisits (DHRV), and explored the predictors of DHRV.

Methods

72-hour ED revisits were analyzed using Taiwan’s National Health Insurance Research Database that contained one-third patient records from 2012 to 2013. Rates of SHRV and DHRV were calculated and compared among levels of hospital accreditation. Linear regression analyses were used to measure the correlation between revisit rates and average monthly volumes of the index ED. Multilevel logistic analyses were performed to evaluate the predictors of DHRV.

Results

There were 4 065 215 index ED visits. Of them, 234 826 (5.8%) were associated with 72-hour revisits and 36.7% of them occurred at different institutions. The revisit rates showed differences across distinct hospital levels. DHRV rates had significant inverse correlation with the average monthly volume of the index ED. Independent predictors associated with the increased odds of DHRV were: ED visits on weekend or holiday, or the index ED being at a local hospital.

Conclusions

About one in three ED revisits occurred in another hospital. SHRV rate alone would inevitably underestimate the true revisit rate. DHRV is associated with the hospital level and annual ED volume, and there is increased likelihood of DHRV if patient’s index ED visit being a local hospital.
Apolipoprotein M: new connections with diet, adipose tissue and metabolic syndrome
Authors: Tavernier Geneviève , Caspar-Bauguil Sylvie , Viguerie Nathalie
Published: December 2019

Purpose of review

To focus on state-of-the-art knowledge on the apolipoprotein M (ApoM) physiology and physiopathology regarding metabolism.

Recent findings

In humans, the ApoM was recently described as secreted by adipocytes. Obesity, metabolic syndrome and type 2 diabetes are associated with low circulating ApoM and adipose tissue APOM expression. Dieting-induced weight loss enhances adipose tissue expression and secretion, and exercise training increases plasma ApoM. The ApoM is a chaperone for the bioactive sphingolipid, sphingosine-1-phosphate (S1P), which has a specific role in inflammation. Its association with S1P in the inhibition of brown adipose tissue activity and subsequent insulin sensitivity was reported with the model of ApoM-deficient mouse.

The adipose tissue is an endocrine organ responsible for obesity-related comorbidities. Obesity and dieting impact the adipose tissue secretory profile. The recent demonstration of ApoM being secreted by healthy adipocytes questions about the possible role of this adipose production in metabolic diseases. Low-circulating ApoM is associated with unhealthy metabolic phenotype. The lower circulating apoM during metabolic syndrome might be a cause of obesity-related comorbidities. Lifestyle interventions enhance ApoM production. Whether it acts in combination to S1P or other small lipidic molecules deserves further investigations.
The Creation of an Interprofessional Evidence-Based Practice Council
Authors: Copeland Donna , Miller Kristina , Clanton Clista
Published: December 2019

Evidence-based practice (EBP), communication, and interprofessional collaboration are all essential for safe, quality care. As members of the interprofessional team, nurse leaders are in a unique position to advance patient safety with a strategic plan, infrastructure, resources, reporting structure, and recognition program to guide the way. Leaders of a 152-bed children's and women's hospital formed an academic-practice partnership to create an interprofessional council to foster the principles of collaboration and EBP among frontline staff.
Vestibular Rehabilitation for a Child With Posterior Fossa Syndrome: A Case Report
Authors: Flowers Meredith , Reneker Jennifer , Karlson Cynthia
Published: December 2019

Purpose:

This case report assesses gaze stability, postural control, and balance pre- and post–physical therapy intervention, including vestibular rehabilitation, in a 4-year-old child with posterior fossa syndrome following gross total resection of a juvenile astrocytoma brain tumor.

Summary of Key Points:

The child in this case study had improved balance and gaze stability, as determined by the Pediatric Balance Scale and the Dynamic Visual Acuity test upon completion of the 10-week intervention.

