To evaluate whether a structured exercise programme improved functional and health related quality of life outcomes compared with usual care for women at high risk of upper limb disability after ...breast cancer surgery.
Multicentre, pragmatic, superiority, randomised controlled trial with economic evaluation.
17 UK National Health Service cancer centres.
392 women undergoing breast cancer surgery, at risk of postoperative upper limb morbidity, randomised (1:1) to usual care with structured exercise (n=196) or usual care alone (n=196).
Usual care (information leaflets) only or usual care plus a physiotherapy led exercise programme, incorporating stretching, strengthening, physical activity, and behavioural change techniques to support adherence to exercise, introduced at 7-10 days postoperatively, with two further appointments at one and three months.
Disability of Arm, Hand and Shoulder (DASH) questionnaire at 12 months, analysed by intention to treat. Secondary outcomes included DASH subscales, pain, complications, health related quality of life, and resource use, from a health and personal social services perspective.
Between 26 January 2016 and 31 July 2017, 951 patients were screened and 392 (mean age 58.1 years) were randomly allocated, with 382 (97%) eligible for intention to treat analysis. 181 (95%) of 191 participants allocated to exercise attended at least one appointment. Upper limb function improved after exercise compared with usual care (mean DASH 16.3 (SD 17.6) for exercise (n=132); 23.7 (22.9) usual care (n=138); adjusted mean difference 7.81, 95% confidence interval 3.17 to 12.44; P=0.001). Secondary outcomes favoured exercise over usual care, with lower pain intensity at 12 months (adjusted mean difference on numerical rating scale -0.68, -1.23 to -0.12; P=0.02) and fewer arm disability symptoms at 12 months (adjusted mean difference on Functional Assessment of Cancer Therapy-Breast+4 (FACT-B+4) -2.02, -3.11 to -0.93; P=0.001). No increase in complications, lymphoedema, or adverse events was noted in participants allocated to exercise. Exercise accrued lower costs per patient (on average -£387 (€457; $533) (95% confidence interval -£2491 to £1718; 2015 pricing) and was cost effective compared with usual care.
The PROSPER exercise programme was clinically effective and cost effective and reduced upper limb disability one year after breast cancer treatment in patients at risk of treatment related postoperative complications.
ISRCTN Registry ISRCTN35358984.
How stellar feedback from high-mass stars (e.g., H ii regions) influences the surrounding interstellar medium and regulates new star formation is still unclear. To address this question, we observed ...the G9.62+0.19 complex in 850 m continuum with the James Clerk Maxwell Telescope/POL-2 polarimeter. An ordered magnetic field has been discovered in its youngest clump, the G9.62 clump. The magnetic field strength is determined to be ∼1 mG. Magnetic field plays a larger role than turbulence in supporting the clump. However, the G9.62 clump is still unstable against gravitational collapse even if thermal, turbulent, and magnetic field support are taken into account together. The magnetic field segments in the outskirts of the G9.62 clump seem to point toward the clump center, resembling a dragged-in morphology, indicating that the clump is likely undergoing magnetically regulated global collapse. However, the magnetic field in its central region is aligned with the shells of the photodissociation regions and is approximately parallel to the ionization (or shock) front, indicating that the magnetic field therein is likely compressed by the expanding H ii regions that formed in the same complex.
