Accurate detection of copy number aberrations in FFPE samples using the mFAST-SeqS approach.

BACKGROUND: Shallow whole genome sequencing (Shallow-seq) is used to determine the copy number aberrations (CNA) in tissue samples and circulating tumor DNA. However, costs of NGS and challenges of small biopsies ask for an alternative to the untargeted NGS approaches. The mFAST-SeqS approach, relying on LINE-1 repeat amplification, showed a good correlation with Shallow-seq to detect CNA in blood samples. In the present study, we evaluated whether mFAST-SeqS is suitable to assess CNA in small formalin-fixed paraffin-embedded (FFPE) tissue specimens, using vulva and anal HPV-related lesions. METHODS: Seventy-two FFPE samples, including 36 control samples (19 vulva;17 anal) for threshold setting and 36 samples (24 vulva; 12 anal) for clinical evaluation, were analyzed by mFAST-SeqS. CNA in vulva and anal lesions were determined by calculating genome-wide and chromosome arm-specific z-scores in comparison with the respective control samples. Sixteen samples were also analyzed with the conventional Shallow-seq approach. RESULTS: Genome-wide z-scores increased with the severity of disease, with highest values being found in cancers. In vulva samples median and inter quartile ranges [IQR] were 1[0-2] in normal tissues (n = 4), 3[1-7] in premalignant lesions (n = 9) and 21[13-48] in cancers (n = 10). In anal samples, median [IQR] were 0[0-1] in normal tissues (n = 4), 14[6-38] in premalignant lesions (n = 4) and 18[9-31] in cancers (n = 4). At threshold 4, all controls were CNA negative, while 8/13 premalignant lesions and 12/14 cancers were CNA positive. CNA captured by mFAST-SeqS were mostly also found by Shallow-seq. CONCLUSION: mFAST-SeqS is easy to perform, requires less DNA and less sequencing reads reducing costs, thereby providing a good alternative for Shallow-seq to determine CNA in small FFPE samples.

Enterotoxigenic Staphylococcus aureus in Brazilian artisanal cheeses: Occurrence, counts, phenotypic and genotypic profiles.

The present study aimed to assess the occurrence and counts of Staphylococcus aureus in Brazilian artisanal cheeses (BAC) produced in five regions of Brazil: Coalho and Manteiga (Northeast region); Colonial and Serrano (South); Caipira (Central-West); Marajó (North); and Minas Artisanal cheeses, from Araxá, Campos das Vertentes, Cerrado, Serro and Canastra microregions (Southeast). The resistance to chlorine-based sanitizers, ability to attach to stainless steel surfaces, and antibiogram profile of a large set of S. aureus strains (n = 585) were assessed. Further, a total of 42 isolates were evaluated for the presence of enterotoxigenic genes (sea, seb, sec, sed, see, seg, sei, sej, and ser) and submitted to typing using pulsed-field gel electrophoresis (PFGE). BAC presented high counts of S. aureus (3.4-6.4 log CFU/g), varying from 25 to 62.5%. From the S. aureus strains (n = 585) assessed, 16% could resist 200 ppm of sodium hypochlorite, whereas 87.6% produced strong ability to attach to stainless steel surfaces, corroborating with S. aureus ability to persist and spread in the environment. Furthermore, the relatively high frequency (80.5%) of multidrug-resistant S. aureus and the presence of enterotoxin genes in 92.6% of the strains is of utmost attention. It reveals the lurking threat of SFP that can survive when conditions are favorable. The presence of enterotoxigenic and antimicrobial-resistant strains of S. aureus in cheese constitutes a potential risk to public health. This result calls for better control of cheese contamination sources, and taking hygienic measures is necessary for food safety. More attention should be paid to animal welfare and hygiene practices in some dairy farms during manufacturing to enhance the microbiological quality of traditional cheese products.

Can Intubation Be Improved with Endotracheal Tubes Marked with a Color Scale? Randomized Controlled Study.