Statement of Conclusion and Recommendations for Clinical Practice:

This case provides preliminary support of the need for vestibular screening in children with a diagnosis of posterior fossa syndrome. The success of the intervention suggests that vestibular rehabilitation exercises can be modified for use in preschool-aged children, and the specific intervention outlined in this case report can be easily replicated in a variety of treatment settings.
Continuous Albuterol in Pediatric Acute Care: Study Demonstrates Safety Outside the Intensive Care Unit
Authors: Messer Amanda F. , Sampayo Esther M. , Mothner Brent , Camp Elizabeth A. , Jones Jennifer , Brown Terri , Vachani Joyee
Published: December 2019

Introduction:

There are little data to support the use of continuous aerosolized albuterol (CAA) in the non-intensive care unit (ICU) or non-emergency department (ED) setting for pediatric asthma patients. A 2014 study demonstrated low rates of adverse outcomes associated with administration of CAA on the acute care unit; however, the authors do not describe additional outcomes. We sought to determine whether administration of CAA within a respiratory cohort on an acute care floor was feasible and safe.

Methods:

This quasi-experimental study evaluates data 1 year before and after (2014–2016) the initiation of CAA on the acute care inpatient unit for asthma patients 2−18 years of age. Outcome measures included ED and hospital length of stay (LOS), readmission rate, rapid response team activations, and transfers to ICU. Use of chest x-rays, viral studies, and hospital charges were also studied.

Results:

Seven hundred thirty-two patients met study criteria. Population demographics and severity of acute presentation were similar pre- and poststudy. ED LOS decreased poststudy, whereas overall hospital LOS was unchanged. Fifteen-day readmission rate decreased in the poststudy group. Only 4 rapid response activations occurred in the poststudy population. The poststudy group utilized fewer chest x-rays and viral studies. There was no change in overall hospital charges.

Conclusions:

With appropriate resources and safety processes in place, care of pediatric patients with status asthmaticus receiving CAA on an acute care unit, outside of the ICU, resulted in improved ED LOS with evidence of lower resource utilization and rare adverse outcomes.
Monocytes from men living with HIV exhibit heightened atherogenic potential despite long-term viral suppression with antiretroviral therapy
Authors: Angelovich Thomas A. , Trevillyan Janine M. , Hoy Jennifer F. , Wong Michelle E. , Agius Paul A. , Hearps Anna C. , Jaworowski Anthony
Published: December 2019

Objective:

People living with HIV have an increased risk of cardiovascular disease (CVD) despite effective antiretroviral therapy (ART). Monocytes play a key role in the early stages of atherosclerosis-driven CVD by forming lipid-laden foam cells within artery walls. HIV infection potentiates foam cell formation ex vivo, but the mechanisms contributing to this are not known.

Methods:

We investigated the atherosclerosis-promoting potential of monocytes from 39 virologically suppressed men living with HIV (MLHIV) on ART and no evidence of CVD, and 25 HIV-uninfected controls of comparable age, sex, smoking status and CVD risk.

Results:

Despite absence of clinical atherosclerosis in both MLHIV and uninfected cohorts (evidenced by a carotid intima–media thickness of 0.6 mm for both groups; P = 0.254), monocytes from MLHIV showed increased potential to form atherosclerosis-promoting foam cells compared with controls in an ex-vivo assay (36.6% vs. 27.6%, respectively, P = 0.003). Consistent with observations of persistent inflammation and immune/endothelial activation in ART-treated HIV infection, levels of soluble tumour necrosis factor receptor II, CXCL10 and soluble VCAM-1 were elevated in MLHIV (P ≤ 0.005 for all), but were not significantly associated with foam cell formation. Foam cell formation was associated with an impaired ability of monocytes to undergo reverse transmigration, and a reduced ability to efflux cholesterol ex vivo (P < 0.05 for both). Importantly, foam cell formation declined significantly with duration of viral suppression (P = 0.004).

Conclusion:

These findings highlight the persistence of HIV-related changes to the atherogenic potential of monocytes despite long-term viral suppression, and provide insights into mechanisms potentially driving increased CVD in ART-treated HIV infection.
Characteristics of Acquired Inhibitors to Factor VIII and Von Willebrand Factor Secondary to Systemic Lupus Erythematosus
Authors: Cao Xiao-Yu , Li Meng-Tao , Zhang Xuan , Zhao Yan , Zeng Xiao-Feng , Zhang Feng-Chun , Hou Yong , Zhu Li-Xiu
Published: December 2019

Objective

Because acquired hemophilia (AH) is a rare entity in systemic lupus erythematosus (SLE), we aimed to investigate the clinical features of SLE-related AH in Chinese patients.