Agri-environmental management has been promoted as an approach to enhance delivery of multiple ecosystem services. Most agri-environment agreements include several actions that the farmer agrees to ...put in place. But, most studies have only considered how individual agri-environmental actions affect particular ecosystem services. Thus, there is little understanding of how the range of agri-environmental actions available to a farmer might be deployed on any individual farm to enhance multiple services. To address this knowledge gap, we carried out an experimental study in which we deployed a set of agri-environmental actions on a commercial farm in southern England. Agri-environmental actions comprised wildflower margins and fallow areas in arable fields, creating and enhancing grassland with wildflowers, and digging ponds. Alongside biodiversity responses, we measured effects on a number of ecosystem services: pollination, pest control, crop and forage yield, water quality, climate regulation and cultural services. Wildflower margins enhanced invertebrates, pest control and crop yield, and aesthetic appeal. A greater number of pollinators was linked to enhanced oilseed rape yield. But these margins and the fallows did not prevent run-off of nutrients and sediment into waterways, and showed limited carbon sequestration or reduction of greenhouse gas emissions. Newly-dug ponds captured large amounts of sediment and provided aesthetic appeal. Grasslands had higher soil carbon content and microbial biomass, lower N20 emissions, and net sequestration of carbon compared to arable land. Enhancement of grassland plant diversity increased forage quality and aesthetic appeal. Visitors and residents valued a range of agri-environmental features and biodiversity across the farm. Our findings suggest one cannot necessarily expect any particular agri-environmental action will enhance all of a hoped-for set of ecosystem services in any particular setting. A bet-hedging strategy would be for farmers to apply a suite of options to deliver a range of ecosystem service benefits, rather than assuming that one or two options will work as catch-all solutions.
•We measured ecosystem services under multiple agri-environmental (AE) actions.•Specific AE actions enhanced some cultural, regulating and provisioning services.•For example, AE features enhanced aesthetic appeal across the farm.•Not all expected benefits of AE actions on ecosystem services were realised.•Deploying several AE options may facilitate enhancement of many ecosystem services.
Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD ...pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through “humanization” rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.
Display omitted
•We generate and characterize >300 (TG4 and cDNA) Drosophila mutants and transgenics•Humanization and overexpression strategies to functionally assess ASD variants in vivo•ASD variant data in flies help identify GLRA2-related neurodevelopmental disorders•Basic and clinical collaboration facilitates variant testing and disease gene discovery
Marcogliese et al. generate >300 Drosophila mutants and use complementary rescue-based and overexpression approaches to study the function of de novo missense variants found in autism. They find that 38% of missense changes have functional consequences and identify variants in GLRA2 that cause a variable neurological disorder.
Adolescents and young adults with food allergies are at increased risk of adverse events, including death from anaphylaxis. Epinephrine is the cornerstone of emergency response, yet few individuals ...with serious food allergies consistently carry their emergency medication. Behavioral economics offers promising, previously untapped opportunities for behavior change in this arena.
To test the effectiveness of modest financial incentives in promoting the carrying of epinephrine and to evaluate the acceptability of text messaging for delivering reminders and key health messages to young adults with food allergies.
A mixed-methods randomized controlled trial in young adults with food allergies investigated the carrying of epinephrine auto-injectors using financial incentives plus text message reminders vs text message reminders alone. Epinephrine carriage was assessed 10 times during the 49-day intervention using rapid-reply cell phone photographs plus daily code words.
The intervention (financial incentive) group had their epinephrine auto-injectors at 54% of check-ins vs 27% of check-ins in the control (text-only) group (P = .023). Participants in the 2 groups consistently reported favorable impressions of text messaging as a desirable, unobtrusive way to receive information and support for food allergy management.
Although the intervention and control groups reported favorable impressions of text message-based reminder systems, the intervention group performed significantly better than the control group on a photograph-based measurement of epinephrine carriage. There remained ample room for improvement in the 2 groups given the goal of consistent, uninterrupted epinephrine carriage by people with potentially life-threatening food allergies.
https://clinicaltrials.gov; NCT02354729.
The Earth Hologenome Initiative (EHI) is a global collaboration to generate and analyse hologenomic data from wild animals and associated microorganisms using standardised methodologies underpinned ...by open and inclusive research principles. Initially focused on vertebrates, it aims to re-examine ecological and evolutionary questions by studying host–microbiota interactions from a systemic perspective.
