Blood Biomarkers of Glioma in Response Assessment Including Pseudoprogression and Other Treatment Effects: A Systematic Review.

Imaging-based monitoring of disease burden in glioma patients is frequently confounded by treatment effects. Circulating biomarkers could theoretically augment imaging-based response monitoring. This systematic review aimed to present and evaluate evidence for differential expression and diagnostic accuracy of circulating biomarkers with respect to outcomes of tumor response, progression, stable disease, and treatment effects (pseudoprogression, radionecrosis, pseudoresponse, and pseudolesions) in patients undergoing treatment for World Health Organization grades II-IV diffuse astrocytic and oligodendroglial tumors. MEDLINE, EMBASE, Web Of Science, and SCOPUS databases were searched until August 18, 2019, for observational or diagnostic studies on multiple circulating biomarker types: extracellular vesicles, circulating nucleic acids, circulating tumor cells, circulating proteins, and metabolites, angiogenesis related cells, immune cells, and other cell lines. Methodological quality of included studies was assessed using an adapted Quality Assessment of Diagnostic Accuracy Studies-2 tool, and level of evidence (IA-IVD) for individual biomarkers was evaluated using an adapted framework from the National Comprehensive Cancer Network guidelines on evaluating tumor marker utility. Of 13,202 unique records, 58 studies met the inclusion criteria. One hundred thirty-three distinct biomarkers were identified in a total of 1,853 patients across various treatment modalities. Fifteen markers for response, progression, or stable disease and five markers for pseudoprogression or radionecrosis reached level IB. No biomarkers reached level IA. Only five studies contained data for diagnostic accuracy measures. Overall methodological quality of included studies was low. While extensive data on biomarker dysregulation in varying response categories were reported, no biomarkers ready for clinical application were identified. Further assay refinement and evaluation in larger cohorts with diagnostic accuracy study designs are required. PROSPERO Registration: CRD42018110658.

Pollen Loads of Flower Visitors to Açaí Palm (Euterpe oleracea) and Implications for Management of Pollination Services.

Understanding the functional roles of different pollinator species is crucial to the development of sustainable farming practices in pollinator-dependent crops. However, this can be challenging for crop plants in tropical regions with hyper-diverse pollinator communities. Here, we assess pollen loads of different insect visitors to inflorescences of açaí palm (Euterpe oleracea), the most important native crop in the Amazon estuary region. Flower-visiting insects were collected from pistillate (female) inflorescences at eight sites, including four managed floodplain forests and four plantations. Pollinator Importance Value Index (PIVI) and Relative Importance (RI) scores were calculated for common visitor taxa (≥ 10 individuals) using sum visit frequencies and median pollen loads. Pollen load analyses revealed that over seventy insect taxa, including bees, flies, beetles, wasps and ants, were effective vectors of E. oleracea pollen. Native bees, including both solitary and eusocial taxa, were the most efficient pollen vectors, with median pollen loads at least eight times higher than those of the next best insect group (flies). Insect pollen loads were at their highest between 0800 and 1300 hours, and four insect taxa had RI scores > 0.05, including two meliponine bees belonging to the Trigona genus (Trigona branneri Cockerell and Trigona pallens Fabricius) and two halictid bee genera (Augochloropsis and Dialictus). Our results suggest that native bees play an important role in açaí pollination and should be the primary focus of pollinator management in açaí production systems.

Manual therapy, exercise therapy, or both, in addition to usual care, for osteoarthritis of the hip or knee. 2: economic evaluation alongside a randomized controlled trial.