Methods

This is a medical records review study carried out at a large tertiary care hospital in China from years 1986 to 2018. We searched the case database in Peking Union Medical College Hospital using the International Classification of Diseases. The clinical data on SLE-related AH patients were collected.

Results

A total of 9282 SLE patients had been hospitalized. Six female SLE-related AH patients were identified. Four patients had acquired hemophilia A (AHA), and 2 patients had acquired von Willebrand syndrome. Their mean age was 33.67 ± 13.77 years. Five patients had active disease. The mean SLE disease activity index measured at the time of diagnosis of AH was 10.50 ± 5.28. The average level of activated partial thromboplastin time was 86.5 seconds. Coexistence of secondary antiphospholipid syndrome and AHA was found in one case, and pulmonary embolism was observed 3 years later. After immunosuppressive therapy and symptomatic treatment, an overall remission rate of 83.3% was achieved.

Conclusions

The frequency of SLE-related AH was low. The development of AH in SLE patients frequently occurs with active disease. The AH could be the first clinical presentation of SLE. Secondary antiphospholipid syndrome and AHA could appear in the same SLE patient. Early and aggressive treatment contributes to a favorable prognosis.
Minimizing Risks of Liver Transplantation With Steatotic Donor Livers by Preferred Recipient Matching
Authors: Jackson Kyle R. , Motter Jennifer D. , Haugen Christine E. , Long Jane J. , King Betsy , Philosophe Benjamin , Massie Allan B. , Cameron Andrew M. , Garonzik-Wang Jacqueline , Segev Dorry L.
Published: December 2019

Background.

Donor livers with ≥30% macrosteatosis (steatotic livers) represent a possible expansion to the donor pool, but are frequently discarded as they are associated with an increased risk of mortality and graft loss. We hypothesized that there are certain recipient phenotypes that would tolerate donor steatosis well, and are therefore best suited to receive these grafts.

Methods.

Using national registry data from the Scientific Registry of Transplant Recipients between 2006 and 2017, we compared 2048 liver transplant recipients of steatotic livers with 69 394 recipients of nonsteatotic (<30%) livers. We identified recipient factors that amplified the impact of donor steatosis on mortality and graft loss using interaction analysis, classifying recipients without these factors as preferred recipients. We compared mortality and graft loss with steatotic versus nonsteatotic livers in preferred and nonpreferred recipients using Cox regression.

Results.

Preferred recipients of steatotic livers were determined to be first-time recipients with a model for end-stage liver disease 15–34, without primary biliary cirrhosis, and not on life support before transplant. Preferred recipients had no increased mortality risk (hazard ratio [HR]:0.921.041.16;P= 0.5) or graft loss (HR:0.931.031.15;P= 0.5) with steatotic versus nonsteatotic livers. Conversely, nonpreferred recipients had a 41% increased mortality risk (HR:1.171.411.70;P< 0.001) and 39% increased risk of graft loss (HR:1.161.391.66;P< 0.001) with steatotic versus nonsteatotic livers.

Conclusions.

The risks of liver transplantation with steatotic donor livers could be minimized by appropriate recipient matching.
Normothermic Ex Vivo Kidney Perfusion Improves Early DCD Graft Function Compared With Hypothermic Machine Perfusion and Static Cold Storage
Authors: Urbanellis Peter , Hamar Matyas , Kaths J. Moritz , Kollmann Dagmar , Linares Ivan , Mazilescu Laura , Ganesh Sujani , Wiebe Aryn , Yip Paul M. , John Rohan , Konvalinka Ana , Mucsi Istvan , Ghanekar Anand , Bagli Darius J. , Robinson Lisa A. , Selzner Markus
Published: December 2019

Background.

Better preservation strategies for the storage of donation after circulatory death grafts are essential to improve graft function and to increase the kidney donor pool. We compared continuous normothermic ex vivo kidney perfusion (NEVKP) with hypothermic anoxic machine perfusion (HAMP) and static cold storage (SCS) in a porcine kidney autotransplantation model.

Methods.

