TEM‐examined foals contained degenerated endothelial cells that were detached from the basement membrane, resulting in gap formation. Thirty‐three percent of all canals were surrounded by a hypercellular rim that was interpreted as contribution of chondrocytes to growth cartilage. On LM, 69% of all cartilage canals were surrounded by a ring of matrix that stained intensely eosinophilic and consisted of collagen fibres on TEM that were confirmed to be collagen type I by immunohistochemistry. In summary, two types of discontinuity were observed in the endothelium of equine epiphyseal cartilage canal vessels: fenestrations were observed in a patent cartilage canal in the 118‐day‐old foal; and gaps were observed in chondrifying cartilage canals in all TEM‐examined foals. Canals were not surrounded by any cellular wall, but a large proportion was surrounded by an acellular wall consisting of collagen type I. Bacterial binding can therefore probably occur in horses by mechanisms that are similar to those previously demonstrated in pigs and chickens.Cartilage canals have been shown to contain discontinuous blood vessels that enable circulating bacteria to bind to cartilage matrix, leading to vascular occlusion and associated pathological changes in pigs and chickens. It is also inconsistently reported that cartilage canals are surrounded by a cellular or acellular wall that may influence whether bacterial binding can occur. It is not known whether equine cartilage canals contain discontinuous endothelium or are surrounded by a wall. This study aimed to examine whether there were discontinuities in the endothelium of cartilage canal vessels, and whether canals had a cellular or acellular wall, in the epiphyseal growth cartilage of foals. Epiphyseal growth cartilage from the proximal third of the medial trochlear ridge of the distal femur from six healthy foals that were 1, 24, 35, 47, 118 and 122 days old and of different breeds and sexes was examined by light microscopy (LM), transmission electron microscopy (TEM) and immunohistochemistry. The majority of patent cartilage canals contained blood vessels that were lined by a thin layer of continuous endothelium. Fenestrations were found in two locations in one venule in a patent cartilage canal located deep in the growth cartilage and close to the ossification front in the 118‐day‐old foal. Chondrifying cartilage canals in all  Cartilage canals are channels that carry blood vessels from the perichondrium into the specialised metaphyseal and epiphyseal growth cartilage of long bones during normal development . A minimum of two 5‐μm‐thick sections were cut from each formaldehyde‐fixed slab and stained with haematoxylin and eosin (HE) or toluidine blue (TB), respectively. The sections were examined in an Axio Lab.A1 microscope  and photographed using an AxioCam ERc 5s (Zeiss).The skin on the cranial aspect of the distal femur was incised and the underlying soft tissues were reflected. The femoro‐patellar joint capsule was opened, and the lateral and medial trochlear ridges were exposed by dislocating the patella proximo‐medially Fig. A. Parallm cacodylate buffer and post‐fixed in 1% osmium tetroxide for 2 h at 4 °C, rinsed and dehydrated in ethanol, followed by acetone, and embedded in epoxy resin LX‐112 . Semi‐thin sections (0.5 μm) were cut and stained with TB and examined with LM in order to select areas for preparation of ultra‐thin sections (approximately 60–70 nm). The ultra‐thin sections were picked up on formvar‐coated copper grids, contrasted with uranyl acetate and lead citrate, and examined at 100 kV in a Tecnai 12 Spirit Bio TWIN TEM . Digital images were captured using a Veleta camera .Areas were selected from the superficial and deep parts Fig. C of the Selected formalin‐fixed blocks were immunostained for collagen type I. A rabbit polyclonal anti‐collagen I antibody  was used at a dilution of 1 : 100. The full staining protocol is available in Data S1.The criteria used for LM evaluation were identical to those previously described in Carlson et al.  and OlstMaterial from six foals aged 1, 24, 35, 47, 118 and 122 days  of all cartilage canals were surrounded by a narrow zone where cell density was increased relative to the density of chondrocytes between adjacent canals (Fig. 3% of allOn LM, the innermost layer of the hypercellular rim consisted of spindle‐shaped cells that resembled mesenchymal cells, with sparse basophilic cytoplasm and no lacuna Fig. A. These On TEM Fig. B–D, the The above LM and TEM observations in canals surrounded by a hypercellular rim were interpreted as differentiation of perivascular mesenchymal cells into chondrocytes in order to contribute to growth of the epiphyseal cartilage model. The cartilage production observed on the margin of canals with a hypercellular rim resembled cartilage production during chondrification, but could be differentiated from it on the basis that hypercellular‐rimmed canals contained patent vessels.On LM, some of the cartilage canals were surrounded by an ECM that was basophilic‐staining and similar to the inter‐territorial matrix between adjacent cartilage canals. Other cartilage canals were surrounded by a narrow zone of intensely eosinophilic‐staining matrix Figs A and 4A.A zone of matrix surrounding cartilage canals corresponding to the eosinophilic ring was examined with TEM Fig. A–D. ProtThe intermediate zone contained randomly distributed individual collagen fibrils that were embedded in a granular proteoglycan‐rich matrix as is characteristic of hyaline cartilage. Individual collagen fibrils measured 20–30 nm in diameter and were interpreted as collagen type II. The border between the inner and intermediate zones was sometimes sharp and other times more difficult to distinguish because it contained a mixture of collagen types I and II Fig. D.The eosinophilic ring corresponded to the fibrils that were interpreted as collagen type I with TEM. In immunostained sections, it was confirmed that some of the cartilage canals were surrounded by a thin zone of matrix that stained immunopositive for collagen type I compared with the immunonegative matrix surrounding other cartilage canals or between adjacent cartilage canals Fig. A–D. PosiTo the authors' knowledge, the current study is the first ultrastructural description of epiphyseal cartilage canals in horses. The main finding was that there were two types of discontinuity in the endothelium of equine epiphyseal cartilage canal vessels: fenestrations were observed in a patent cartilage canal in the 118‐day‐old foal; and gaps were observed in chondrifying cartilage canals in all TEM‐examined foals.There are several possible explanations for the fact that fenestrations were observed in the 118‐day‐old foal and not in the other two foals where endothelium was examined by TEM. The cartilage canal where fenestrations were observed was located deep within the epiphyseal growth cartilage. This mirrors previous observations that fenestrations were more common deep compared with superficial in the growth cartilage of chicks (Hunt et al. Parascaris equorum impaction and bladder rupture, and had signs of systemic inflammation. With the current methodology, it was not possible to answer whether the observed fenestrations represented constitutively present (Cogger et al. The current study included relatively few individuals, and it is not possible to conclude whether fenestrations are less common in the cartilage canal vessels of horses, compared with other species. In addition to being constitutively present in the vessels of some organs, fenestrations can represent a dynamic response to a wide variety of physiological, chemical and pathological stimuli, including cytokines and inflammatory mediators (Cogger et al. In the current study, an additional type of discontinuity was also observed in terms of endothelial cells detaching from the vascular basement membrane leading to gap formation in the vessels of early chondrifying cartilage canals. Ultrastructural studies have tended to focus on patent, rather than chondrifying, canals. Two types of discontinuity were previously observed in sheep foetuses: 60‐nm‐diameter pores and wider discontinuities; the latter tended to be observed superficially within the cartilage and as this is where chondrification begins, it potentially agrees with the currently observed gaps in chondrifying canals (Stockwell, Some of the current observed cartilage canals were surrounded by a hypercellular rim. An apparently similar hypercellular rim was previously observed in several different studies Lutfi, . In one In the currently studied foals, the majority of cartilage canals were surrounded by an eosinophilic ring that was immunohistochemically confirmed to consist of collagen type I. This agrees with previous observations from LM studies in foals (Olstad et al. The current study is the first where the fact that individual cartilage canals within the same histological section can be surrounded by different types of collagen has been quantified in the horse Table . HistoriTwo types of discontinuity were observed in the endothelium of equine epiphyseal cartilage canal vessels: fenestrations were observed in a patent cartilage canal in the 118‐day‐old foal; and gaps were observed in chondrifying cartilage canals in all TEM‐examined foals. Canals were not surrounded by any cellular wall, but a large proportion was surrounded by an acellular wall consisting of collagen type I. Bacterial binding can therefore probably occur in horses by mechanisms that are similar to those previously demonstrated in pigs and chickens.I.R.H. contributed to the study design, study execution, data analysis and interpretation and writing of the manuscript. K.O. and S.E. contributed to the study design, study execution, data analysis and interpretation. K. H. performed the data preparation and contributed to the data interpretation for TEM. N.I.D. contributed to the study design and data interpretation. All authors contributed to the preparation of the manuscript, critically revised the manuscript and have approved the final version of the manuscript.The authors declare that they have no competing interests.Data S1. Immunohistochemistry.Click here for additional data file.