OBJECTIVE: This study aimed to assess if a color scale in the endotracheal tube (ETT) can help operators to correctly select the size and depth of placement of the ETT and decrease the time required to complete the procedure and compared with the usual numeric ETT scale in a mannequin model. STUDY DESIGN: The study was conducted in eight centers. Each size of the ETT was identified with a different color. The experimental ETTs had two different colored areas, one for the mouthpiece and another to identify where the ETT should be taped above the lip (an area of 1 cm. The operators were trained as part of the protocol using an instructional video. Four clinical scenarios requiring endotracheal intubation were designed and randomly assigned. Each operator had to select the size and depth of ETT based on the birth weight (BW), and then had to perform four intubations. RESULTS: A total of 108 operators performed 432 intubations. No differences were found in the correct placement and selection of the ETT. Median time (in seconds) required for intubation using numeric versus experimental tube was: for ETT Ø NRP (Neonatal Resuscitation Program) 2.5, 11.5 versus 8 (p < 0.001), ETT Ø 3, 12 versus 10 (p < 0.001), ETT Ø 3.5, 15.5 versus12 (p = 0.003), ETT Ø 4, 12 versus11 (p = 0.019). CONCLUSION: No significant difference was observed in the selection and correct placement of the ETT. However, the intubation time was significantly shorter using the experimental ETT. This device could improve the effectiveness of intubation by reducing the time needed to properly place the ETT at mid trachea. KEY POINTS: · It is an innovative intervention to try to solve a great inconvenience of daily practice.. · The study also raises the difficulty in maintaining the ability of endotracheal intubation.. · It proposes a scale that ensures the correct location with a safe fixation zone..

The use and safety of corticosteroid injections for shoulder pain in general practice: a retrospective cohort study.

BACKGROUND: Guidelines for shoulder pain in general practice recommend treatment with corticosteroid injections (CSI) if initial pain management fails. However, little is known about the actual use and safety of CSIs in treatment by general practitioners (GP). OBJECTIVE: The objective of this study was to gain insight into the use and safety of CSIs for patients with a new episode of shoulder pain in general practice. METHODS: A retrospective cohort study was conducted using a healthcare database containing the electronic medical records of approximately 200,000 patients in general practice. A search algorithm was constructed to identify patients with a new episode of shoulder pain between January 2012 and December 2017. Data on the use of CSIs in 2 random samples (n = 1,000) were manually validated for a 12-month period after the diagnosis. RESULTS: In total, 26% of the patients with a new episode of shoulder pain received a CSI. The patient's age (OR 1.03, 95% CI 1.02-1.04) and a history of shoulder pain (OR 1.52, 95% CI 1.13-2.12) were significantly associated with the administration of a CSI. Half of the patients received the CSI in the first consultation. The patient's age was positively associated with the likelihood of receiving the CSI in the first consultation (OR 1.01, 95% CI 1.00-1.02). No serious adverse reactions were recorded by the GP. CONCLUSION: In contrast to the guidelines, CSIs were frequently administered in the first consultation. Older patients and patients with a history of shoulder pain were more likely to receive a CSI for shoulder pain.

Shoulder muscle changes in patients with type 2 diabetes mellitus who have a painful shoulder: a quantitative muscle ultrasound study.

BACKGROUND: It is assumed that in patients with diabetic neuropathy, muscle denervation can result in shoulder disorders. Muscle denervation will lead to changes in muscle architecture, which can be assessed by quantitative muscle ultrasound (QMUS). The aim was to investigate whether increased muscle echogenicity, as a sign of neuropathy, is more often present in patients with shoulder pain who have type 2 diabetes mellitus (T2DM) than in those without. METHODS: Sixty-six patients with T2DM and 23 patients without diabetes mellitus (DM) having shoulder pain were included. Quantitative muscle ultrasound images were obtained bilaterally from the biceps brachii, deltoid, and supra- and infraspinatus muscles. The mean echogenicity (muscle ultrasound grey value) was transformed into z-scores and compared to reference values obtained from 50 healthy participants. Associations between muscle echogenicity and clinical variables were explored. RESULTS: In painful shoulders of both patients with T2DM and patients without DM, mean echogenicity z-scores of all muscles were significantly increased compared to healthy controls. No significant differences in echogenicity between patients with T2DM and those without DM were found. In patients with T2DM, a distal symmetric polyneuropathy was significantly associated with increased echogenicity of all muscles except the infraspinatus muscle. CONCLUSIONS: These findings indicate that patients with painful shoulders, irrespective of having T2DM, seem to have abnormal shoulder muscles. Future studies are needed to elucidate whether neuropathy or other conditions lead to these muscle changes.