Porcine kidneys were exposed to 30 minutes of warm ischemia and then reimplanted following either 16 hours of either SCS, HAMP (LifePort 1.0), or NEVKP before autotransplantation (n = 5 per group). The contralateral kidney was removed. Animals were followed for 8 days.

Results.

Grafts preserved by NEVKP demonstrated improved function with more rapid recovery compared with HAMP and SCS (mean peak serum creatinine: 3.66 ± 1.33 mg/dL [postoperative d 1 [(POD1)], 8.82 ± 3.17 mg/dL [POD2], and 12.90 ± 2.19 mg/dL [POD3], respectively). The NEVKP group demonstrated significantly increased creatinine clearance calculated on POD3 (63.6 ± 19.0 mL/min) compared with HAMP (13.5 ± 10.3 mL/min, P = 0.001) and SCS (4.0 ± 2.6 mL/min, P = 0.001). Histopathologic injury scores on POD8 were lower in both perfused groups (NEVKP and HAMP, score: 1–1.5) compared with SCS (score: 1–3, P = 0.3), without reaching statistical significance.

Conclusions.

NEVKP storage significantly improved early kidney function compared with both cold preservation strategies, although HAMP also demonstrates improvement over SCS. NEVKP may represent a novel, superior preservation option for donation after circulatory death renal grafts compared with conventional hypothermic methods.
Psychiatric Patients on Neuroleptics: Evaluation of Parkinsonism and Quantified Assessment of Gait
Authors: Yahalom Hila , Israeli-Korn Simon , Linder Muli , Yekutieli Ziv , Karlinsky Keren Tchelet , Rubel Yarin , Livneh Vered , Fay-Karmon Tsvia , Hassin-Baer Sharon , Yahalom Gilad
Published: December 2019

Objectives

We aimed to characterize parkinsonian features and gait performance of psychiatric patients on neuroleptics (PPN) and to compare them to Parkinson's disease (PD) and healthy controls (HC).

Methods

Hospitalized PPN (n = 27) were recruited, examined, and rated for parkinsonian signs according to the motor part of the Movement Disorders Society Unified Parkinson's Disease Rating Scale and performed a 10-m “timed-up-and-go” (TUG) test with a smartphone-based motion capture system attached to their sternum. Gait parameters and mUPDRS scores were compared to those of consecutive age-matched PD patients (n = 18) and HC (n = 27).

Results

Psychiatric patients on neuroleptics exhibited parkinsonism (mUPDRS score range: 8–44) but less than that of PD patients (18.2 ± 9.2 vs 29.8 ± 10.3, P = 0.001). TUG times were slower for PPN and PD versus HC (total: 30.6 ± 7.6 seconds vs 30.0 ± 7.3 seconds vs 20.0 ± 3.2 seconds, straight walking: 10.6 ± 2.7 seconds vs 10.6 ± 2.4 seconds vs 6.8 ± 1.2 seconds) (P < 0.001), and cadence and step length were similar among PPN and PD and different from HC as well. Although their gait speed was slower than HC but similar to PD, PPN had lower mediolateral sway (4.3 ± 1.1 cm vs 6.7 ± 2.9 cm vs 6.9 ± 2.9 cm, respectively, P < 0.001) than both.

Conclusions

Parkinsonism is very common in hospitalized PPN, but usually milder than that of PD. It seems that wearable sensor-based technology for assessing gait and balance may present a more sensitive and quantitative tool to detect clinical aspects of neuroleptic-induced parkinsonism than standard clinical ratings.
Three-manifold quantum invariants and mock theta functions
Authors: Cheng Miranda C. N. , Ferrari Francesca , Sgroi Gabriele
Published: December 2019

Mock modular forms have found applications in numerous branches of mathematical sciences since they were first introduced by Ramanujan nearly a century ago. In this proceeding, we highlight a new area where mock modular forms start to play an important role, namely the study of three-manifold invariants. For a certain class of Seifert three-manifolds, we describe a conjecture on the mock modular properties of a recently proposed quantum invariant. As an illustration, we include concrete computations for a specific three-manifold, the Brieskorn sphere
Σ
(2, 3, 7).