OBJECTIVE: To evaluate the cost effectiveness of manual physiotherapy, exercise physiotherapy, and a combination of these therapies for patients with osteoarthritis of the hip or knee. METHODS: 206 Adults who met the American College of Rheumatology criteria for hip or knee osteoarthritis were included in an economic evaluation from the perspectives of the New Zealand health system and society alongside a randomized controlled trial. Resource use was collected using the Osteoarthritis Costs and Consequences Questionnaire. Quality-adjusted life years (QALYs) were calculated using the Short Form 6D. Willingness-to-pay threshold values were based on one to three times New Zealand's gross domestic product (GDP) per capita of NZ$ 29,149 (in 2009). RESULTS: All three treatment programmes resulted in incremental QALY gains relative to usual care. From the perspective of the New Zealand health system, exercise therapy was the only treatment to result in an incremental cost utility ratio under one time GDP per capita at NZ$ 26,400 (-$34,081 to $103,899). From the societal perspective manual therapy was cost saving relative to usual care for most scenarios studied. Exercise therapy resulted in incremental cost utility ratios regarded as cost effective but was not cost saving. For most scenarios combined therapy was not as cost effective as the two therapies alone. CONCLUSIONS: In this study, exercise therapy and manual therapy were more cost effective than usual care at policy relevant values of willingness-to-pay from both the perspective of the health system and society. Trial registration number Australian New Zealand Clinical Trials Registry ACTRN12608000130369.

Manual therapy, exercise therapy, or both, in addition to usual care, for osteoarthritis of the hip or knee: a randomized controlled trial. 1: clinical effectiveness.

OBJECTIVE: To evaluate the clinical effectiveness of manual physiotherapy and/or exercise physiotherapy in addition to usual care for patients with osteoarthritis (OA) of the hip or knee. DESIGN: In this 2 × 2 factorial randomized controlled trial, 206 adults (mean age 66 years) who met the American College of Rheumatology criteria for hip or knee OA were randomly allocated to receive manual physiotherapy (n = 54), multi-modal exercise physiotherapy (n = 51), combined exercise and manual physiotherapy (n = 50), or no trial physiotherapy (n = 51). The primary outcome was change in the Western Ontario and McMaster osteoarthritis index (WOMAC) after 1 year. Secondary outcomes included physical performance tests. Outcome assessors were blinded to group allocation. RESULTS: Of 206 participants recruited, 193 (93.2%) were retained at follow-up. Mean (SD) baseline WOMAC score was 100.8 (53.8) on a scale of 0-240. Intention to treat analysis showed adjusted reductions in WOMAC scores at 1 year compared with the usual care group of 28.5 (95% confidence interval (CI) 9.2-47.8) for usual care plus manual therapy, 16.4 (-3.2 to 35.9) for usual care plus exercise therapy, and 14.5 (-5.2 to 34.1) for usual care plus combined exercise therapy and manual therapy. There was an antagonistic interaction between exercise therapy and manual therapy (P = 0.027). Physical performance test outcomes favoured the exercise therapy group. CONCLUSIONS: Manual physiotherapy provided benefits over usual care, that were sustained to 1 year. Exercise physiotherapy also provided physical performance benefits over usual care. There was no added benefit from a combination of the two therapies. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12608000130369.

Startle induces early initiation of classically conditioned postural responses.

Startling acoustic stimuli (SAS) induce the early release of prepared motor responses. The current study used SAS, in conjunction with a classical conditioning paradigm, to examine advanced motor preparation of conditioned postural responses (PRs). After generalized startle responses were induced, standing posture was perturbed in 2 blocks of 15 Conditioning trials, where in each trial the onset of a nonstartling auditory cue [i.e., a conditioned stimulus (CS)] preceded a leftward support-surface translation. Upon completion of each block, a single trial was conducted. After block 1, a CS-Only trial was used to induce conditioned PRs in the absence of balance perturbations. After block 2, a post-Conditioning Startle trial that involved a CS subsequently followed by a SAS was used to examine motor preparation of conditioned PRs. PRs were quantified in terms of center of pressure displacements, ankle and hip kinematics, as well as surface electromyography of proximal and distal bilateral muscle pairs. Results indicated that repeated experience with cued balance perturbations led to PR conditioning and, more importantly, motor preparation of PRs. Conditioning was evidenced in biomechanical and electromyographic responses observed in CS-Only trials, as well as the progressive changes to evoked response parameters during repeated Conditioning trials. SAS presented in post-Conditioning Startle trials evoked early onsets of biomechanical and electromyographic responses, while preserving relative response parameters that were each distinct from generalized startle responses. These results provide important insight into both the consequences of using cues in dynamic postural control studies and the neural mechanisms governing PRs.

An outbreak of severe iodine-deficiency goitre in a sheep flock in north-east Victoria.