Cancer Risk Stratification of Anal Intraepithelial Neoplasia in Human Immunodeficiency Virus-Positive Men by Validated Methylation Markers Associated With Progression to Cancer.

BACKGROUND: High-grade anal intraepithelial neoplasia (HGAIN; AIN2-3) is highly prevalent in HIV+ men, but only a minority of these lesions progress towards cancer. Currently, cancer progression risk cannot be established; therefore, no consensus exists on whether HGAIN should be treated. This study aimed to validate previously identified host cell DNA methylation markers for detection and cancer risk stratification of HGAIN. METHODS: A large independent cross-sectional series of 345 anal cancer, AIN3, AIN2, AIN1, and normal control biopsies of HIV+ men was tested for DNA methylation of 6 genes using quantitative methylation-specific PCR. We determined accuracy for detection of AIN3 and cancer (AIN3+) by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Methylation levels were assessed in a series of 10 anal cancer cases with preceding HGAIN at similar anatomic locations, and compared with the cross-sectional series. RESULTS: Methylation levels of all genes increased with increasing severity of disease (P < .05). HGAIN revealed a heterogeneous methylation pattern, with a subset resembling cancer. ZNF582 showed highest accuracy (AUC = 0.88) for AIN3+ detection, slightly improved by addition of ASCL1 and SST (AUC = 0.89), forming a marker panel. In the longitudinal series, HGAIN preceding cancer displayed high methylation levels similar to cancers. CONCLUSIONS: We validated the accuracy of 5 methylation markers for the detection of anal (pre-) cancer. High methylation levels in HGAIN were associated with progression to cancer. These markers provide a promising tool to identify HGAIN in need of treatment, preventing overtreatment of HGAIN with a low cancer progression risk.

Characterisation of anal intraepithelial neoplasia and anal cancer in HIV-positive men by immunohistochemical markers p16, Ki-67, HPV-E4 and DNA methylation markers.

Human papillomavirus (HPV)-induced anal intraepithelial neoplasia (AIN, graded 1-3) is highly prevalent in HIV-positive (HIV+) men who have sex with men (MSM), but only a minority of lesions progresses to cancer. Our study aimed to characterise comprehensively anal tissue samples from a cross-sectional series (n = 104) of HIV+ MSM and longitudinal series (n = 40) of AIN2/3 progressing to cancer using different biomarkers. The cross-sectional series consisted of 8 normal, 26 AIN1, 45 AIN2, 15 AIN3 and 10 anal squamous cell carcinoma. Tissue sections were immunohistochemically (IHC) stained for p16 (viral transformation marker), Ki-67 (cellular proliferation marker) and HPV-E4 (viral production marker). We evaluated the expression of IHC markers and compared it with DNA methylation, a marker for malignant transformation. E4 positivity decreased, whereas p16 and Ki-67 scores and methylation marker positivity increased (P values < .001) with increasing severity of anal lesions. Within AIN2, a heterogeneous biomarker pattern was observed concerning E4, p16 and methylation status, reflecting the biological heterogeneity of these lesions. In the longitudinal series, all AIN2/3 and carcinomas showed high p16 and Ki-67 expression, strong methylation positivity and occasional E4 positivity. We earlier showed that high methylation levels are associated with progression to cancer. The observed E4 expression in some AIN2/3 during the course of progression to cancer and absence of E4 in a considerable number of AIN1 lesions make the potential clinical significance of E4 expression difficult to interpret. Our data show that IHC biomarkers can help to characterise AIN; however, their prognostic value for cancer risk stratification, next to objective methylation analysis, appears to be limited.

Phenotyping the shoulder patient based on ultrasound-detected pathologies: a cross-sectional study in general practice.