The aim of this paper was to ascertain whether greater familiarity with a smartphone or tablet was associated with participants’ preferred mobile delivery modality for eHealth interventions.Data from 1865 people who participated in the Australian Health and Social Science panel study were included into two multinomial logistic regression analyses in which preference for smartphone and tablet delivery for general or personalised eHealth interventions were regressed onto device familiarity and the covariates of sex, age and education.People were more likely to prefer both general and personalised eHealth interventions presented on tablets if they reported high or moderate tablet familiarity (compared to low familiarity) and people were more likely to prefer both general and personalised eHealth interventions presented on smartphones if they reported high or moderate smartphone familiarity, were younger, and had university education (compared to completing high school or less).People prefer receiving eHealth interventions on the mobile devices they are most familiar with. These findings have important implications that should be considered when developing eHealth interventions, and demonstrates that eHealth interventions should be delivered using multiple platforms simultaneously to optimally cater for as many people as possible. Across the developed world, two-thirds of recorded deaths are attributed to preventable chronic diseases such as cardiovascular and respiratory diseases, obesity, diabetes, and depression . The majThe Internet has become an increasingly popular mode of communication, both in terms of awareness raising as well as in terms of behavioural modification , and hasAlthough a large amount of research conducted on eHealth behaviour change interventions has shown to be effective to some extent –16, thermHealth). The cognitive demands required to navigate unfamiliar eHealth technology may be high and interfere with a person’s ability to change their health behaviour [It may be that people prefer to use the mobile devices they are most familiar with for eHealth interventions  . The ubiThe aim of this paper was to ascertain whether greater familiarity with a smartphone or tablet was associated with participants’ preferred delivery modality for mHealth interventions. Current eHealth interventions vary greatly in how information is presented to people; therefore the study investigated two outcomes: preferences for delivery of general health information and preferences for delivery of health information personally tailored to them. It was hypothesised that people would prefer the delivery of eHealth information on mobile devices they are most familiar with. Technology use tends to vary as a function of demographic characteristics ; therefoStudy participants were members of the Australian Health and Social Science (AHSS) panel study conducted by the Population Research Laboratory at Central Queensland University. AHSS panel study members were a randomly selected sample of Australian adults recruited through annual population surveys conducted by the Population Research Laboratory. Panel members provided concent to complete regular online surveys on various health-related topics. Between October and November 2013, 3901 panel members across all States and Territories in Australia were invited to participate in an online survey for the current study. Of these, 2034 respondents (52.1 %) completed the survey. Participants provided informed consent and the Human Ethics Committee at Central Queensland University approved the study (H13/09-163).What is your preferred platform for delivery of general health information?’) and personalised  health information from the options ‘through a desktop computer with internet access,’ ‘through a laptop computer with internet access,’ ‘through a computer-tablet via the internet, ‘through a telephone call,’ ‘through video conferencing,’ ‘through a mobile phone,’ ‘through a smartphone via the internet,’ ‘through a smartphone via an application,’ through e-mail,’ or ‘I do not want to use technology to receive disease management or health information’. Since this study aim focused on smartphones and tablet preferences, responses were collapsed into the categories of ‘smartphone,’ ‘tablet,’ and ‘other.’Using two items, participants reported their preferred device for the delivery of general , moderate  and low .Device familiarity for smartphones and tablets was assessed using the questions, ‘female or male), age in years, and education (11 response options). Based on response frequencies, education was categorized into the nominal categories of: high school completion or less, university education , and technical studies .Participants also reported their sex . Study sample characteristics are shown in Table M = 55.96, SD = 13.68). Most participants completed some university schooling . The majority of participants had low smartphone  and tablet familiarity . When asked which device they would prefer to receive general health information on, most reported preferring non-mobile devices . However, 12.9 % (n = 241) of participants said smartphones and 10.2 % (n = 191) of participants said tablets. Response frequencies were similar in regards to which devices participants would prefer to receive personalised health information on: 19.9 % (n = 371) said desktop computers, 13.2 % (n = 246) said laptops, 10.1 % (n = 188) said smartphones and 10.2 % (n = 191) said tablets. A full break-down of the participants’ preferences are reported in Table Of 2034 participants included in the study, 169 were excluded from analyses because they did not respond to any of the questions used in this study leaving a sample size of 1865. Amongst the sample, there was minimal missing data  than people who were unfamiliar with tablets. Similarly, high frequency users of smartphone applications were more likely to prefer health information delivered via their smartphone . Thoma and Williams  showed tOf note, more participants reported a preference for non-mobile devices  for delivery of eHealth interventions, though one should keep in mind that the average age of this sample was 56 years. This is probably due to lack of familiarity of using mobile devices for eHealth in this sample. This is in contrast to the rapid transformation of the field in incorporating mobile devices for eHealth . As suchYounger people and people with university education were more likely to prefer general health information delivered to a smartphone. These findings are consistent with the results from a recent study showing that highly educated millennials are more familiar using smartphones for interacting within their professional and social worlds than their peers . This suThis study utilised a self-report method of data collection which has limitations . Social This study demonstrates that device familiarity significantly impacts device preference for eHealth interventions. People in this study tended to report preferring non-mobile devices for eHealth interventions overall, suggesting that these may still need to be options for the delivery of eHealth interventions. Amongst the mobile devices, a preference for smartphones was found to be more likely amongst younger and more educated populations. These findings are important for improving the methods by which state health agencies, non-government organizations, health promoters, health insurance companies, and intervention developers deliver health interventions to the public. The field of eHealth has already had a significant impact on increasing health literacy and improving health behaviours. The current literature has confirmed the utility of smartphones and tablets in delivering health behaviour change interventions, and the findings of this study suggest these effects might be enhanced by providing eHealth interventions using the devices people are familiar with.


The purpose of this analysis was to determine whether in office diagnostic needle arthroscopy (Visionscope Imaging System [VSI]) can provide for improved diagnostic assessment and; more cost effective care.Data on arthroscopy procedures in the US for deep seated pathology in the knee and shoulder were used . These procedures represent approximately 25-30% of all arthroscopic procedures performed annually. Sensitivities, specificities, positive predictive, and negative predictive values for MRI analysis of this deep seated pathology from systematic reviews and meta-analyses were used in assessing for false positive and false negative MRI findings. The costs of performing diagnostic and surgical arthroscopy procedures (using 2013 Medicare reimbursement amounts); costs associated with false negative findings; and the costs for treating associated complications arising from diagnostic and therapeutic arthroscopy procedures were then assessed.In patients presenting with medial meniscal pathology ; use of the VSI system in place of MRI assessment (standard of care) resulted in a net cost savings to the system of $151 million. In patients presenting with rotator cuff pathology ; use of VSI in place of MRI similarly saved $59 million. These savings were realized along with more appropriate care as; fewer patients were exposed to higher risk surgical arthroscopic procedures.The use of an in-office arthroscopy system can: possibly save the US healthcare system money; shorten the diagnostic odyssey for patients; potentially better prepare clinicians for arthroscopic surgery (when needed) and; eliminate unnecessary outpatient arthroscopy procedures, which commonly result in surgical intervention. Magnetic resonance imaging (MRI) or arthrography (MRA) and clinical evaluation are the tools most commonly used to assess soft tissue injuries to the shoulder and knee joints. However, MRI (A) assessment has associated drawbacks, including a relatively high incidence of false negative [FN]  and false positive [FP]  findings. The high incidence of FP and FN occurs most commonly with deep intra-articular structures such as the medial meniscus of the knee and with the rotator cuff. In the US, for the year 2012, over 540,000 procedures for tears of the medial meniscus of the knee and; over 165,000 procedures for tears of the rotator cuff were performed. In systematic reviews and meta-analyses of MRI diagnostic findings for these types of lesions the sensitivity, specificity, positive predictive value, and negative predictive values were found to be 91.4%, 81.1%, 83.2%, and 90.1% for medial meniscal tears . AdditioSmall bore (needle arthroscopy) has been available for a number of years and appears to be well established in its efficacy. The results reported on the literature have demonstrated similar accuracy and complications to standard, larger sized arthroscopes – for knee, shoulder, and other joints -27.A newer and smaller bore arthroscope with improved optics and visualization, the VisionScope System (VSI), was recently introduced which enables office-based pre-operative and post-operative arthroscopic imaging and diagnostics. These types of procedures include: diagnostics of joints such as the knee, shoulder, ankle, wrist, hip and elbow. The key component of this system is a proprietary 1.4 mm diameter semi-rigid/fiber-lens endoscope system, which is small enough to fit through an arthrocentesis needle. The VSI technique is described in Appendix 1.The VSI provides a minimally invasive option with only one entry portal. It does not require general anesthesia, irrigation fluid, and is disposable. The advantages of the VSI are that patients gain a diagnosis during their first office visit and can eliminate the need for a diagnostic MRI. Overall, it can create a “better” experience for the patient, with fewer office visits, a timelier and definitive diagnosis and treatment plan, and lower health care costs.To date no one had examined the economic effect of more widespread use of office based needle arthroscopy products. The purpose of this analysis is to examine the overall costs  to the US health care system of a needle arthroscope such as the VSI compared to current diagnostic and treatment modalities offered (defined as standard of care or SOC) . The hypData sources:• National Survey Ambulatory Surgery 2006 . This su• Sensitivity and specificity estimates for shoulder and knee arthroscopy were derived from systematic reviews and meta-analyses as described above ,2. The a• Costs for diagnostic and treatment paradigms using current methods and for the VSI are Medicare’s national average actual reimbursement rates for each procedure (unless otherwise specified). Costs for complications or unnecessary care associated with either method were estimated using either current national average Current Procedural Terminology (CPT) [physician work component], Ambulatory Payment Classification (APC) [hospital outpatient procedure] or Diagnostic Related Group (DRG) [hospital inpatient procedure] associated with treating complications or unnecessary care. Costs were calculated for both MRI and VSI positive and negative findings.