BACKGROUND: Several outbreaks of goitre, considered to be related to iodine deficiency, occurred in sheep flocks throughout Victoria in 2010. OBJECTIVE: We describe one outbreak in Merino-Border Leicester-cross ewes and their lambs in north-east Victoria that appeared to be associated with increased rainfall and pasture growth, particularly during the preceding summer and autumn. RESULTS: The outbreak was characterised by a four-fold increase in neonatal lamb deaths and goitre, alopecia and poor skeletal development in the lambs. Most cases occurred in lambs born to 2-year-old crossbred ewes that had grazed long, lush perennial pastures throughout their entire pregnancy, whereas few cases occurred in mature crossbred or Merino ewes that had grazed shorter, annual pastures on hill country for 3 weeks in late pregnancy but were otherwise managed similarly. CONCLUSION: Existing recommendations for south-eastern Australia are that only spring-lambing ewes in iodine-deficient areas require iodine supplementation to prevent goitre in years with high autumn-winter rainfall. Aspects of this outbreak suggest that ewes lambing at other times of the year and grazing abundant pasture for prolonged periods may also require supplementation to prevent goitre, even if autumn-winter rainfall does not exceed previously established thresholds.

Comprehensive approach to fall prevention on a national level: New Zealand.

Individual assessment and treatment are important for older people at high risk of falls and injury. But falls are common. The problem cannot be addressed solely on an individual patient, individual clinician basis. Fall prevention programs that have broad coverage, good uptake and adherence, and can be seen to maintain independent living benefit individuals and help control health service costs. Two such programs have been successfully introduced in New Zealand: the home-based Otago Exercise Programme and tai chi classes. The difficulty now is in maintaining the nationwide commitment to these preventive measures.

Postural responses explored through classical conditioning.

The purpose of the study was to determine whether the central nervous system (CNS) requires the sensory feedback generated by balance perturbations in order to trigger postural responses (PRs). In Experiment 1, twenty-one participants experienced toes-up support-surface tilts in two blocks. Control blocks involved unexpected balance perturbations whereas an auditory tone cued the onset of balance perturbations in Conditioning blocks. A single Cue-Only trial followed each block (Cue-Only(Control) and Cue-Only(Conditioning) trials) in the absence of balance perturbations. Cue-Only(Conditioning) trials were used to determine whether postural perturbations were required in order to trigger PRs. Counter-balancing the order of Control and Conditioning blocks allowed Cue-Only(Control) trials to examine both the audio-spinal/acoustic startle effects of the auditory cue and the carryover effects of the initial conditioning procedure. In Experiment 2, six participants first experienced five consecutive Tone-Only trials that were followed by twenty-five conditioning trials. After conditioning, five Tone-Only trials were again presented consecutively to first elicit and then extinguish the conditioned PRs. Surface electromyography (EMG) recorded muscle activity in soleus (SOL), tibialis anterior (TA) and rectus femoris (RF). EMG onset latencies and amplitudes were calculated together with the onset latency, peak and time-to-peak of shank angular accelerations. Results indicated that an auditory cue could be conditioned to initiate PRs in multiple muscles without balance-relevant sensory triggers generated by balance perturbations. Postural synergies involving excitation of TA and RF and inhibition of SOL were observed following the Cue-Only(Conditioning) trials that resulted in shank angular accelerations in the direction required to counter the expected toes-up tilt. Postural synergies were triggered in response to the auditory cue even 15 min post-conditioning. Furthermore, conditioned PRs were quickly extinguished as participants became unresponsive by the third trial in extinction. In conclusion, our results reveal that the CNS does not require sensory feedback from postural perturbations in order to trigger PRs.

Exercise therapy, manual therapy, or both, for osteoarthritis of the hip or knee: a factorial randomised controlled trial protocol.