BACKGROUND: Shoulder complaints arise from a single pathology or a combination of different underlying pathologies that are hard to differentiate in general practice. Subgroups of pathologies have been identified on the basis of ultrasound imaging that might affect treatment outcomes. OBJECTIVE: Our aim was to validate the existence of different subgroups of patients with shoulder complaints, based on ultrasound-detected pathology, and compare clinical features among them. Profiling shoulder patients into distinct shoulder pathology phenotypes could help designing tailored treatment trials. METHODS: This was a cross-sectional study in general practice. Data were extracted from 840 first visit patient records at a single diagnostic centre in the Netherlands. Exclusion criteria were age <18 years and previous shoulder surgery. Latent class analysis was used to uncover cross-combinations of ultrasound detected pathologies, yielding subgroups of shoulder patients. The uncovered subgroups were compared for demographic and clinical characteristics. RESULTS: We uncovered four distinct subgroups of patients with shoulder complaints: (i) Frozen shoulder group (11%), (ii) Limited pathology group (44%), (iii) Degenerative pathology group (31%) and (iv) Calcifying tendinopathy group (15%). Group comparisons showed significant differences in demographic and clinical characteristics among subgroups, consistent with the literature. CONCLUSION: In a general practice population, we uncovered four different phenotypes of shoulder patients on the basis of ultrasound detected pathology. These phenotypes can be used designing tailored treatment trials in patients with shoulder complaints.

The incidence and management of shoulder complaints in general practice: a retrospective cohort study.

BACKGROUND: Shoulder pain is the third most common musculoskeletal complaint in primary care. The international guidelines for general practitioners (GPs) recommend a stepwise treatment of shoulder pain. Little is known about the actual distribution of these treatments in current practice. OBJECTIVE: To gain insight in the incidence and current management of shoulder complaints in Dutch general practice. METHODS: A retrospective cohort study was conducted using a health care database containing the full electronic medical records of approximately 200 000 patients in Dutch general practice. A search algorithm was constructed to identify incident cases of shoulder complaints from January 2012 to December 2017. Data on the management of shoulder complaints were manually validated in a random sample of 1000 cases. RESULTS: The overall incidence of shoulder complaints was 30.3 (95% confidence interval 29.9-30.7) per 1000 person-years. More than half of the patients (58.6%) consulted their GP only once, 44.4% two times or more and 19.7% three times or more. For most patients (58.1%), the GP applied a wait-and-see policy or prescription of oral medication in the first consultation. However, no less than 42.9% of the patients were referred or received an injection already in the first consultation. CONCLUSIONS: There is a wide variety of treatments for shoulder complaints applied by the GP. Some patients are referred or received an injection already in the first consultation. The stepwise approach recommended by the guideline, might not always be applicable due to the diversity of patient- and shoulder characteristics presented in general practice.

High throughput screening of technological and biopreservation traits of a large set of wild lactic acid bacteria from Brazilian artisanal cheeses.

This study aimed to evaluate technological (acidification, proteolysis, lipolysis, resistance to low pH, NaCl, and bile salts) and biopreservation (antimicrobial activity against foodborne pathogens) features of 1002 LAB by high throughput screening (HTS) methods. The LAB was isolated from 11 types of Brazilian artisanal cheeses (BAC) marketed in the main 5 producing regions. Remarkable intra-species variability in acidification rates have been found, which was most pronounced between isolates from Mina's artisanal cheeses, Caipira and Coalho cheeses. Lacticaseibacillus paracasei and Levilactobacillus brevis showed the fastest acidification rate; however, all isolates showed slower acidification rates than a lactococcal control strain (4.3 × lower). When testing inhibitory effects, > 75% of LAB isolates could inhibit the growth of Staphylococcus aureus ATCC 19095 and Listeria monocytogenes ATCC 7644. Two of these isolates, identified as Lactiplantibacillus plantarum and Lentilactobacillus buchneri, the sterile and neutral supernatants alone, were sufficient to inhibit L. monocytogenes growth. Principal component analysis (PCA) allowed the identification of functional groups based on proteolytic and lipolytic activity, osmotic stress resistance, and inhibition of L. monocytogenes. The type of cheese the isolates were recovered from influenced properties such as anti-listerial compounds and lipolytic enzyme production. The use of HTS and multivariate statistics allowed insights into a diverse set of LAB technological and biopreservation properties. These findings allow a profound knowledge of the heterogeneity of a large set of isolates, which can be further used to design starter cultures with varied and combined properties, such as biopreservation and technological features. Besides that, HTS makes it possible to analyze a vast panel of LAB strains, reducing costs and time within laboratory analysis, while avoiding the loss of information once all LAB are tested at the same time (differently from the traditional labor-intensive approach, in which a few numbers of strains is tested per time).