• Estimates for complications  from each diagnostic method were derived from the literature and are outlined below along with their sources.• Direct experience in using the VSI system.Direct cost calculation:• The following diagnostic and treatment paradigms were used for both current (MRI) and VSI [all assumed to be performed in either the physician office or outpatient settings]: 836.0 ; 840.4 . The reasons for using these particular diagnoses were that they represent a large portion of all US therapeutic arthroscopic knee (32%)  and shou• For the knee:SOC: Orthopedic consult  + Xray (CPT 73560 – radiologic exam 1 or 2 views) + MRI  + MRI  + Arthrocentesis (CPT 20610 – aspiration or injection of a major joint @ 10% of time ) + HospiVSI: Orthopedic consult  + Xray (CPT 73560 – radiologic exam 1 or 2 views) + VSI (CPT 29870 nonfacility) + Hospital Outpatient Arthroscopy [assumes a chondroplasty was performed when a patient was diagnosed accurately for pathology [i.e. a TP] – CPT 29877] + CPT 01440 (anesthesia @ 45 minutes) + Follow up orthopedic consult (if VSI is positive) (CPT 99213 – E & M existing patient).• For the shoulder:SOC: Orthopedic consult  + MRI  + MRI  + Arthrocentesis (CPT 20610 – aspiration or injection of a major joint @ 8% of time ) + HospiVSI: Orthopedic consult (using CPT 99203 – E & M) + VSI (CPT 29805) + Hospital Outpatient Arthroscopy [CPT 29827 – arthroscopy with rotator existing patient) cuff repair] + CPT 01630 (anesthesia @ 90 minutes) + Follow up orthopedic consult (if VSI is positive) (CPT 99213 – E & M).• The costs for each of the above services/procedures are (2013 Medicare reimbursement data) (Table 1) Overlay of the incidence and costs for complications associated with each procedure above and treated in the appropriate care setting. The complications evaluated were those seen with standard arthroscopy. The complication rates used for knee arthroscopy were derived from a recent article 2011) appearing in the Journal of Bone and Joint Surgery  (Table 2011 appea2) False positive results on MRI examination were assumed to be treated via a surgical arthroscopic procedure. False positive results were assumed not to be treated upon VSI examination.3) False negative results on MRI were assumed to be treated first via physical therapy [PT]  True positives and FPs on MRI were assumed to undergo PT post surgical arthroscopy procedure and; FN crossover (FN CO) patients who underwent surgery were also assumed to undergo PT. True positive and FN patients with VSI were assumed to undergo PT post surgical arthroscopy. The same assumptions were made for VSI regarding number of PT sessions.Based on the sensitivity, specificity, positive and negative predictive values obtained from the literature  it was fFor medial meniscal tears, the overall cost savings per patient using VSI was $155  and the overall savings to the health care system equated to $151 million   and the overall savings to the health care system was $59 million   of MRIs that result in FN findings – which also can result in care that may not be needed as a first course of action . This analysis examined the issues of FP and FN MRI findings on the potential downstream care associated with MRI findings and found that the excess costs in unnecessary care (from MRI assessment) approached $210 million. False positive MRI findings expose patients to potentially unnecessary arthroscopic surgeries and their concomitant risks and; since patients are also misdiagnosed with MRI as FN (not having a lesion when in fact they do) – undergo more care than may be necessary.Another potential positive outcome of using a VSI like technology, not discussed above, is a potential shortening of the patient’s diagnostic odyssey. With such a system the patient is awake and can view and review their pathology actively with the physician. This also engages the patient in the course of diagnosis and potential treatment and; may reduce any patient anxiety that results from not knowing.The use of in-office arthroscopy may also assist the physician in their preparation (based on better and more accurate information) for surgical intervention (when needed). There is likely a benefit of being better prepared as; the clinician can plan and prepare for the appropriate surgical intervention. An example of this is allograft tissue which must be procured ahead of a surgical procedure; the use of which cannot be determined inter-operatively. While not quantified above, this may also shorten the procedure time, outcome, and costs of the therapeutic procedure.The issue of unnecessary and inefficient use of services in healthcare is a major concern for policy makers and payers . Use of The following limitations of the above analysis should be taken into account:• It assumes the most conservative treatment when a FP result was treated under SOC with knee procedures (i.e. meniscectomy versus repair). This may have underestimated the complication rates and costs reported on above with SOC as; more aggressive treatment may have been undertaken with these FP findings.• It assumes that false positive MRI results always end up as a surgical arthroscopy procedure. This may not always be the case. However, in pathology that appears positive under MRI and is difficult to interpret as in the pathology described herein , surgical arthroscopy is commonly performed. This in turn may have overestimated the actual costs of the MRI paradigm. Since MRI is used in conjunction with a physical exam, especially in complex injuries like those described above, surgical arthroscopy may be lower than what is evaluated on in this paper. However, it also should be noted that MRI diagnosis of meniscal tears, appears to be more accurate (using fitted Receiver Operating Characteristic [ROC] curves) versus physical examination. Thus the combination of the two  may not necessarily be more accurate than MRI alone .• The results are likely conservative for cost savings with VSI than what would be found in the community setting. In community settings the sensitivities and specificities of MRI findings are less accurate -6 than w• It assumes that false positive MRI results, upon a VSI finding were not treated. This is not always the case. Although unlikely, VSI may also result in a false positive finding – resulting in a surgical arthroscopy procedure. This may have underestimated the actual costs under the VSI diagnostic/treatment paradigm.• It focuses on difficult to diagnose conditions with MRI (i.e. intra-articular pathology) where a product such as VSI would likely have the most clinical utility. This is only a part (~30%) of the annual number of surgical arthroscopic procedures performed in the US. If the VSI diagnostic procedure were performed prior to other deep seated pathology in the knee and shoulder  additional and significant savings would be realized. It was the intention of this analysis to determine if any savings could be realized in common procedures.• Since no “good” data exist in the literature on the complication rates seen with small needle/single access site arthroscopy, the complication rate assumed in this analysis with the VSI procedure was an estimate based on ½ of what the complication rate would be with arthroscopy . In reports of case series on small needle arthroscopy, none of the complication rates noted above were seen . The onl• The use of a full course of PT  was assumed to be 85% in the FN, FN CO, TP, and FP SOC patients and; at 85% in the TP and FN VSI patients. The assumption was that since an orthopedist prescribed the PT, it was closely adhered to ,42. Howe• This evaluation and the safety and efficacy of VSI does not include patients who may present with acute hemarthrosis.• It assumes Medicare savings only. Since private pay in the US (e.g. BCBS) commonly pays 15-20% higher than Medicare and most patients who are evaluated for meniscal and rotator cuff damage are <65 years of age, the cost savings to the US health care system may be higher.• The analysis assumes 100% sensitivity and specificity of small bore arthroscopy to traditional arthroscopy. This may not be the case. Additionally, traditional arthroscopy is not perfect in its assessment of pathology.• For patients who are highly likely to have negative pathology, the preference might be for a non-invasive test such as an MRI versus VSI. Thus the overall costs savings using VSI versus MRI might be mitigated due to this.Utilization of the VSI system can reduce costs. The cost of a VSI diagnostic and treatment paradigm is less than a similar MRI paradigm on a per patient basis for both shoulder and knee pathology (by $138-$155 respectively) and; many arthroscopies for FPs are eliminated along with their concomitant risks. These cost savings may translate to other countries that perform arthroscopy procedures in similar settings .The procedure is an in-office diagnostic technique performed in a clinical exam room. The patient is brought into an exam room with their legs hanging over the table and lying supine with their hands on their stomach. The surgeon drapes the knee with sterile drapes and uses Betadine to clean the area. The joint is then injected with 5–10 ccs of Lidocaine to use as a local anesthetic. Once the area is numb, a sharp trocar is used to insert the cannula into the joint to an initial depth of 45 mm parallel to the tibial midline and flush with the surface of the proximal tibia. Once inside the joint, 1.44 mm diameter camera is inserted into the cannula. A diagnostic arthroscopy is performed. During the procedure, 1 cc increments of sterile saline are injected into the joint to clear the view. Patients are able to see real time diagnostic images during their procedure.The patient is brought into an exam room with their legs hanging over the table and the patient-sitting upright on the exam table. The surgeon drapes the shoulder with sterile drapes and uses Betadine to clean the area. A 22–25 gauge needle with a 10 cc syringe is used to administer analgesia. Then 1–2 ccs of Lidocaine is injected into the joint and 8–9 ccs is fanned out in the capsule and soft tissue around the insertion point. Once the area is numb, a sharp trocar is used to insert the cannula into the joint about 1.5 cm below the lateral corner of the acromion  through a transcuff portal. Once inside the joint, 1.44 mm diameter camera is inserted into the cannula. A diagnostic arthroscopy is performed.Jeff Voigt works as a reimbursement consultant for Visionscope Technologies, an office based arthroscopy technology mentioned in the manuscript.Michal Mosier, PhD has not competing interests.Bryan Huber, MD is user of the Visionscope arthroscopy technology.JV, MM, BH developed the hypothesis and laid out the methodology for testing the hypothesis. JV and BH developed the first draft of the manuscript. MM provided the appropriate statistical analysis. JV performed the literature search for relevant articles. MM extensively reviewed the first draft and made edits. MM further reviewed the statistics and ensured the integrity of the data. JV, MM, BH read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/14/203/prepubSensitivity, specificity, positive predictive value and negative predictive values.Click here for fileCost analysis SOC versus VSI – Medial meniscal diagnosis, therapy and surgery.Click here for fileCost analysis SOC versus VSI – rotator cuff diagnosis, therapy, and surgery.Click here for file