BACKGROUND: Non-pharmacological, non-surgical interventions are recommended as the first line of treatment for osteoarthritis (OA) of the hip and knee. There is evidence that exercise therapy is effective for reducing pain and improving function in patients with knee OA, some evidence that exercise therapy is effective for hip OA, and early indications that manual therapy may be efficacious for hip and knee OA. There is little evidence as to which approach is more effective, if benefits endure, or if providing these therapies is cost-effective for the management of this disorder. The MOA Trial (Management of OsteoArthritis) aims to test the effectiveness of two physiotherapy interventions for improving disability and pain in adults with hip or knee OA in New Zealand. Specifically, our primary objectives are to investigate whether:1. Exercise therapy versus no exercise therapy improves disability at 12 months;2. Manual physiotherapy versus no manual therapy improves disability at 12 months;3. Providing physiotherapy programmes in addition to usual care is more cost-effective than usual care alone in the management of osteoarthritis at 24 months. METHODS: This is a 2 x 2 factorial randomised controlled trial. We plan to recruit 224 participants with hip or knee OA. Eligible participants will be randomly allocated to receive either: (a) a supervised multi-modal exercise therapy programme; (b) an individualised manual therapy programme; (c) both exercise therapy and manual therapy; or, (d) no trial physiotherapy. All participants will continue to receive usual medical care. The outcome assessors, orthopaedic surgeons, general medical practitioners, and statistician will be blind to group allocation until the statistical analysis is completed. The trial is funded by Health Research Council of New Zealand Project Grants (Project numbers 07/199, 07/200). DISCUSSION: The MOA Trial will be the first to investigate the effectiveness and cost-effectiveness of providing physiotherapy programmes of this kind, for the management of pain and disability in adults with hip or knee OA. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ref: ACTRN12608000130369.

Mandibular advancement splint titration in obstructive sleep apnoea.

INTRODUCTION: Mandibular advancement splints (MAS) allowing self-adjustment may be better tolerated, but the optimum titration protocol needs systematic study. AIM: The aims of the study are to assess the effectiveness of a titratable MAS device in consecutive patients with body mass index (BMI) < 35 kg/m(2) and obstructive sleep apnoea [OSA, apnoea-hypopnoea index (AHI) 10-40/h] and compare two methods of adjustment [self-adjustment or adjustment after polysomnographic (PSG) feedback]. MATERIALS AND METHODS: Twenty-eight patients (24 M, mean age 49 years, mean BMI 27.6 kg/m(2)) with symptomatic (Epworth Sleepiness score > 8/24, snoring, choking or poor sleep quality) OSA (mean AHI 25.7/h, range 10-46/h) had a MAS set at 70% maximal protrusion and were randomised to subjective self-adjustment for 6 weeks (n = 16) or objective adjustment (n = 12; fixed position for 3 weeks, then PSG based feedback at 3 weeks with self-adjustment instructions). Primary outcome variable (AHI) and OSA symptoms were compared by t tests and chi-squared tests at baseline and after 6 weeks. Resolution of apnoea was defined as AHI < 5/h; improvement was defined as AHI decreased by >50% but still >5/h. RESULTS: The groups had similar baseline demographics, OSA severity and occlusal type. MAS therapy improved or resolved OSA in 20 out of 28 (71%) and was reportedly used nightly by 91% of the objective group and 63% of the subjective group (p = 0.04). MAS were used all night by 75% of the objective group and 69% of the subjective group (p > 0.05). MAS adjustment following PSG feedback did not lower AHI further from 3 weeks (baseline 26.5 +/- 12.0/h, 3 weeks 15.3 +/- 13.5/h p = 0.01, 6 weeks 11.7 +/- 10.0/h, p = 0.11). The overall improvement was similar to that achieved with subjective adjustment (baseline AHI 25.4 +/- 7.4/h, 6 weeks 14.3 +/- 10.7/h, p = 0.0002). Symptomatic benefit was reported by both groups. CONCLUSION: In selected patients, titratable MAS improved or resolved OSA in the majority of patients and was well tolerated. PSG-based feedback at 3 weeks allowed objective confirmation of efficacy and increased device use but did not result in greater improvement in AHI or symptoms. Neither titration method was significantly superior for us to provide firm endorsement. However, we recommend a follow-up sleep study to confirm MAS efficacy.

Reducing hazard related falls in people 75 years and older with significant visual impairment: how did a successful program work?