This article is part of a discussion meeting issue ‘Srinivasa Ramanujan: in celebration of the centenary of his election as FRS’.
Reprogramming of the apoplast metabolome ofLolium perenneupon infection with the mutualistic symbiontEpichloë festucae
Authors: Green Kimberly A , Berry Daniel , Feussner Kirstin , Eaton Carla J. , Ram Arvina , Mesarich Carl H. , Solomon Peter , Feussner Ivo , Scott Barry
Published: December 2019

Epichloë festucaeis an endophytic fungus that forms a mutualistic symbiotic association withLolium perenne. Here we analysed how the metabolome of the ryegrass apoplast changed upon infection of this host with sexual and asexual isolates ofE. festucae. A metabolite fingerprinting approach was used to analyse the metabolite composition of apoplastic wash fluid from non-infected and infectedL. perenne. Metabolites enriched or depleted in one or both of these treatments were identified using a set of interactive tools. A genetic approach in combination with tandem mass spectrometry was used to identify a novel product of a secondary metabolite gene cluster. Metabolites likely to be present in the apoplast were identified using the MarVis Pathway in combination with the BioCyc and KEGG databases, and an in-houseEpichloëmetabolite database. We were able to identify the known endophyte-specific metabolites, peramine and epichloëcyclins, as well as a large number of unknown markers. To determine whether these methods can be applied to the identification of novelEpichloë-derived metabolites, we deleted a gene encoding a NRPS (lgsA) that is highly expressedin planta. Comparative mass spectrometric analysis of apoplastic wash fluid from wild-type- versus mutant- infected plants identified a novel Leu/Ile glycoside metabolite present in the former.
Large scale genome-wide association study reveals that drought induced lodging in grain sorghum is associated with plant height and traits linked to carbon remobilisation
Authors: Wang Xuemin , Mace Emma , Tao Yongfu , Cruickshank Alan , Hunt Colleen , Hammer Graeme , Jordan David
Published: December 2019

Sorghum is generally grown in water limited conditions and often lodges under post-anthesis drought, which reduces yield and quality. Due to its complexity, our understanding on the genetic control of lodging is very limited. We dissected the genetic architecture of lodging in grain sorghum through genome-wide association study (GWAS) on 2308 unique hybrids grown in 17 Australian sorghum trials over 3 years. The GWAS detected 213 QTL, the majority of which showed a significant association with leaf senescence and plant height (72% and 71% respectively). Only 16 lodging QTL were not associated with either leaf senescence or plant height. The high incidence of multi-trait association for the lodging QTL indicates that lodging in grain sorghum is mainly associated with plant height and traits linked to carbohydrate remobilisation. This result supported the selection for stay-green (delayed leaf senescence) to reduce lodging susceptibility, rather than selection for short stature and lodging resistanceper se, which likely reduces yield. Additionally, our data suggested a protective effect of stay-green on weakening the association between lodging susceptibility and plant height. Our study also showed that lodging resistance might be improved by selection for stem composition but was unlikely to be improved by selection for classical resistance to stalk rots.

Key message

We detected 213 lodging QTL and demonstrated that drought induced stem lodging in grain sorghum is substantially associated with stay-green and plant height, suggesting a critical role of carbon remobilisation.
In silicon emergence of an autonomous artificial metabolic system
Authors: Chen Shijian
Published: December 2019

In this work, we establish and evolve an artificial metabolic system in silicon to shed light on how the metabolic mechanism emerged. This system is composed of two subsystems: the artificial genome subsystem (AGS) and the artificial metabolite subsystem (AMS). The whole system is designed to be capable of being autonomous: the dynamics of AGS is capable of situating itself to the dynamics of AMS to provide it with enzymes in the right time and quantity; the dynamics of AMS is capable of implementing the metabolic function and harvest energy so as to pay back the energy consumption of AGS. This kind of autonomous state requires an intricate structure of the AGS. So it is almost impossible to be predetermined manually. With the help of an evolutionary computational method that has a hierarchical mutational structure, the artificial metabolic system with this kind of autonomous state eventually emerged in silicon. We find that ATP and ADP molecules have an important role in making the state of the system autonomous. We also find that the emerged structure of AGS ensemble existing biological structures in the natural cells.
Faecal DNA to the rescue: Shotgun sequencing of non-invasive samples reveals two subspecies of Southeast Asian primates to be Critically Endangered species
Authors: Ang Andie , Roesma Dewi Imelda , Nijman Vincent , Meier Rudolf , Srivathsan Amrita , Rizaldi
Published: December 2019