Despite the large impact that NCDs are predicted to have, particularly in developing countries, estimates of disease burden are sparse and inconsistent. This systematic review transparently estimates prevalence of type 2 diabetes mellitus in Southern Asia, its association with urbanization and provides insight into the policy challenges facing the region.Diabetes mellitus is one of the diseases considered to be the main constituents of the global non–based studies providing estimates of diabetes prevalence in the Southern Asia region. Studies using WHO diagnostic criteria of fasting plasma glucose (FPG) ≥7.0mmol/L and/or 2h–plasma glucose (2hPG) ≥11.1mmol/L were included. Data from eligible studies was extracted into bubble graphs, and trend lines were applied to UNPD figures to estimate age–specific prevalence in the regional population. Estimates specific to sex, area of residency, and diagnostic method were compared and trends analysed.The databases Medline and PubMed were searched for population–specific prevalence estimates were extracted from 39 studies. Diabetes prevalence was estimated to be 7.47% for 2005 and 7.60% for 2010. Prevalence was strongly associated with increased age, male gender and urban residency (P < 0.001).A total of 151 ageDiabetes prevalence in Southern Asia is high and predicted to increase in the future as life expectancy rises and the region continues to urbanise. Countries in this region need to improve NCD surveillance and monitoring so policies can be informed with the best evidence. Programs for prevention need to be put in place, and health system capacity and access needs to be assessed and increased to deal with the predicted rise in NCD prevalence. NCDs are the leading causes of death and disability worldwide [–thirds of all deaths for that year [–thirds of new NCD cases and increase the risk of exacerbations in those who already have these diseases [–income countries – a disproportionate NCD burden is borne by developing countries. Over 80% of diabetes and cardiovascular deaths worldwide occur in low– and middle–income countries (LMICs), and many of the risk factors for these NCDs are associated with the country development process through globalisation and urbanisation [In recent years the issue of nonorldwide . It was hat year . In addihat year . Type 2 hat year ,4. Imporhat year . Shared diseases . These rnisation . The pre–communicable diseases are more likely to affect people who are socioeconomically disadvantaged, furthering health inequalities [–term care that NCDs require and the high cost of health care in many developing countries have major impacts on household income, potentially leading to vicious cycles of poverty and illness [Nonualities . This caualities . The higualities ,7. In adualities . These dualities ,8. On in illness . The ove illness .–Level Meeting on NCDs in 2011 led the way for an international response, providing guidance on how to integrate NCD prevention and control across sectors and at all levels of government [–burden countries have shown an increased capacity in recent years [–sectoral responses – may take several years to implement, particularly in the LMICs that bear the brunt of the global NCD burden. Meanwhile it is essential that these regions have reliable estimates of NCD burden to inform policy decisions with relevant evidence and help set appropriate health care and research priorities [–to–date estimates of NCD burden allow monitoring of the diseases as well as evaluation of current policies, and are vital tools for planning policies and interventions to tackle the global NCD pandemic. This paper will attempt to address part of this need by carrying out a systematic literature review to estimate the prevalence of type 2 DM in Southern Asia.Despite the serious implications of the global NCD burden, it is only recently that determined policy action has been seen. The UN Highvernment . Furtheriorities . Transpa–middle income countries [ountries . The totountries . India wountries  and 2010ountries , and botBox 1Type 2 diabetes mellitus (DM) is a metabolic disease characterised by persistent hyperglycaemia and disturbed carbohydrate, protein, and fat metabolism. It may present with combinations of typical symptoms such as polydipsia (increased thirst), polyphagia (excessive hunger), polyuria (increased passage of urine), glycosuria (glucose in urine), lethargy, and weight loss. These symptoms reflect the underlying DM pathophysiology of peripheral insulin resistance combined with inadequate pancreatic insulin secretion . Many diC) for diagnostic purposes [Online Supplementary Document(Online Supplementary Document).Under World Health Organisation (WHO) guidelines, there are currently two main diagnostic tests used to diagnose DM – the Fasting Plasma Glucose (FPG) test and the Oral Glucose Tolerance Test (OGTT) . FPG invpurposes , the str–dense diet [–modifiable genetic susceptibility for South Asians means it is of even greater importance that policies address modifiable risk factors in order to tackle burgeoning diabetes prevalence in the region.The aetiology of type 2 DM is complex and likely involves a host of different factors, many of which are not fully understood. Common risk factors in the general population include older age, being overweight or obese, hypertension, leading an inactive lifestyle, smoking, and consuming an energynse diet ,15. Sevense diet ,17. Soutnse diet , and havnse diet . This noThis paper aims: (i) to contribute to the evidence base on type 2 diabetes mellitus in Southern Asia by systematically reviewing the relevant literature; (ii) to compare the prevalence estimates provided through different methods of diagnosing type 2 diabetes mellitus; (iii) to provide an assessment of the role of urbanization on the burden of Type 2 diabetes mellitus in the UN Southern Asia region based on the best available evidence; and (iv) to discuss the significance of the regional estimate and the implications it may have on public health policy.–based prevalence estimates of type 2 diabetes mellitus in Southern Asia was carried out. The online databases Medline and PubMed were searched, using the OVID search form for the Medline database and the default search engine for PubMed. Search terms for Medline and PubMed are given in A systematic literature search of published studies providing populationBox 2Inclusion criteria:– or community–based study in a Southern Asian country providing prevalence estimates of type 2 diabetes mellitus based on primary data.• Population• All published study designs and all languages.–1980 with ≥200 participants.• Studies post• Studies looking at adults (≥20 years).• Studies diagnosing diabetes through biochemical measurements.Exclusion criteria:• Studies investigating other forms of diabetes, such as gestational diabetes or diabetes insipidus.– or clinic–based studies.• Hospital–reported questionnaires or symptoms only.• Studies diagnosing diabetes through self• Study populations specifically predisposed to diabetes, such as relatives of known diabetics.• Studies investigating prevalence of complications in a diabetic cohort without commenting on actual prevalence of diabetes in area or community.Quality evaluation criteria:• Diabetes diagnosed through fasting plasma glucose (FPG) after ≥8 hours fasting, and/or oral glucose tolerance test (OGTT) two hours after ingestion of 75g anhydrous glucose or equivalent.• Appropriate diagnostic criteria for diabetes – most recent WHO recommendations of FPG ≥7.0mmol/L and/or 2hPG ≥11.1mmol/L for venous plasma, or equivalent for other sample types. Stated whether blood samples were venous or capillary, and whether whole blood or plasma was analysed.• Clearly defined population recruited through representative sampling methods.• Description of how known diabetics were accounted for.The literature search of online databases resulted in a total of 5653 studies: 1754 from Medline and 3899 from PubMed. After initial analysis of titles and abstracts, 402 studies were selected that matched inclusion and exclusion criteria. 51 duplicate studies were removed and full texts of the remaining 351 studies were further analysed and quality assessed. 39 studies were included in the final analysis, including 2 papers identified through reference lists of other assessed studies. A visual summary of the study selection process is presented in Online Supplementary Document(Online Supplementary Document). Studies for which full text was not available were requested through inter–library loans. Duplicate studies were identified through study locations and matching sample sizes, and were removed. In addition, the reference lists of the selected studies were examined for relevant papers not captured by the literature search. These new studies were subsequently evaluated and added to the spreadsheet.Titles and abstracts of all studies obtained through the database searches were evaluated. Inclusion and exclusion criteria were applied. Basic details of all studies such as title, authors, country, study year, year of publication, and sample size were extracted into an Excel spreadsheet for ease of full text evaluation. After initial extraction, full texts of the studies were analysed and assessed for quality criteria. Quality assessment information is presented in –specific sample size, mean age, and diabetes prevalence. Many studies looked at several different cohorts in various areas, often for purpose of comparison. These multiple cohorts were recorded separately so that individual sample characteristics could be differentiated. Three separate sheets were created for studies depending on their method of diagnosing new diabetes: one for studies that diagnosed diabetes on the basis of both FPG and OGTT results; one for studies using only FPG results; and one for studies using only OGTT results. These spreadsheets were the basis for prevalence estimation.Another Excel spreadsheet was created for eligible studies selected through full text analysis. All the above data was extracted in addition to data on method of diagnosis; diagnostic criteria; specific location of the study; whether the study described the surveyed area as urban, rural, mixed or none; age range of participants and mean age if provided; diabetes prevalence in sample; and sexTo allow for comparison between studies, all reported prevalence estimates were converted to prevalence/1000 population through the equation:Prevalence = Number of diabetes cases ×1000 / Sample size–specific prevalence estimates (per 1000 population) of all selected studies were used to create bubble graphs representing the data. If this information was missing for particular cohorts, it was calculated from the data that was available, as detailed in Online Supplementary Document(Online Supplementary Document). Several bubble graphs were created: for overall prevalence, sex–specific prevalence, urban/rural prevalence, and prevalence for specific diagnostic methods.During data modelling, the mean age, sample size, and age–squared (R2) values for these graphs and therefore accounted for the highest fraction of variance in the data. Statistical significance  of differences observed through any comparisons was derived directly from the model. The resulting equations for overall combined prevalence, total male prevalence and total female prevalence were applied to 2005 UNPD population estimates, the closest to the median study year of 2006 [In order to calculate population prevalence estimates for the region, trend lines with the power function were computed from the graphs to represent the relationship between age and prevalence for the selected data set. These were chosen because they had the highest r of 2006 . Prevale–specific prevalence estimates were represented individually if available. Of the 39 studies included in the analysis, 15 studies diagnosed diabetes using both FPG and OGTT methods, 20 solely using FPG, and 4 studies using OGTT only. Several studies looked at more than one cohort when estimating diabetes prevalence, often for purposes of comparison. A total of 57 cohorts were investigated by the 39 studies .The country with the largest number of studies, of all types, was by far India. It was also the only country for which suitable OGTT–specific prevalence were plotted from 57 cohorts. 