BACKGROUND: In a randomized controlled trial testing a home safety program designed to prevent falls in older people with severe visual impairment, it was shown that the program, delivered by an experienced occupational therapist, significantly reduced the numbers of falls both at home and away from home. OBJECTIVES: To investigate whether the success of the home safety assessment and modification intervention in reducing falls resulted directly from modification of home hazards or from behavioral modifications, or both. METHODS: Participants were 391 community living women and men aged 75 years and older with visual acuity 6/24 meters or worse; 92% (361 of 391) completed one year of follow up. Main outcome measures were type and number of hazards and risky behavior identified in the home and garden of those receiving the home safety program, compliance with home safety recommendations reported at six months, location of all falls for all study participants during the trial, and environmental hazards associated with each fall. RESULTS: The numbers of falls at home related to an environmental hazard and those with no hazard involved were both reduced by the home safety program (n = 100 participants) compared with the group receiving social visits (n = 96) (incidence rate ratios = 0.40 (95% confidence interval, 0.21 to 0.74) and 0.43 (0.21 to 0.90), respectively). CONCLUSIONS: The overall reduction in falls by the home safety program must result from some mechanism in addition to the removal or modification of hazards or provision of new equipment.

Randomised controlled trial of prevention of falls in people aged > or =75 with severe visual impairment: the VIP trial.

OBJECTIVES: To assess the efficacy and cost effectiveness of a home safety programme and a home exercise programme to reduce falls and injuries in older people with low vision. DESIGN: Randomised controlled trial. SETTING: Dunedin and Auckland, New Zealand. PARTICIPANTS: 391 women and men aged > or =75 with visual acuity of 6/24 or worse who were living in the community; 92% (361 of 391) completed one year of follow-up. INTERVENTIONS: Participants received a home safety assessment and modification programme delivered by an occupational therapist (n = 100), an exercise programme prescribed at home by a physiotherapist plus vitamin D supplementation (n = 97), both interventions (n = 98), or social visits (n = 96). MAIN OUTCOME MEASURES: Numbers of falls and injuries resulting from falls, costs of implementing the home safety programme. RESULTS: Fewer falls occurred in the group randomised to the home safety programme but not in the exercise programme (incidence rate ratios 0.59 (95% confidence interval 0.42 to 0.83) and 1.15 (0.82 to 1.61), respectively). However, within the exercise programme, stricter adherence was associated with fewer falls (P = 0.001). A conservative analysis showed neither intervention was effective in reducing injuries from falls. Delivering the home safety programme cost NZ650 dollars (234 pounds sterling, 344 euros, US432 dollars) (at 2004 prices) per fall prevented. CONCLUSION: The home safety programme reduced falls and was more cost effective than an exercise programme in this group of elderly people with poor vision. The Otago exercise programme with vitamin D supplementation was not effective in reducing falls or injuries in this group, possibly due to low levels of adherence. Trial registration number ISRCTN15342873.

Retardation of brain aging by chronic treatment with melatonin.

Slowing the functional decline in the aging brain is not only relevant to nonpathological senescence but also to a broad range of neurodegenerative diseases. Although disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) are not found in the young adult, they gradually manifest with increasing age. AD, in particular, is an increasing major public health concern as the population ages; therapies that delay disease onset will markedly reduce overall disease prevalence. Aging of the brain has been repeatedly associated with cumulative oxidative damage to macromolecules and to abnormal levels of inflammatory activity. Melatonin has attained increasing prominence as a candidate for ameliorating these changes occurring during senescence. Recent research has focused on supplementation with dietary melatonin designed to elucidate the specific key intracellular targets of age-related inflammatory events, and the optimal means of affording protection of these targets. This report summarizes the progress made in this area.

Health and performance of Holstein calves that suckled or were hand-fed colostrum and were fed one of three physical forms of starter.