Long-term sickness absence in a working population: development and validation of a risk prediction model in a large Dutch prospective cohort.

BACKGROUND: Societal expenditures on work-disability benefits is high in most Western countries. As a precursor of long-term work restrictions, long-term sickness absence (LTSA) is under continuous attention of policy makers. Different healthcare professionals can play a role in identification of persons at risk of LTSA but are not well trained. A risk prediction model can support risk stratification to initiate preventative interventions. Unfortunately, current models lack generalizability or do not include a comprehensive set of potential predictors for LTSA. This study is set out to develop and validate a multivariable risk prediction model for LTSA in the coming year in a working population aged 45-64 years. METHODS: Data from 11,221 working persons included in the prospective Study on Transitions in Employment, Ability and Motivation (STREAM) conducted in the Netherlands were used to develop a multivariable risk prediction model for LTSA lasting ≥28 accumulated working days in the coming year. Missing data were imputed using multiple imputation. A full statistical model including 27 pre-selected predictors was reduced to a practical model using backward stepwise elimination in a logistic regression analysis across all imputed datasets. Predictive performance of the final model was evaluated using the Area Under the Curve (AUC), calibration plots and the Hosmer-Lemeshow (H&L) test. External validation was performed in a second cohort of 5604 newly recruited working persons. RESULTS: Eleven variables in the final model predicted LTSA: older age, female gender, lower level of education, poor self-rated physical health, low weekly physical activity, high self-rated physical job load, knowledge and skills not matching the job, high number of major life events in the previous year, poor self-rated work ability, high number of sickness absence days in the previous year and being self-employed. The model showed good discrimination (AUC 0.76 (interquartile range 0.75-0.76)) and good calibration in the external validation cohort (H&L test: p = 0.41). CONCLUSIONS: This multivariable risk prediction model distinguishes well between older workers with high- and low-risk for LTSA in the coming year. Being easy to administer, it can support healthcare professionals in determining which persons should be targeted for tailored preventative interventions.

Host Cell Deoxyribonucleic Acid Methylation Markers for the Detection of High-grade Anal Intraepithelial Neoplasia and Anal Cancer.

BACKGROUND: High-grade anal intraepithelial neoplasia (AIN2/3; HGAIN) is highly prevalent in human immunodeficiency virus positive (HIV+) men who have sex with men (MSM), but only a minority will eventually progress to cancer. Currently, the cancer risk cannot be established, and therefore all HGAIN is treated, resulting in overtreatment. We assessed host cell deoxyribonucleic acid (DNA) methylation markers for detecting HGAIN and anal cancer. METHODS: Tissue samples of HIV+ men with anal cancer (n = 26), AIN3 (n = 24), AIN2 (n = 42), AIN1 (n = 22) and HIV+ male controls (n = 34) were analyzed for methylation of 9 genes using quantitative methylation-specific polymerase chain reaction. Univariable and least absolute shrinkage and selection operator logistic regression, followed by leave-one-out cross-validation, were used to determine the performance for AIN3 and cancer detection. RESULTS: Methylation of all genes increased significantly with increasing severity of disease (P < 2 × 10-6). HGAIN samples revealed heterogeneous methylation patterns, with a subset resembling cancer. Four genes (ASCL1, SST, ZIC1,ZNF582) showed remarkable performance for AIN3 and anal cancer detection (area under the curve [AUC] > 0.85). ZNF582 (AUC = 0.89), detected all cancers and 54% of AIN3 at 93% specificity. Slightly better performance (AUC = 0.90) was obtained using a 5-marker panel. CONCLUSIONS: DNA methylation is associated with anal carcinogenesis. A marker panel that includes ZNF582 identifies anal cancer and HGAIN with a cancer-like methylation pattern, warrantingvalidation studies to verify its potential for screening and management of HIV+ MSM at risk for anal cancer.

Awareness of limited joint mobility in type 2 diabetes in general practice in the Netherlands: an online questionnaire survey.