65 individual points were available from FPG and OGTT combined studies, 77 from FPG–only studies, and 9 from OGTT–only studies . –54 age group had the highest proportion of the burden at 11.31%, and the 20–24 group had the lowest proportion of the burden at 4.64%. A total of 51.3% of the burden was seen in those aged 50 or more. The diabetes burden increases with age until the ages of 50 and 54, after which it decreases. This is due to the population age structure in 2005 –diabetes prevalence per 1000 population is shown to increase continuously with age.–79 age group is 336.08 per 1000, whereas female prevalence is 297.57 per 1000. –specific prevalence for all diagnostic methods. Sex– and age–specific prevalence data are presented in Online Supplementary Document(Online Supplementary Document).P < 0.001). These do not total the combined prevalence estimate of 65 848 000 cases (7.47%) since several studies did not provide enough data to calculate male and female age–specific prevalence, only enough to calculate combined sexes age–specific prevalence. To account for this incomplete data, the combined prevalence estimate was used as an envelope and a correction factor of 0.881 was applied to male and female prevalence estimates. Resultantly, the adjusted 2005 population prevalence estimates are 7.72% for males and 7.20% for females. –year age intervals.The crude population prevalence estimate for males in 2005 is 8.76% (39 622 000 cases), and for females is 8.18% (35 102 000 cases) (P < 0.001).  and Online Supplementary Document(Online Supplementary Document).32 out of the 39 selected studies (50 out of 57 cohorts) specifically defined their study population as residing in an urban area or a rural area. Incidentally, out of the reporting studies, 25 cohorts were specified as urban and 25 as rural. –only studies. 65 age–specific data points were used to calculate the FPG+OGTT trend line, 77 data points used to calculate the FPG–only trend line, but due to the small number of available OGTT studies only 9 age–specific data points were used in calculating the OGTT trend line. –only studies when applied to UNPD figures, as shown by –only studies result in a prevalence of 7.32%. The small number of OGTT–only studies predicted a population prevalence of 6.95%, as shown in –to–date transparent estimation of diabetes prevalence in the UN Southern Asia region, building upon previous studies looking at prevalence in comparable regions or in specific constituent countries [–based studies in addition to broader national population studies.This study provides the most upountries ,22,63,64–defined inclusion and quality criteria narrowed down 39 studies from an initial 5653 results. Search terms were specified, and quality assessment criteria for selected studies were provided in Appendices. Enough studies were captured for estimation of overall diabetes prevalence, male and female prevalence, and urban and rural prevalence for each sex. Study cohort sites had a wide geographic distribution within the countries that were analysed, as shown in –only studies captured in the search meant that all recognised diagnostic methods could not be fully compared in terms of prevalence estimates, and so this objective was only partially met.A transparent systematic literature review of two online databases was carried out. PreBy applying this study’s prevalence estimates to UNPD population figures , the ove–54 age group for both sexes, and within this age group there was a 9.35% difference between estimated male and female prevalence. Prevalence/1000 population continued to increase with age for both sexes but due to the population age structure the burden attributed to older age groups was progressively smaller after the ages of 50–54. After correction for missing data, the 2005 population prevalence estimate for males was 7.72%, and for females was 7.20%. This translates into an estimated 34 915 000 male and 30 933 000 female diabetics in Southern Asia in 2005.It was found that diabetes prevalence was consistently higher for males than for females. The burden was highest in the 50This study found that urban residency was strongly associated with higher diabetes prevalence for both sexes. The observed difference is noteworthy – past the age of 55 the urban prevalence was estimated to be more than twice the rural prevalence. Although males had higher prevalence than females in both urban and rural settings, the difference was noticeably smaller in urban cohorts than rural cohorts: a 6.03% difference between urban males and females, but a 16.74% difference between their rural counterparts. Higher rates of diabetes among urban residents may be explained through increases in physical inactivity and consumption of high sugar and fat diets – both strong risk factors for diabetes – that have become synonymous with urban lifestyles. Mohan suggested that diabetes rates in India are quickly escalating because of the rapid urbanisation that is sweeping the country . Convers–only and FPG+OGTT combined studies were identified to allow comparison between these two diagnostic methods. The small number of OGTT–only studies also provided interesting trends. Overall the differences between these methods appeared to be minimal. The higher prevalence estimates of FPG+OGTT compared to FPG–only were to be expected since the former used an additional diagnostic method. FPG–only studies estimated higher diabetes prevalence at younger ages (<52) and lower prevalence at older ages (>52) compared to OGTT–only. Combined FPG+OGTT prevalence estimates lay in between the FPG and OGTT estimates at both ends of the age spectrum. In addition, FPG–only studies estimated the highest burden proportion to be at a younger age – in the 45–49 age group – followed by a small decrease in the 50–54 age group. FPG+OGTT studies and the limited number of OGTT–only studies found highest burden proportion in the 50–54 age group. These findings suggest that FPG may have greater sensitivity at younger ages, while OGTT may be more sensitive to diabetes in older age.Sufficient numbers of FPG–plots, and the resultant trend lines can be used to estimate the expected prevalence for any given age rather than just the specific age group means. Therefore, bubble graphs are preferable over weighted mean box–plots when considering a disease such as diabetes, for which the steady prevalence increase with age has previously been well established [2 values – specified on each graph for purposes of transparency – indicating that they were representative of the data and took into account a high degree of variance.This study’s prevalence estimates were primarily based on trend line equations obtained by plotting study size, mean age and prevalence estimates on bubble graphs. Bubble graphs accommodate gaps in data better than weighted mean boxablished . The tre–10.3% for the period 1995–2006[–East Asia[–East Asia in 2011 [–East Asia region. In addition, different studies often use widely varying methods for study selection and estimating prevalence, contributing to the observed inconsistencies. Nevertheless, a substantial body of evidence including this study indicate that the diabetes burden in this area of the world is large and growing.Several of this study’s findings are in line with previous estimations of diabetes burden in comparable regions. Estimates for 2000  and 20101995–2006. This stEast Asia, a geogr in 2011 . However–2013. However, suitable studies were only identified for the period 1992–2013. Not looking at studies prior to 1980 may have excluded viable studies, but older studies often used previous diabetes diagnostic criteria which underestimated prevalence. Most of the identified studies carried out prior to 1990 used the old 1980/1985 WHO criteria with the higher FPG cut–off of 7.8mmol/L for diabetes diagnosis. Including such studies in the analysis would distort the prevalence estimate because of the differing diabetes case definitions.This systematic review considered published studies from 1980–reported surveys were also excluded. Several studies found low knowledge of diabetes in Southern Asia, even in diabetic patients [Several recent studies did not detail the diagnostic criteria used to identify diabetics, despite explaining their method of diagnosis. These studies were excluded to ensure that the case definition of diabetes in the selected studies remained constant. Other studies did not make it clear whether the biochemical samples they used were venous or capillary, or whether whole blood or plasma was analysed. WHO provides diagnostic guidelines for each of these sample types ,12, but patients ,67, and –onset diabetes mellitus” and “childhood–onset diabetes mellitus”. In addition, it has been noted that while type 1 DM rarely causes death by ketoacidosis in developed countries, sufferers in many developing countries may unfortunately have a radically shortened lifespan due to limited insulin availability which is crucial for type 1 DM management [Studies investigating other forms of diabetes such as gestational diabetes or diabetes insipidus were excluded. These studies were easy to identify because of the specific nature of gestational diabetes, and the different clinical presentation of diabetes insipidus to diabetes mellitus (DM). However, a major limitation of this paper was the inadequate ability to distinguish between type 1 DM and type 2 DM. Many risk factors for type 2 DM, such as diet and physical inactivity, are modifiable and therefore may be amenable to policy intervention, but there are no known preventative measures against type 1 DM. Most analysed studies did not further investigate identified diabetics to exclude type 1 DM, meaning that this study’s findings may be an overestimation of the prevalence of type 2 DM. However, in the adult age range that was being investigated, type 2 DM is more common than type 1 DM, hence their previous names of “adultnagement . This ma–English studies. This may have resulted in exclusion of viable non–English studies. However, even without setting language limits, only a very small number of non–English studies were identified by the literature search. This might be due to the status of English as an official language in several ex–colonial countries in the Southern Asia region, most notably India and Pakistan.Only published studies were reviewed. The resulting analysis may have suffered from publication bias as the reviewed papers may only show those studies in which significant results were found. Publication bias may have prevented studies that did not show significant diabetes prevalence from being published in the first place, preventing these studies from being captured in this review. While no limits were set on language, time constraints also prevented translation and therefore inclusion of nonNo suitable studies were identified for three out of nine of the countries in the region – Afghanistan, Bhutan, and the Maldives. As mentioned, however, these are the least populous countries in the region, and combined only account for 1.34% of the regional adult population. Nevertheless it is a noteworthy limitation that no data was available for these countries when the estimated regional population prevalence took their populations into account as well. Another limitation arose when comparing urban and rural studies. Cohorts were classified as urban or rural on the basis of individual study descriptions. No standardised definitions of ‘urban’ or ‘rural’ were used, meaning there may be discrepancies between different studies on their cohort classification.