Intake of colostrum by neonatal calves and early transition to calf starter are two important factors in successful calf programs. Thirty-one Holstein calves were used to determine health and performance of calves that were 1) allowed to remain with their dams for 3 d and suckle (suckled calves) or were removed from their dams and fed colostrum only by bottle (bottle calves); and were 2) fed ground, pelleted, or textured starters, formulated to be isonitrogenous. Bottle calves were removed from their dams at birth, fed 2.84 L of colostrum, placed in individual hutches, and fed 1.89 L of colostrum 12 h after the first feeding. Suckled calves were removed from their dams after 3 d and placed in individual hutches. Once calves were housed in hutches, they were fed 2 L of whole milk twice daily and were provided starters and water beginning on d 3. Calves were weighed at birth and weekly for 6 wk. Blood samples were obtained at birth, 24 h, and weekly for serum protein determination. Starter intake, fecal scores, and electrolyte treatments were recorded daily. Weaning began when calves had consumed 0.68 kg starter for 2 d consecutively. There were no differences in treatment means between suckled and bottle calves for total gain, grain consumption, days with fecal scores >2, or electrolyte treatments per calf. Average days to weaning was greater for bottle calves compared with suckled calves. Mean serum protein concentration at 24 h was greater for bottle (6.0 g/dl) compared with suckled calves (5.8 g/dl) and only 2 of 15 bottle calves had serum protein concentrations <5.0 g/dl compared with 6 of 16 suckled calves. For starter treatments, calves fed textured starter consumed more total grain, were weaned earlier, and weighed more at 6 wk of age than calves fed pelleted starter. Based on 24-h serum protein concentrations, transfer of passive immunity was greater for bottle calves compared with suckled calves.

The effect of fermented liquid feeding on the faecal microbiology and colostrum quality of farrowing sows.

This study investigated the effects of fermented liquid feed (FLF) on the lactic acid bacteria (LAB):Coliform (L:C) ratio in the faeces of farrowing sows and the quality of sow colostrum. Eighteen multiparous sows were randomly allocated to one of three dietary treatments for approximately 2 weeks prior to farrowing and for 3 weeks after parturition. The three dietary treatments were dry pelleted feed (DPF), nonfermented liquid feed (NFLF), and fermented liquid feed (FLF). A rifampicin-resistant mutant of Lactobacillus plantarum was used to ferment liquid feed. Coliforms and lactic acid bacteria (LAB) in the faeces of farrowing sows and piglets were estimated by standard microbiological techniques. Intestinal epithelial cells (IEC-6) and blood lymphocytes were used to evaluate the mitogenic activity of colostral samples taken at parturition. Results demonstrated that while the LAB population was not significantly affected by dietary treatment, significant differences in coliform population were observed in the sow faecal samples taken 7 days after parturition. Faeces excreted from sows fed FLF had significantly (P < 0.001) lower numbers of coliforms than sows fed NFLF or DF. Piglets from sows fed FLF excreted faeces that were higher in LAB (7.7 vs. 7.3 log10 CFU g (-1); P < 0.01) and lower in coliforms (7.5 vs. 8.1 log10 CFU g (-1); P < 0.001) than faeces from the piglets of DF-fed dams. Colostrum from sows fed FLF had a significantly greater (P < 0.001) mitogenic activity on both intestinal cells (IEC-6) (79326 +/- 3069 CPM) and blood lymphocytes (1903 +/- 204 CPM) compared with colostrum from dry feed fed sows (53433 +/- 1568 and 1231 +/- 61.4 CPM, respectively). The combined effects of enhanced maternal/passive immunity and the reduction in the level of environmental contamination with faecal pathogens, achieved by FLF, may be important in achieving improved health status for both sows and piglets.

Inhibition of glutathione S-transferases (GSTs) from parasitic nematodes by extracts from traditional Nigerian medicinal plants.

Piliostigma thonningii, Ocimum gratissimum, Nauclea latifolia and Alstonia boonei are used in Nigerian traditional medicines against gastrointestinal helminths of animals and man. Proanthocyanidins were detected in Piliostigma and Nauclea, but not Alstonia or Ocimum. Extracts of these plants killed 50% of brine shrimp nauplii at <10 ppm (Nauclea), 100 ppm (Piliostigma) and <1000 ppm (Ocimum and Alstonia), the Nauclea LD50 being similar to the anthelmintic drug piperazine. Extracts were also toxic to the parasitic nematode Haemonchus infective L3 stage. Nematode glutathione-S-transferases (GSTs) are potential drug targets. Apart from Alstonia all the medicinal plants contained heat-stable inhibitory activities against recombinant Ascaris and Onchocerca GSTs in vitro. Piliostigma, Ocimum and Nauclea had IC50s of 2, 10 and 15 microg/mL respectively for Ascaris GST and 4, 8, 28 microg/mL respectively for Onchocerca GST. We suggest that the inhibitory properties of some of these Nigerian plant extracts against GST may contribute to the pharmacological basis of their efficacy against helminths in traditional herbal use.