BACKGROUND: Next to the well-known micro- and macrovascular complications, type 2 diabetes mellitus (T2DM) is associated with musculoskeletal disorders of the upper extremities referred to as limited joint mobility (LJM), e.g. carpal tunnel syndrome (CTS) and adhesive capsulitis. Unrecognized and untreated LJM can lead to poor quality of life and non-compliance to diabetes treatment which aggravates LJM. Despite its reported higher prevalence in international prevalence studies, examination of the upper extremities is still no part of the regular diabetes mellitus (DM) check-ups. The primary aim of this study was therefore to evaluate the awareness of Dutch GPs and nurse practitioners concerning LJM. Secondary aims were to evaluate the current management of a patient with LJM, and to assess opinions regarding the question of who should screen for LJM if this is done in the near future. METHODS: An online survey was conducted among 390 general practitioners (GPs) and 245 nurse practitioners (NPs) of three diabetes care groups in The Netherlands to assess their awareness of the association between DM and LJM. RESULTS: Most GPs are not aware that LJM is a DM complication, with an unawareness for specific upper extremity disorders ranging from 59 to 73%. Of the NPs, 76% is not aware either. Only 41% of GPs would advise the most optimal treatment for diabetes patient with CTS. Finally, only 25% of the GPs believe that screening for LJM should be performed during the regular diabetes check-up compared to 63% of the NPs. CONCLUSION: The majority of GPs and NPs are not aware of LJM as a T2DM complication. In contrast to NPs, most GPs do not believe that screening for LJM should be performed during the regular diabetes check-up.

Does the implementation of a care pathway for patients with hip or knee osteoarthritis lead to fewer diagnostic imaging and referrals by general practitioners? A pre-post-implementation study of claims data.

BACKGROUND: The Dutch care for hip and knee osteoarthritis (OA) is of good quality, but there is room for improvement regarding the efficient use of diagnostic imaging and conservative treatment. Therefore a stepped-care approach, in the shape of the care pathway 'Better exercise in osteoarthritis', was implemented to reduce the number of diagnostic imaging requested by GPs and referrals of GPs to orthopaedic care. METHODS: In 2015, the pathway is implemented with the use of educational meetings, distributing guidelines and incorporating reminders in the GPs' referral application. To evaluate the effect of the pathway on the diagnostic and referral behaviour of GPs, hip and knee related health insurance claims are used together with claims of other joints and of a control region for comparison. The average number of claims and the percentage change in the post-implementation period are described. Binary logistic regression analysis is used to examine the interaction between region (intervention and control) and period (pre- and post-implementation). Using random sampling of patient records, information about the practical application of the pathway and the number of hip or knee arthroplasties is added. RESULTS: In both regions, the number of diagnostic imaging decreased and the number of initial orthopaedic consultations increased during the post-implementation period. Significant interaction effects were found in knee-related diagnostics (p ≤ 0.001) and diagnostics of other joints (p = 0.039). No significant interaction effects were found in hip-related diagnostics (p = 0.060) and in initial orthopaedic consultation claims of hip (p = 0.979), knee (p = 0.281), and other joints (p = 0.464). Being referred according to the pathway had no significant effect on the probability of undergoing arthroplasty. CONCLUSION: The implementation of the pathway had a positive effect on GPs diagnostic behaviour related to the knee, but not to the hip. The referral behaviour of GPs to orthopaedic care needs attention for future interventions and research, since an increase (instead of a desired decrease) in the number of initial orthopaedic consultations was found. Focusing on the entire width of care for hip and knee OA could be helpful.

Perioperative goal-directed therapy: A systematic review without meta-analysis.