A significant number of Southeast Asian mammal species described in the 19thand 20thcentury were subsequently synonymized and are now considered subspecies. Many are affected by rapid habitat loss and there is thus an urgent need to re-assess the conservation status based on species boundaries established with molecular data. However, such data are lacking for many populations and subspecies. We document via a literature survey and empirical study how shotgun sequencing of faecal DNA is a still underutilized but powerful tool for accelerating such evaluations. We obtain 11 mitochondrial genomes for three subspecies in the langur genusPresbytisthrough shotgun sequencing of faecal DNA (P. femoralis femoralis,P. f. percura,P. siamensiscf.cana). The genomes support the resurrection of all three subspecies to species based on multiple species delimitation algorithms (PTP, ABGD, Objective Clustering) applied to a dataset covering 40 species and 43 subspecies of Asian colobines. For two of the newly recognized species (P. femoralis,P. percura), the results lead to an immediate change in the IUCN status to Critically Endangered due to small population estimates and fragmented habitat. We conclude that faecal DNA should be more widely used for clarifying species boundaries in endangered mammals.
Quantitative Structure-Mutation-Activity Relationship Tests (QSMART) Model for Protein Kinase Inhibitor Response Prediction
Authors: Huang Liang-Chin , Yeung Wayland , Wang Ye , Cheng Huimin , Venkat Aarya , Li Sheng , Ma Ping , Rasheed Khaled , Kannan Natarajan
Published: December 2019

Predicting drug sensitivity profiles from genotypes is a major challenge in personalized medicine. Machine learning and deep neural network methods have shown promise in addressing this challenge, but the “black-box” nature of these methods precludes a mechanistic understanding of how and which genomic and proteomic features contribute to the observed drug sensitivity profiles. Here we provide a combination of statistical and neural network framework that not only estimates drug IC50in cancer cell lines with high accuracy (R2= 0.861 and RMSE = 0.818) but also identifies features contributing to the accuracy, thereby enhancing explainability. Our framework, termed QSMART, uses a multi-component approach that includes (1) collecting drug fingerprints, cancer cell line’s multi-omics features, and drug responses, (2) testing the statistical significance of interaction terms, (3) selecting features by Lasso with Bayesian information criterion, and (4) using neural networks to predict drug response. We evaluate the contribution of each of these components and use a case study to explain the biological relevance of several selected features to protein kinase inhibitor response in non-small cell lung cancer cells. Specifically, we illustrate how interaction terms that capture associations between drugs and mutant kinases quantitatively contribute to the response of two EGFR inhibitors (afatinib and lapatinib) in non-small cell lung cancer cells. Although we have tested QSMART on protein kinase inhibitors, it can be extended across the proteome to investigate the complex relationships connecting genotypes and drug sensitivity profiles.
Multiplexed single-cell profiling of post-perturbation transcriptional responses to define cancer vulnerabilities and therapeutic mechanism of action
Authors: McFarland James M. , Paolella Brenton R. , Warren Allison , Geiger-Schuller Kathryn , Shibue Tsukasa , Rothberg Michael , Kuksenko Olena , Jones Andrew , Chambers Emily , Dionne Danielle , Bender Samantha , Wolpin Brian M. , Ghandi Mahmoud , Tirosh Itay , Rozenblatt-Rosen Orit , Roth Jennifer A. , Golub Todd R. , Regev Aviv , Aguirre Andrew J. , Vazquez Francisca , Tsherniak Aviad
Published: December 2019