–specific prevalence breakdowns, while others did not provide sample sizes for sex–specific prevalence or did not report mean age. This limited the number of cohorts that could be analysed for male and female age–specific prevalence. Where possible, sample sizes were calculated based on reported number of cases and corresponding prevalence figures. However, this study’s findings were limited by assumptions that had to be made to account for incomplete data. UNPD national age structures were applied where appropriate [–specific data may have been another source of imprecision. A hypothetical maximum age of 80 was used to calculate mean age for studies that provided no maximum age range. This assumption was made as this was the highest age used in reviewed studies that included a maximum age, and also because the minority of studies that looked at participants aged 80+ had very small sample sizes for those age groups. In addition, the 2005 UNPD population estimates for Southern Asia suggest that the 80+ age group accounts for only 0.58% of the population, so this was not considered a major limitation.Not all selected studies provided male and female sexropriate . This meWhile every effort was made to ensure accuracy and the use of systematic methods, human error may have resulted in accidental exclusion of relevant studies when inclusion and quality criteria were being applied. Having only one person review and evaluate studies is a potential limitation of this study design. Using several independent evaluators to select studies, with a suitable method for resolving disputes, may increase reliability of the study’s findings.–2013 Action Plan for the Prevention and Control of Noncommunicable Diseases highlighted that before prevention and control policies can be implemented, one of the first steps is to assess the burden of disease [–making on NCDs [–to–date estimations of burden are also important in evaluation of current policies, programs, and of health system capacity. A number of policies have shown promise – in 2003 India enacted The Cigarette and Other Tobacco Products Act which is considered to have effectively reduced the public’s exposure to tobacco smoke, through advertisement, and minors’ access to cigarettes [–changing nature of NCDs and the many challenges that governments of developing Southern Asian countries face when attempting to deal with them.Evidence on disease burden is essential for countries to plan and develop programs in response to the NCD pandemic. The WHO 2008 disease . Engelga on NCDs , and impgarettes . India agarettes . The aimgarettes . This isThe findings of this study suggest that future urbanisation and increased life expectancy will lead to a substantial rise in the burden of type 2 DM in the Southern Asia region. Commentators have noted that the process of population ageing currently being observed in developing countries is different to the demographic transition that occurred in developed countries several decades ago. In particular, the current demographic transition in developing countries has occurred on a faster scale than in developed countries, and without the associated improvements in living conditions, social provisions, and access to health care . This ha–level education and health promotion schemes should be put into place to improve awareness of the risk factors for diabetes and the other main NCDs. Diabetes has many lifestyle–modifiable risk factors, and by improving knowledge regarding these, the Southern Asian population can be empowered to pursue healthier lifestyle choices. Increased risk factor awareness and the resulting community empowerment have been seen to have a positive effect in the past. Mohan and colleagues reported that following such efforts, an Indian community was prompted to create a public park with their own funds which resulted in significant improvements in physical activity levels for local resident [Prevention efforts for diabetes can come in many forms, but there are several that may be especially relevant to Southern Asia. Before any successful prevention policies can be implemented it is important that knowledge and awareness regarding diabetes is improved in the general population. Many studies have shown that in Southern Asian populations, awareness of diabetes and its risk factors is poor ,72, evenresident .– and poly–unsaturated fats, and high consumption of refined carbohydrates, saturated fats and trans–fats have been identified as problematic dietary habits leading to insulin resistance in Southern Asian populations [–fat cooking oils such as ghee and vanaspati to poly–unsaturated alternatives [Departure from traditional dietary patterns and the uptake of diets high in saturated fats and heavily refined carbohydrates are believed to be important underlying factors in rising rates of obesity and diabetes in Southern Asia . In partulations . Policieulations . Focus srnatives .–income countries [–wide health education and training capacities may help fill human resource gaps across the region by taking advantage of economies of scale [The health sector has an important role to play in the management and treatment of NCDs. ountries . Howeverountries . NCDs unountries . The incof scale .–of–pocket medical costs are a major barrier for universal access to health care services in Southern Asia, and result in widening inequalities between rich and poor. In addition to increasing health care capacity, Southern Asian countries should aim to improve access to health care by implementing WHO universal coverage reforms [–sharing; efficiency savings from introducing Health Technologies Assessment (HTA); and simply increasing the priority given to health and thereby increasing governmental health expenditure.Even if health system capacities are expanded to deal with the increasing burden of NCDs, access to appropriate health care remains a major challenge across the Southern Asia region. Studies in several Southern Asian countries have found significant personal expenditure and substantial financial loss associated with paying for diabetes treatment, with the main costs being the direct expenses of investigation, treatment, and hospital admission ,77,78. T reforms . Successc as a diagnostic method [c measurements also presents new avenues for diabetes epidemiological research. If appropriate quality assurance measures are put in place, as per WHO recommendations, HbA1c presents a valuable method for investigating long term changes in glycaemic status in study subjects.Following the recent WHO addendum approving the use of HbA1–scale population estimates of NCDs becomes more commonplace, it is hoped authors carrying out community–based studies begin to employ common standards to allow effective utilisation of their work in burden of disease analyses.Studies calculating overall prevalence inadvertently calculate male and female prevalence as well, but as seen in this paper, in many cases these were not reported. Additionally many studies failed to report basic information such as mean age of sample, age group of sample, type of biochemical sample taken, or diagnostic criteria used to define diabetes. Access to this information would reduce the number of assumptions that have to be made for incomplete data, and additionally would allow for a more accurate estimate as far fewer studies would have to be excluded from analysis. As awareness of the need for largeDiabetes is one end of a spectrum of glycaemic states, and future studies could estimate the burden of different forms of prediabetes as well. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are diagnosed with FPG and OGTT respectively so many studies report their prevalence alongside diabetes. Regional estimation of the burden of both prediabetes as well as diabetes would allow for a more comprehensive analysis of the challenges these hyperglycaemic diseases pose.–risk populations: urban residents, and, as life expectancy increases, the growing number of elderly people as well.This study found that diabetes is strongly associated with urban residency in Southern Asia. As the region continues a process of rapid globalisation and urbanisation, it is important to maintain diabetes surveillance in both urban and rural cohorts. Urban migration and the increasing accessibility of inactive, sedentary lifestyles suggest that the diabetes burden will increase in the future. Projections for 2030 predict that several Southern Asian nations will continue to rank among the countries with the largest numbers of diabetic residents ,22. HoweThis systematic literature review found a high prevalence of type 2 DM in the Southern Asia region. Diabetes prevalence was associated with male gender, and strongly associated with older age and urban residency. On the basis of these findings this study also predicted that diabetes prevalence will continue to increase in the future as life expectancy in the region rises and countries continue to undergo processes of urbanisation. The findings of this study were consistent with several past studies, but dissimilar to the results of others. This highlights that inconsistent surveillance and conflicting estimations of burden are some of the many challenges faced by the Southern Asia region and its constituent countries in their effort to respond to the rising burden of NCDs.–to–date estimates of burden of disease are essential for planning of policies, target and priority setting, as well as monitoring and assessment of existing programs. However, greater standardisation and shared principles are needed across different studies so that strong, clear messages are given to policymakers. It is hoped that improved surveillance capabilities in Southern Asian countries will encourage common standards for prevalence estimation to be established.Accurate and up–sharing coupled with the long–term care needed for NCDs such as diabetes means that access to health care may be limited for a large proportion of people in the region.While current policies and programs on diabetes control have met with some success, the region faces numerous hurdles. Rising life expectancies coupled with ‘unhealthy’ ageing present a new set of challenges to those faced by developed countries several decades ago. Policies focusing on prevention have to deal with a population that largely has little awareness of diabetes and its risk factors, and is becoming increasingly accustomed to a sedentary lifestyle and unhealthy eating patterns. Health sectors also have their own set of issues – total health expenditure is low in many Southern Asian countries, there are significant human resource gaps, and already struggling health systems are predicted to be put under even greater strain as diabetes prevalence continues to increase. In addition, from an equity perspective, high costHowever, despite these numerous policy challenges and the projected increase in diabetes prevalence, slow progress is being made. NCDs are at the forefront of the international health agenda, several Southern Asian countries have greatly improved their NCD surveillance and monitoring capacities, and the numbers of studies estimating burden of type 2 diabetes mellitus appears to be increasing in recent years. Greater attention needs to be paid to this disease and its risk factors on national and regional levels in Southern Asia so that the growing burden of diabetes can be adequately addressed in the future.