BACKGROUND: Perioperative goal-directed therapy aims to optimise haemodynamics by titrating fluids, vasopressors and/or inotropes to predefined haemodynamic targets. Perioperative goal-directed therapy is a complex intervention composed of several independent component interventions. Trials on perioperative goal-directed therapy show conflicting results. We aimed to conduct a systematic review and meta-analysis to investigate the benefits and harms of perioperative goal-directed therapy. METHODS: PubMED, EMBASE, Web of Science and Cochrane Library were searched. Trials were included if they had a perioperative goal-directed therapy protocol. The primary outcome was all-cause mortality. The first secondary outcome was serious adverse events excluding mortality. Risk of bias was assessed, and GRADE was used to evaluate quality of evidence. RESULTS: One hundred and twelve randomised trials were included of which one trial (1%) had low risk of bias. Included trials varied in patients: types of surgery which was expected due to inclusion criteria; in intervention and comparison: timing of intervention, monitoring devices, haemodynamic variables, target values, use of fluids, vasopressors and/or inotropes as well as combinations of these within protocols; and in outcome: mortality was reported in 87 trials (78%). Due to substantial clinical heterogeneity also within the various types of surgery a meta-analysis of data, including subgroup analyses, as defined in our protocol was considered inappropriate. CONCLUSION: Clinical heterogeneity in patients, interventions and outcomes in perioperative goal-directed therapy trials is too large to perform meta-analysis on all trials. Future trials and meta-analyses highly depend on universally agreed definitions on aspects beyond type of surgery of the complex intervention and its evaluation.

Minimally invasive cardiac output technologies in the ICU: putting it all together.

PURPOSE OF REVIEW: Haemodynamic monitoring is a cornerstone in the diagnosis and evaluation of treatment in critically ill patients in circulatory distress. The interest in using minimally invasive cardiac output monitors is growing. The purpose of this review is to discuss the currently available devices to provide an overview of their validation studies in order to answer the question whether these devices are ready for implementation in clinical practice. RECENT FINDINGS: Current evidence shows that minimally invasive cardiac output monitoring devices are not yet interchangeable with (trans)pulmonary thermodilution in measuring cardiac output. However, validation studies are generally single centre, are based on small sample sizes in heterogeneous groups, and differ in the statistical methods used. SUMMARY: Minimally and noninvasive monitoring devices may not be sufficiently accurate to replace (trans)pulmonary thermodilution in estimating cardiac output. The current paradigm shift to explore trending ability rather than investigating agreement of absolute values alone is to be applauded. Future research should focus on the effectiveness of these devices in the context of (functional) haemodynamic monitoring before adoption into clinical practice can be recommended.

PANLAR Consensus Recommendations for the Management in Osteoarthritis of Hand, Hip, and Knee.

OBJECTIVE: The objective of this consensus is to update the recommendations for the treatment of hand, hip, and knee osteoarthritis (OA) by agreeing on key propositions relating to the management of hand, hip, and knee OA, by identifying and critically appraising research evidence for the effectiveness of the treatments and by generating recommendations based on a combination of the available evidence and expert opinion of 18 countries of America. METHODS: Recommendations were developed by a group of 48 specialists of rheumatologists, members of other medical disciplines (orthopedics and physiatrists), and three patients, one for each location of OA. A systematic review of existing articles, meta-analyses, and guidelines for the management of hand, hip, and knee OA published between 2008 and January 2014 was undertaken. The scores for Level of Evidence and Grade of Recommendation were proposed and fully consented within the committee based on The American Heart Association Evidence-Based Scoring System. The level of agreement was established through a variation of Delphi technique. RESULTS: Both "strong" and "conditional" recommendations are given for management of hand, hip, and knee OA and nonpharmacological, pharmacological, and surgical modalities of treatment are presented according to the different levels of agreement. CONCLUSIONS: These recommendations are based on the consensus of clinical experts from a wide range of disciplines taking available evidence into account while balancing the benefits and risks of nonpharmacological, pharmacological, and surgical treatment modalities, and incorporating their preferences and values. Different backgrounds in terms of patient education or drug availability in different countries were not evaluated but will be important.

Ultrasound imaging for tailored treatment of patients with acute shoulder pain.

PURPOSE: The objective of this study was to assess the frequencies of ultrasound findings in patients with acute rotator cuff disorders in family medicine. METHODS: In a prospective observational study, 129 patients aged 18 to 65 years with acute shoulder pain in whom the family physician suspected rotator cuff disease underwent ultrasound imaging. RESULTS: Rotator cuff disease was present in 81% of the patients, and 50% of them had multiple disorders. Calcific tendonitis was the most frequently diagnosed specific disorder. An age of 40 years or older was most strongly related to rotator cuff disease. CONCLUSIONS: Ultrasound imaging enables family physicians to rationalize treatment in nearly all patients who are aged 40 years and older with acute shoulder pain.

Ultrasound-diagnosed disorders in shoulder patients in daily general practice: a retrospective observational study.