The Earth Hologenome Initiative (EHI) is a global collaboration to generate and analyse hologenomic data from wild animals and associated microorganisms using standardised methodologies underpinned by open and inclusive research principles. Initially focused on vertebrates, it aims to re-examine ecological and evolutionary questions by studying host–microbiota interactions from a systemic perspective.
Pediatric optic neuritis (ON) is a rare disease that has not been well characterized. The Pediatric ON Prospective Outcomes Study (PON1) was the first prospective study to our knowledge aiming to ...evaluate visual acuity (VA) outcomes, including VA, recurrence risk, and final diagnosis 2 years after enrollment.
Nonrandomized observational study at 23 pediatric ophthalmology or neuro-ophthalmology clinics in the United States and Canada.
A total of 28 (64%) of 44 children initially enrolled in PON1 (age 3-<16 years) who completed their 2-year study visit.
Participants were treated at the investigator's discretion.
Age-normal monocular high-contrast VA (HCVA). Secondary outcomes included low-contrast VA (LCVA), neuroimaging findings, and final diagnoses.
A total of 28 participants completed the 2-year outcome with a median enrollment age of 10.3 years (range, 5-15); 46% were female, and 68% had unilateral ON at presentation. Final 2-year diagnoses included isolated ON (n = 11, 39%), myelin oligodendrocyte glycoprotein-associated demyelination (n = 8, 29%), multiple sclerosis (MS) (n = 4,14%), neuromyelitis optica spectrum disease (NMOSD) (n = 3, 11%), and acute disseminated encephalomyelitis (n = 2, 7%). Two participants (7%; 95% confidence interval CI, 1-24) had subsequent recurrent ON (plus 1 participant who did not complete the 2-year visit); all had MS. Two other participants (7%) had a new episode in their unaffected eye. Mean presenting HCVA was 0.81 logarithm of the minimum angle of resolution (logMAR) (∼20/125), improving to 0.14 logMAR (∼20/25
) at 6 months, 0.12 logMAR (∼20/25
) at 1 year, and 0.11 logMAR (20/25
) at 2 years (95% CI, -0.08 to 0.3 20/20
-20/40
). Twenty-four participants (79%) had age-normal VA at 2 years (95% CI, 60-90); 21 participants (66%) had 20/20 vision or better. The 6 participants without age-normal VA had 2-year diagnoses of NMOSD (n = 2 participants, 3 eyes), MS (n = 2 participants, 2 eyes), and isolated ON (n = 2 participants, 3 eyes). Mean presenting LCVA was 1.45 logMAR (∼20/500
), improving to 0.78 logMAR (∼20/125
) at 6 months, 0.69 logMAR (∼20/100
) at 1 year, and 0.68 logMAR (∼20/100
) at 2 years (95% CI, 0.48-0.88 20/50
-20/150
).
Despite poor VA at presentation, most children had marked improvement in VA by 6 months that was maintained over 2 years. Associated neurologic autoimmune diagnoses were common. Additional episodes of ON occurred in 5 (18%) of the participants (3 relapses and 2 new episodes).
Syphilis infections continue to increase among men who have sex with men (MSM) in many countries, with rates often higher among HIV-positive MSM. There is limited understanding of the risk and ...determinants of syphilis transmission between men. We aimed to examine the concordance of early syphilis infection between male sexual partners and clinical factors associated with transmission.
Men attending Melbourne Sexual Health Centre with their male partners, where at least one was diagnosed with early syphilis, were identified from linkage of partner records between March 2011 and April 2016. Early latent syphilis was defined as a new asymptomatic syphilis presentation of less than 2 years' duration. Associations between concordance and potential risk factors were examined using Fisher's exact test.