PRO) measures (PROMs) are standard measures in the assessment of colorectal cancer (CRC) treatment, but the range and complexity of available PROMs may be hindering the synthesis of evidence. This systematic review aimed to: (i) summarize PROMs in studies of CRC surgery and (ii) categorize PRO content to inform the future development of an agreed minimum ‘core’ outcome set to be measured in all trials.Patient‐reported outcome , and most PROMs  were used in only one study. Detailed examination of the 50 available measures identified 917 items, which were categorized into 51 domains. The domains comprising the most items were ‘anxiety’ , ‘fatigue’  and ‘physical function’ . No domains were included in all PROMs.Fifty‐eight different PRO measurement and a wide variation in content assessed in the PROMs available for CRC. A core outcome set will improve PRO outcome measurement and reporting in CRC trials.There is major heterogeneity of  The measurement of patient‐reported outcomes (PROs) has become standard in the assessment of colorectal cancer (CRC) treatments, and their use is recommended by funding and regulatory agencies Trials may use different PROMs A proposed solution to these issues are ‘core outcome sets’. Core outcomes are the minimum set of outcomes that patients and professionals agree should be measured in all trials of a certain condition A systematic review of prospective CRC surgical studies measuring PROs was undertaken to: (i) summarize PRO measurement in CRC surgical studies, and (ii) examine each PROM in detail and categorize analogous concepts into domains to inform the future development of a core outcome set.reference manager 12  and the duplicates removed.This systematic review adhered to a predefined protocol (available on request from the authors). Validated terms relating to ‘surgery’, ‘colorectal cancer’ and ‘prospective studies’ Table  were useTitles and abstracts of identified publications were screened by one researcher. If there was uncertainty about the eligibility of a publication the full paper was also accessed. Articles were included if they were original research papers reporting PROs of CRC surgery , with or without neoadjuvant or adjuvant therapies, or systematic reviews of such publications. PROs were defined as end‐points provided by patients themselves and not interpreted by observers. Studies of nonbiomedical interventions , palliative treatments that did not include a surgical component , screening studies, treatment of colorectal metastases and molecular and genetic prognostic studies were all excluded. Studies of more than one cancer site or of mixed benign and malignant disease were included provided the data for CRC patients was presented separately from that of the other diseases.n = 25) and any disagreements were discussed and resolved with the senior author (JMB).Data extraction included: participant demographics ; treatment received ; treatment intent ; the study design ; the PRO questionnaire used; and the individual items included in each questionnaire. When the individual questionnaires were not available in publications, internet searches and direct contact with authors were used to obtain the information. All data were entered into a Microsoft Access  database to facilitate data management and analyses. The data extraction was checked by a second reviewer (ROF) for a sample of included articles  generic , (ii) cancer specific , (iii) CRC specific (for use in CRC patients), (iv) symptom specific , or (v) Individual items from all questionnaires were extracted and formed into a long‐list before categorization into health domains by two researchers (RNW and JR). Both were kept masked as to which PRO questionnaire the items were derived from. Two patient representatives (JEJ and GS) and one consultant colorectal surgeon (AMP) subsequently checked this process. Discrepancies were discussed and resolved with the senior author (JMB).Categorization was summarized using descriptive statistics to explore the distribution of items and PROMs between domains. The number of items included in each domain was counted, as were the number of PROMs from which they were sourced. The contribution of each source PROM was demonstrated by calculating the median number and range of items included from the measures.A total of 5644 titles and abstracts were identified, of which 2127 were duplicates. The remaining 3517 were screened and 29 original research articles included. In addition to this, six systematic reviews of PROs in CRC surgery identified a further 72 original research articles  were not categorized.Fifty‐eight different PRO questionnaires were identified and these were reported 184 times in the included publications Table . There wn = 40, 69.0%). The most frequently reported were the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ‐C30 , the EORTC QLQ‐CR38  and the Medical Outcome Study Short Form‐36 . The median number of items per PROM was 14, ranging from one  to 65 (the Profile of Mood States). Some 159 scales were evident, and most PROMs  included a total score.Most questionnaires were reported only once (n = 6) or lack of an English language translation (n = 2). The 50 questionnaires comprised some 917 individual items, and were categorized into 51 domains as described above , ‘fatigue’  and ‘physical function’ . The disease‐specific domains comprising most items were ‘faecal incontinence’  and ‘stoma problems’ . Most domains  contained 10 or more items.Fifty (86.2%) full questionnaires were available. Reasons for unavailability were inability to obtain the questionnaires from authors or web searches  were measured by less than a quarter of PROMs, highlighting further heterogeneity. There were two domains with a high median number of items included per PROM: ‘stoma problems’, which contained 52 items from only five PROMs (median seven items per PROM) and ‘satisfaction with care’, which featured six items from just one PROM. This may reflect specialization of PROMs, with some measures focusing on very specific concepts.There was little evidence of consistency between PROMs. No domains were measured in all the PROMs. The two domains that were best represented were ‘anxiety’ and ‘social function’, each measured by 22 (44%) PROMs. Otherwise, most domains  were only ever used once, and even the most common (EORTC QLQ‐C30) was measured in less than half of the studies. PROMs also varied greatly in terms of their content, with some as simple as a single item while others included up to 65. Most (52%) PROMs were not designed to be specific to CRC surgery or symptoms thereof, and although this may bring benefits in terms of comparison between diseases they may not be sensitive enough to issues that are of specific importance to patients with CRC. Over 900 individual questionnaire items were evident from 50 PROMs, and through a rigorous process, these were categorized into 51 ‘health domains’. This demonstrated a further lack of consistency, with no domains being measured in all the PROMs, and most health domains only being measured by less than a quarter of PROMs. All of this highlights potentially major questions for evidence synthesis and clinical interpretation of results in studies of CRC surgery, and demonstrates the need for a standardized core outcome set.This systematic review aimed to summarize PRO measurement in current CRC surgical studies and categorize PRO items into analogous concepts to inform the development of a core outcome set. There was evidence of significant heterogeneity of PRO measurement in the included studies. Fifty‐eight different PROMs were used to assess patient experience of colorectal surgery. Most  group In conclusion, this systematic review of CRC surgery demonstrated significant heterogeneity of PRO measurement that may hinder comparisons between studies, limit meta‐analysis and allow outcome reporting bias. A long‐list of patient reported ‘health domains’ was generated using robust methodology to inform the development of a core outcome set.Table S1. Full categorization of patient reported outcome items.Click here for additional data file.