BACKGROUND: Ultrasound imaging (US) is considered an accurate and widely available method to diagnose subacromial disorders. Yet, the frequency of the specific US-diagnosed shoulder disorders of patients with shoulder pain referred from general practice is unknown. We set out to determine the frequency of specific US-diagnosed shoulder disorders in daily practice in these patients and to investigate if the disorders detected differ between specific subgroups based on age and duration of pain. METHODS: A predefined selection of 240 ultrasound reports of patients with shoulder pain (20 reports for each month in 2011) from a general hospital (Orbis Medical Centre Sittard-Geleen, The Netherlands) were descriptively analysed. Inclusion criteria were: (i) referral from general practice, (ii) age ≥ 18 years, and (iii) unilateral shoulder examination. Subgroups were created for age (<65 years and ≥ 65 years) and duration of pain (acute or subacute (<12 weeks) and chronic (≥ 12 weeks)). The occurrence of each specific disorder is expressed as absolute and relative frequencies. RESULTS: With 29%, calcific tendonitis was the most frequently diagnosed disorder, followed by subacromial-subdeltoid bursitis (12%), tendinopathy (11%), partial-thickness tears (11%), full-thickness tears (8%) and AC-osteoarthritis (0.4%). For 40% of patients, no disorders were found on US. Significantly more full thickness-tears were found in the ≥ 65 years group. 'No disorders' was reported significantly more often in the <65 years group. The supraspinatus tendon was the most frequently affected tendon (72%). CONCLUSIONS: Calcific tendonitis is the most common US-diagnosed disorder affecting patients in general practice, followed by subacromial-subdeltoid bursitis, tendinopathy, partial- and full-thickness tears and AC-osteoarthritis. Full-thickness tears were diagnosed significantly more frequently in patients ≥ 65 years, while 'no disorders' was more frequently reported in patients <65 years. Our findings imply that patients can be stratified into diagnostic subgroups, allowing more tailored treatment than currently applied.

Estimation of country-specific tuberculosis resistance antibiograms using pathogen genomics and machine learning.

BACKGROUND: Global tuberculosis (TB) drug resistance (DR) surveillance focuses on rifampicin. We examined the potential of public and surveillance Mycobacterium tuberculosis (Mtb) whole-genome sequencing (WGS) data, to generate expanded country-level resistance prevalence estimates (antibiograms) using in silico resistance prediction. METHODS: We curated and quality-controlled Mtb WGS data. We used a validated random forest model to predict phenotypic resistance to 12 drugs and bias-corrected for model performance, outbreak sampling and rifampicin resistance oversampling. Validation leveraged a national DR survey conducted in South Africa. RESULTS: Mtb isolates from 29 countries (n=19 149) met sequence quality criteria. Global marginal genotypic resistance among mono-resistant TB estimates overlapped with the South African DR survey, except for isoniazid, ethionamide and second-line injectables, which were underestimated (n=3134). Among multidrug resistant (MDR) TB (n=268), estimates overlapped for the fluoroquinolones but overestimated other drugs. Globally pooled mono-resistance to isoniazid was 10.9% (95% CI: 10.2-11.7%, n=14 012). Mono-levofloxacin resistance rates were highest in South Asia (Pakistan 3.4% (0.1-11%), n=111 and India 2.8% (0.08-9.4%), n=114). Given the recent interest in drugs enhancing ethionamide activity and their expected activity against isolates with resistance discordance between isoniazid and ethionamide, we measured this rate and found it to be high at 74.4% (IQR: 64.5-79.7%) of isoniazid-resistant isolates predicted to be ethionamide susceptible. The global susceptibility rate to pyrazinamide and levofloxacin among MDR was 15.1% (95% CI: 10.2-19.9%, n=3964). CONCLUSIONS: This is the first attempt at global Mtb antibiogram estimation. DR prevalence in Mtb can be reliably estimated using public WGS and phenotypic resistance prediction for key antibiotics, but public WGS data demonstrates oversampling of isolates with higher resistance levels than MDR. Nevertheless, our results raise concerns about the empiric use of short-course fluoroquinolone regimens for drug-susceptible TB in South Asia and indicate underutilisation of ethionamide in MDR treatment.