Among 43 couples (86 men) identified, there were 13 couples (26 men) where both were diagnosed with early syphilis, representing a concordance rate of 30.2% (95% CI 17.2% to 46.1%). Among the 13 concordant couples, 5 men had primary syphilis (4 penile, 1 anal), 11 secondary syphilis (8 generalised rash, 3 penile, 2 anal, 1 oral lesion) and 10 early latent infections. Concordance was higher among couples where at least one partner had secondary syphilis compared with couples where neither partner had secondary syphilis (53% (9/17) vs 15% (4/26), P=0.016). Furthermore, concordance was higher among couples where one was HIV positive compared with couples where both were HIV negative (62% (5/8) vs 23% (8/35), P=0.042).
There was an overall concordance rate of 30%. Higher concordance rates for early syphilis infection between male sexual partners were associated with HIV and secondary syphilis.
Abstract only
Methamphetamine is a potent and highly addictive psychostimulant abused by more than 10 million people in the US (NSDUH). Epidemiological studies suggest that methamphetamine increases ...the risk for developing Parkinson's disease (PD) by as much as ~3 fold (Callaghan
et al
., 2012,
Drug Alcohol Depend
p.35; Curtin
et al
., 2015
Drug Alcohol Depend
p.30; Curtin
et al
., 2016,
Neuropharmacology
p.30). In spite of this connection, it is unclear why methamphetamine might promote PD. Mitochondrial oxidant stress in substantia nigra pars compacta (SNc) dopaminergic neurons is widely thought to be a key component of pathogenesis in PD. In these neurons, pacemaking activity is associated with Ca
2+
oscillations and elevated somatic mitochondrial stress (Surmeier & Schumacker, 2013,
JBC
p.10736). However, bath application of methamphetamine reduced pacemaking activity and had no effect on somatic mitochondrial stress. Another potential stressor of SNc dopaminergic neurons is cytosolic dopamine (DA), which can be oxidized to reactive quinones (Hattoria
et al
., 2009,
Parkinsonism Relat Disord
p.S35). To evaluate the role of oxidized DA in mediating the effects of methamphetamine, a genetically encoded, redox sensitive fluorescent probe (roGFP) targeted to either the mitochondria or cytosol was monitored with two‐photon laser scanning microscopy in
ex vivo
slice preparations. Methamphetamine had no effect on cytosolic oxidant stress but did increase mitochondrial oxidant stress in terminals and dendrites. Levodopa had the same effect, confirming DA‐dependence. A potential mediator of DA‐dependent mitochondrial oxidant stress is monoamine oxidase (MAO), which is anchored to the outer mitochondrial membrane. MAO metabolism of DA generates electrons, which could be shuttled to the electron transport chain through intermembrance space proteins with disulfide bonds. Indeed, pharmacological or genetic inhibition of MAO eliminated methamphetamine (or levodopa)‐induced mitochondrial oxidant stress. To probe the mechanisms involved, iPSCs were transfected with the redox sensitive probe targeted to the intermembrane space. Consistent with our hypothesis, levodopa increased mitochondrial stress in the intermembrane space. Moreover, MAO metabolism of DA was able to hyperpolarize the inner mitochondrial membrane consistent with an electron shuttle to Complex IV. To determine if MAO metabolism of DA, and subsequent increased mitochondrial oxidant stress, could have deleterious effects in the SNc, mice were chronically administered methamphetamine for two weeks with pretreatment of rasagiline (FDA‐approved MAO inhibitor) or saline. Two weeks after withdrawal, mice were sacrificed and tyrosine hydroxylase positive (TH
+
) cells counted in the SNc. Mice treated with methamphetamine alone had a significant loss of SNc TH
+
neurons, but those that were pre‐treated with the MAO inhibitor rasagiline did not. Taken together, these results demonstrate that methamphetamine leads to the loss of SNc dopaminergic neurons not by increasing cytosolic quinones but by increasing mitochondrial oxidant stress through a MAO‐dependent mechanism. Moreover, the toxicity of methamphetamine could be dramatically attenuated with an FDA approved drug, rasagiline.
Support or Funding Information
Supported by USPHSG NS047085 & DA039253, JPB, MJFF, and Northwestern Memorial Foundation.
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