Alzheimer disease (AD) pathogenesis. There is evidence for the contribution of environmental factors, whose effect may be mediated by epigenetic mechanisms. Epigenetics involves the regulation of gene expression independently of DNA sequence and these epigenetic changes are influenced by age and environmental factors, with DNA methylation being one of the best characterized epigenetic mechanisms. The human genome is predominantly methylated on CpG motifs, which results in gene silencing; however methylation within the body of the gene may mark active transcription. There is evidence suggesting an involvement of environmental factors in the pathogenesis of Alzheimer's disease (AD), which prompted our study examining DNA methylation in this disorder.Genetic factors do not seem to account fully for DNA methylation in sporadic and familial AD cases in the entorhinal cortex that exhibits substantial pathology and the cerebellum, which is relatively spared.Using immunohistochemistry with 5‐methylcytosine/5‐hydroxymethylcytosine antibodies we studied, in comparison with age matched controls, mC) and 5‐hydroxymethylcytosine (5hmC) was evident in all cases studied. We did not detect any significant change in the levels of nuclear staining in the AD samples compared to neurologically normal controls. In the entorhinal cortex we also examined global DNA methylation and hydroxymethylation using an enzyme‐linked immunosorbent assay (ELISA).Neuronal nuclear labelling with 5‐methylcytosine (5AD and control cases in global levels of 5mC and 5hmC in the entorhinal cortex using immunohistochemistry and enzyme‐linked immunosorbent assays.No significant differences were found between  Epigenetics is described as changes in gene expression, which do not involve alterations in the DNA sequence CLU, PICALM, BIN1, CR1, ABCA7, MS4A, EPHA1, CD33, CD2AP), which are associated with increased disease risk TREM2 variants with large effects have been recognized  and post mortem delay . Using either the 5mC or 5hmC antibody, staining intensity of the neuronal nuclei showed variation that was evident in both the control and AD cases . 5mC and 5hmC immunohistochemistry staining of the cerebellum, a region relatively unaffected in AD, showed comparable staining patterns in both the neurologically normal controls and AD cases . The variation in staining intensity was evident in all cell types and all neuronal and all glial nuclei were labelled, as no nuclei were observed which contained only the haematoxylin counterstain.For the immunohistochemical analysis of 5mC and 5hmC we examined 6 AD and 6 neurologically normal control cases from the cohort listed in Table Figure S1). Neuronal nuclei were distinguished from glial nuclei by virtue of their larger size. This was also clarified using double immunohistochemical staining with GFAP . Based on the staining intensity, one hundred neuronal nuclei from the entorhinal cortex were assessed. No significant differences were detected between the AD and control cases in the degree of either the 5mC‐ or 5hmC‐labelled neuronal nuclei  ] and post mortem delay . The quantification of the amount of 5mC and 5hmC showed no significant difference between the control and AD cases (P = 0.9960 and 0.6090 respectively)  and 5hmC (P = 0.8255) where seen when the cases were split according to the underlying pathology , while the trend was also positive in the normal control cases, but this was not significant  .Pearson correlation tests were used to determine whether any of the case variables had an effect on the levels of 5mC or 5hmC. No significant correlation was found between the levels of 5mC or 5hmC and the age at death, Braak and Braak tau stages, and total Aβ plaque load . No significant difference was observed between the degree of labelling between AD and control cases in the cohort of cases used in this study.et al., which showed increased DNA methylation not only in late onset AD, but also in the preclinical subset of cases We also determined global DNA methylation using an enzyme‐linked immunosorbent assay and observed no significant differences between AD and control cases. The neuropathological examination showed that some of the clinically normal cases had AD associated pathology, amyloid plaques and neurofibrillary tangles in the brain . These cases were separated from the control group and the data were reanalysed comparing the clinically and pathologically normal control group with both the ‘preclinical’ and the patent AD cohorts. No significant difference was detected in comparison with control, in contrast to the report by Bradley‐Whitman and Lovell et al. and Coppieters et al. [Demethylation of 5mC in DNA is mediated by TET‐catalysed oxidation to 5hmC that, in addition of being an intermediate in the demethylation pathway, has also regulatory functions s et al. , 21.et al., who also found that the relation between DNA modifications and post mortem delay is not significant Using Pearson correlation analysis, we observed no significant effects between DNA modifications and case variables . This is in agreement with the observations of Coppieters et al. et al. found bidirectional changes with about the same number of hypermethylation as hypomethylation sites Our observation that global DNA methylation is not significantly different in the entorhinal cortex of AD cases from controls is consistent with the finding of Condliffe et al. used 5mC immunocytochemistry and reported a very severe reduction of this epigenetic mark in the AD entorhinal cortex [et al., who also detected reduced 5hmC levels in the cerebellum that is relatively unaffected in AD Table S2).In contrast, Mastroeni l cortex , 17. TheThe reason for the differences in the reported DNA methylation in AD is not clear. Different brain regions were studied in the various works and there is evidence that methylated/hydroxymethylated DNA levels vary among brain regions , 29, 30.The limitation of the global DNA methylation approach should be kept in mind. Site‐specific differential DNA methylation has been already shown in AD and might have an important bearing on disease pathology. Due to the heterogeneous cellular composition of the brain, cell‐type specific investigations are of paramount importance. Further studies are needed in which use is made of current technologies, including genome‐wide analysis of specific cell types, to appreciate the involvement of DNA methylation in AD pathology.RB initiated the study. TL, NV and TR selected the cases and undertook the pathological analysis; PG and AL ran the ELISA experiments. TL and RB wrote the paper and all authors were involved in editing the manuscript.Figure S1. 5‐methylcytosine immunohistochemical staining demonstrating the three levels of neuronal nuclei staining intensity; weak, medium and strong. Benchmark values for each of these intensities were established through collective review of stained specimens and arrival at consensus.Figure S2. 5‐hydroxymethylcytosine immunohistochemistry in an AD (case 18) and normal control (case 1). Demonstrating 5hmC staining in the entorhinal cortex of AD cases and normal controls.Figure S3. 5‐Methylcytosine (green) and GFAP (red) double immunohistochemical staining in the entorhinal cortex. The majority of nuclei stained with the 5‐methylcytosine antibody are not labelled with GFAP antibody. Arrows show astrocytes that are both methylcytosine and GFAP positive. Higher magnification is shown in the inserts.Table S1. Pearson correlation analysis to determine whether case variables correlated with the levels of 5mC and 5hmC as measured by ELISA. No significance was found between age at death, Braak and Braak tau staging and Aβ load in comparison with either 5mC and 5hmC levels.Table S2. Summary of recent findings on DNA methylation in the brain in AD. *In AD cases accelerated ageing‐related changes in 2 genes from 50 determined; ** Age‐dependent epigenetic drift is more pronounced in AD than in control cases. IHC, immunohistochemistry.  hypermethylation in AD;  hypomethylation in AD; ‘0’ no significant difference between controls and AD cases.Click here for additional data file.


Both active and passive forest restoration schemes are used in degraded landscapes across the world to enhance biodiversity and ecosystem service provision. Restoration is increasingly also being implemented in biodiversity offset schemes as compensation for loss of natural habitat to anthropogenic development. This has raised concerns about the value of replacing old‐growth forest with plantations, motivating research on biodiversity recovery as forest stands age. Functional diversity is now advocated as a key metric for restoration success, yet it has received little analytical attention to date. We conducted a meta‐analysis of 90 studies that measured differences in species richness for functional groups of fungi, lichens, and beetles between old‐growth control and planted or secondary treatment forests in temperate, boreal, and Mediterranean regions. We identified functional‐group–specific relationships in the response of species richness to stand age after forest disturbance. Ectomycorrhizal fungi averaged 90 years for recovery to old‐growth values (between 45 years and unrecoverable at 95% prediction limits), and epiphytic lichens took 180 years to reach 90% of old‐growth values . Non‐saproxylic beetle richness, in contrast, decreased as stand age of broadleaved forests increased. The slow recovery by some functional groups essential to ecosystem functioning makes old‐growth forest an effectively irreplaceable biodiversity resource that should be exempt from biodiversity offsetting initiatives. The world's forests contain over 80% of global terrestrial biodiversity  of species richness was calculated between secondary forest (treatment group) and old‐growth forest (control group):(x¯2) is the mean species richness of treatment forest stands and (x¯1) is the mean species richness of old‐growth stands. The lnR describes the proportional difference in species richness between control and treatment groups. The natural log transformation of the response ratio both linearizes the metric, treating deviations in the denominator and the numerator as equal, and normalizes its otherwise skewed distribution , indicating no evidence of publication bias.All statistical analyses and calculations were performed in R (version3.1.1) (R Core Team 10 relationships and stand age to test for possible nonlinear biodiversity recovery with stand age. To account for possible pseudoreplication from multiple biodiversity comparisons (studies) per observational chronosequence, each model included chronosequence as a random factor.To quantify how the species richness of different functional groups varies with stand age, we constructed linear mixed models containing an interaction between stand age and functional group. Latitude and transition categories, which are consistently reported in the literature, were added to the model. Transitions included clearcut to planted, clearcut to regenerated, fire to planted, and fire to regenerated. Treatment forest stands were either managed or unmanaged, where managed forests were secondary forests from which many trees had been removed . We included quadratic or logMeta‐analyses may weight study‐wise effect sizes to improve precision of the estimate of overall mean effect and the power of tests  in order to interpret differences among functional groups and their interaction with stand age . These provided 90 separate biodiversity comparisons, hereafter referred to as studies  and log10 stand age , their interaction  Fig. . The besWe found functional‐group–specific relationships between species richness and stand age following forest disturbance. Lichen, ectomycorrhizal fungi, and saproxylic beetle richness was much lower in early successional or young planted forest than undisturbed old‐growth forest Fig. . RecoverThe increase in lichen richness with stand age is likely attributable to the combined effects of time, which favored colonization by dispersal‐limited species, and changes in substrate conditions associated with tree ageing   in which old‐growth was compared with planted or secondary forests in a statistically robust way. For some functional groups, this led to small sample sizes and low precision in lnues Fig. . The smaues Fig. , and theThe primary goal of biodiversity offsetting is to achieve no net loss of biodiversity. Our results show that through restoration offsetting, this goal is unachievable within a reasonable time frame. Functional groups in secondary forest require over a century for lichens and almost a century for ectomycorrhizal fungi to recover species richness values equivalent to old‐growth forest Fig. . The sloOur results support the findings of Curran et al. , who alsThese results support the value of protecting old‐growth forest through reserve creation, set‐aside of overmature stands for biodiversity conservation, and implementation of schemes that extend rotation‐length of secondary forests within production forest landscapes. Examples of the latter include woodland key habitats (WKHs) and green tree retention (GTR) practices in Fennoscandia and the creation of temporary “ageing islands” in French high forests , list of publications included in the meta‐analysis and the geographic distribution of their study , a funnel plot (Appendix S4), and the justification for presenting an unweighted regression (Appendix S5) are available online. The authors are solely responsible for the content and functionality of these materials. Queries  should be directed to the corresponding author.Click here for additional data file.