Assays to study cancer cell responses to pharmacologic or genetic perturbations are typically restricted to using simple phenotypic readouts such as proliferation rate or the expression of a marker gene. Information-rich assays, such as gene-expression profiling, are generally not amenable to efficient profiling of a given perturbation across multiple cellular contexts. Here, we developed MIX-Seq, a method for multiplexed transcriptional profiling of post-perturbation responses across a mixture of samples with single-cell resolution, using SNP-based computational demultiplexing of single-cell RNA-sequencing data. We show that MIX-Seq can be used to profile responses to chemical or genetic perturbations across pools of 100 or more cancer cell lines, and combine it with Cell Hashing to further multiplex additional experimental conditions, such as multiple post-treatment time points or drug doses. Analyzing the high-content readout of scRNA-seq reveals both shared and context-specific transcriptional response components that can identify drug mechanism of action and can be used to predict long-term cell viability from short-term transcriptional responses to treatment.
The hippocampus as a perceptual map: neuronal and behavioral discrimination during memory encoding
Authors: Allegra Manuela , Posani Lorenzo , Schmidt-Hieber Christoph
Published: December 2019

The hippocampus is thought to encode similar events as distinct memory representations that are used for behavioral decisions. Where and how this “pattern separation” function is accomplished in the hippocampal circuit, and how it relates to behavior, is still unclear. Here we perform in vivo 2-photon Ca2+ imaging from hippocampal subregions of head-fixed mice performing a virtual-reality spatial discrimination task. We find that population activity in the input region of the hippocampus, the dentate gyrus, robustly discriminates small changes in environments, whereas spatial discrimination in CA1 reflects the behavioral performance of the animals and depends on the degree of differences between environments. Our results demonstrate that the dentate gyrus amplifies small differences in its inputs, while downstream hippocampal circuits will act as the final arbiter on this decorrelated information, thereby producing a “perceptual map” that will guide behaviour.
Using nonthermal plasma treatment to improve quality and durability of hydrophilic coatings on hydrophobic polymer surfaces
Authors: Learn Greg D. , Lai Emerson J. , von Recum Horst A.
Published: December 2019

Low surface energy substrates, which include many polymers in medicine/industry, present challenges toward achieving uniform, adherent, durable coatings, thus limiting intended coating function. Examples include hydrophobic polymers such as polypropylene, polyethylene, polytetrafluoroethylene, and polydimethylsiloxane. These inert materials are used in various biomedical implants due to favorable bulk properties despite perhaps unfavorable surface properties. The capability to coat such materials holds great value as the surface heavily influences biological response and implant function in vivo. Likewise, paint/ink coatings are often necessary on these same plastics, as their final appearance can be critical for automotive, packaging, and consumer products. Substrate exposure to nonthermal plasma was explored here as a means to improve quality of coatings, specifically cyclodextrin-based polyurethanes previously explored for biomedical applications such as controlled drug delivery and anti-biofouling, upon otherwise incompatible polypropylene substrates. Plasma treatment was found to increase wettability and oxygen content on substrate surfaces. These plasma-induced surface alterations were associated with enhanced coating uniformity, and improved coating/substrate adherence – determined to derive partly from interfacial covalent bond formation. Findings demonstrate the utility of plasma-based surface activation as a strategy to improve coating quality on polymeric substrates, and reveal insights regarding mechanisms by which plasma improves polymer coating adherence.
Sex-based mutational landscape confers sensitivity to checkpoint blockade immunotherapy in cutaneous melanoma
Authors: Jia Mingming , Chi Tian
Published: December 2019

Anti-programmed cell death protein 1 (PD-1) therapy provided superior benefits in skin cutaneous melanoma (SKCM), but only a minority of patients responded. As SKCM had sex-based immunological differences, we sought to explore the potential interactions between sex and clinical responses to anti-PD-1 therapy in SKCM. We found that sex had significant effects on anti-PD-1 therapy. Tumor mutation burden (TMB) and neoantigen burden significantly correlated with the clinical responses to anti-PD-1 therapy only in males. Meanwhile, we recruited The Cancer Genome Atlas (TCGA) database to explore sex-based differences of the tumor microenvironment (TME) in SKCM. We observed that males with high TMB, especially in conjunction with interferon-gamma (IFN-γ) signaling, significantly correlated with increased PD-L1 expression, major histocompatibility complex (MHC) class I gene expression, and the infiltration of cytotoxic T lymphocytes (CTLs). In addition, TMB and anti-PD-1 efficacy in SKCM each correlated with homologous recombination repair (HRR) gene BRCA2 mutations, but only in males. Taken together, these data revealed that in SKCM, high TMB correlated with prominent immunotherapeutic TME only in males, and that gender should be taken into account when predicting the efficacy of anti-PD-1 therapy for SKCM.
Brain computation by assemblies of neurons
Authors: Papadimitriou Christos H. , Vempala Santosh S. , Mitropolsky Daniel , Collins Michael , Maass Wolfgang
Published: December 2019

Assemblies are large populations of neurons believed to imprint memories, concepts, words and other cognitive information. We identifya repertoire of operationson assemblies. These operations correspond to properties of assemblies observed in experiments, and can be shown, analytically and through simulations, to be realizable by generic, randomly connected populations of neurons with Hebbian plasticity and inhibition. Operations on assemblies include: projection (duplicating an assembly by creating a new assembly in a downstream brain area); reciprocal projection (a variant of projection also entailing synaptic connectivity from the newly created assembly to the original one); association (increasing the overlap of two assemblies in the same brain area to reflect cooccurrence or similarity of the corresponding concepts); merge (creating a new assembly with ample synaptic connectivity to and from two existing ones); and pattern-completion (firing of an assembly, with some probability, in response to the firing of some but not all of its neurons). Our analytical results establishing the plausibility of these operations are proved in a simplified mathematical model of cortex: a finite set of brain areas each containingnexcitatory neurons, withrandomconnectivity that is both recurrent (within an area) and afferent (between areas). Within one area and at any time, onlykof thenneurons fire — an assumption that models inhibition and serves to define both assemblies and areas — while synaptic weights are modified by Hebbian plasticity, as well as homeostasis. Importantly, all neural apparatus needed for the functionality of the assembly operations is created on the fly through the randomness of the synaptic network, the selection of thekneurons with the highest synaptic input, and Hebbian plasticity, without any special neural circuits assumed to be in place. Assemblies and their operations constitute a computational model of the brain which we call theAssembly Calculus, occupying a level of detail intermediate between the level of spiking neurons and synapses, and that of the whole brain. As with high-level programming languages, a computation in the Assembly Calculus (that is, a coherent sequence of assembly operations accomplishing a task) can ultimately be reduced — “compiled down” — to computation by neurons and synapses; however, it would be far more cumbersome and opaque to represent the same computation that way. The resulting computational system can be shown, under assumptions, to be in principle capable of carrying out arbitrary computations. We hypothesize that something like it may underlie higher human cognitive functions such as reasoning, planning, and language. In particular, we propose a plausible brain architecture based on assemblies for implementing the syntactic processing of language in cortex, which is consistent with recent experimental results.
Mechanical cell competition in heterogeneous epithelial tissues
Authors: Murphy R. J. , Buenzli P. R. , Baker R. E. , Simpson M. J.
Published: December 2019

Mechanical cell competition is important during tissue development, cancer invasion, and tissue ageing. Heterogeneity plays a key role in practical applications since cancer cells can have different cell stiffness and different proliferation rates than normal cells. To study this phenomenon, we propose a one-dimensional mechanical model of heterogeneous epithelial tissue dynamics that includes cell-length-dependent proliferation and death mechanisms. Proliferation and death are incorporated into the discrete model stochastically and arise as source/sink terms in the corresponding continuum model that we derive. Using the new discrete model and continuum description, we explore several applications including the evolution of homogeneous tissues experiencing proliferation and death, and competition in a heterogeneous setting with a cancerous tissue competing for space with an adjacent normal tissue. This framework allows us to postulate new mechanisms that explain the ability of cancer cells to outcompete healthy cells through mechanical differences rather than by having some intrinsic proliferative advantage. We advise when the continuum model is beneficial and demonstrate why naively adding source/sink terms to a continuum model without considering the underlying discrete model may lead to incorrect results.
ABS Tyres
Authors: Banerjee Arindam
Published: December 2019

ABS Tyres was a medium sized 2-wheeler tyre manufacturer which sold most of its tyres through the OEM channel (sale of tyres fitted in new vehicle). It had minimal presence in the replacement market, the direct to consumer market for tyres. The management felt that an evaluation of the market opportunity in the replacement tyre market was necessary to improve the performance of the company while maintaining the lead in the Original Equipment market. It needed help in drawing up an appropriate market study to find out the opportunity.