A DNA methylation atlas of normal human cell types.

DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2-5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

Fracture Liaison Service for Hip Fractures: Is It A Game Changer?

BACKGROUND: Osteoporosis is a common medical condition in older ages. A devastating result of osteoporosis may be a hip fracture with up to 30% mortality rate in one year. The compliance rate of osteoporotic medication following a hip fracture is 20% in the western world. OBJECTIVES: To evaluate the impact of the fracture liaison service (FLS) model in the orthopedic department on patient compliance following hip fracture. METHODS: We performed a retrospective review of all patients with hip fracture who were involved with FLS. We collected data regarding kidney function, calcium levels, parathyroid hormone levels, and vitamin D levels at admission. We educated the patient and family, started vitamin D and calcium supplementation and recommended osteoporotic medical treatment. We phoned the patient 6-12 weeks following the fracture to ensure treatment initiation. RESULTS: From June 2018 to June 2019 we identified 166 patients with hip fracture who completed at least one year of follow-up. Over 75% of the patients had low vitamin D levels and 22% had low calcium levels at admission. Nine patients (5%) died at median of 109 days. Following our intervention, 161 patients (96%) were discharged with a specific osteoporotic treatment recommendation; 121 (73%) received medication for osteoporosis on average of < 3 months after surgery. We recommended on injectable medications; however, 51 (42%) were treated with oral biphsophonate. CONCLUSIONS: FLS improved the compliance rate of osteoporotic medical treatment and should be a clinical routine in every medical center.

Prediction of Long Bone Fractures in Multiple Myeloma Patients in an Advanced Imaging World.

BACKGROUND: Multiple myeloma (MM) affects the long bones in 25% of patients. The advent of positron-emission tomography/computed tomography (PET/CT) scanners offers the possibility of both metabolic and radiographic information and may help determine fracture risk. To the best of our knowledge, no published study correlates these two factors with long bone fractures. OBJECTIVES: To evaluate the impact of PET/CT on fracture risk assessment in multiple myeloma patients. METHODS: We identified all bone marrow biopsy proven multiple myeloma patients from 1 January 2010 to 31 January 2015 at a single institution. We prospectively followed patients with long bone lesions using PET/CT scan images. RESULTS: We identified 119 patients (59 males/60 females) with 256 long bone lesions. Mean age at diagnosis was 58 years. The majority of lesions were in the femur (n=150, 59%) and humerus (n=84, 33%); 13 lesions in 10 patients (8%) required surgery for impending (n=4) or actual fracture (n=9). Higher median SUVmax was measured for those with cortical involvement (8.05, range 0-50.8) vs. no involvement (5.0, range 2.1-18.1). SUVmax was found to be a predictor of cortical involvement (odds ratio = 1.17, P = 0.026). No significant correlation was found between SUVmax and pain or fracture (P = 0.43). CONCLUSIONS: Improved medical treatment resulted improvement in 8% of patients with an actual or impending fracture. The orthopedic surgeons commonly use the Mirels classification for long bone fracture prediction. Adding PET/CT imaging to study in myeloma long bone lesions did not predict fracture risk directly but suggested it indirectly by cortical erosion.

Knee intra-articular extraskeletal aneurysmal bone cyst: a case report and review of literature.

Aneurysmal bone cyst (ABC) is a benign locally destructive lesion that usually developed in the bone cavity of bones, less commonly on the surface of cortical bones and very rarely develop outside the bone. There are only 35 reports of extraskeletal aneurysmal bone cyst (ESABC) in the English literature. We report a case of a 12-year-old female with no history of trauma who presented with knee pain. Imaging studies revealed an infrapatellar mass that was fast to calcify during a period of 3 months. MRI showed high T2 center, low T1 signal, and heterogenic enhancement with a rim of low intensity consistent with calcified boarders surrounded by severe soft tissue edema. The lesion was surgically excised, and a histological examination revealed an aneurysmal bone cyst possibly arising within myositis ossificans or heterotopic ossification. In her last follow-up 1.5 years after the surgical excision, the patient was symptom free and without signs of recurrence. To the best of our knowledge, this is the first reported case of an intra-articular ESABC located in the knee.

MiR-16-1-3p and miR-16-2-3p possess strong tumor suppressive and antimetastatic properties in osteosarcoma.

Osteosarcoma (OS) is an aggressive malignancy affecting mostly children and adolescents. MicroRNAs (miRNAs) play important roles in OS development and progression. Here we found that miR-16-1-3p and miR-16-2-3p "passenger" strands, as well as the "lead" miR-16-5p strand, are frequently downregulated and possess strong tumor suppressive functions in human OS. Furthermore, we report different although strongly overlapping functions for miR-16-1-3p and miR-16-2-3p in OS cells. Ectopic expression of these miRNAs affected primary tumor growth, metastasis seeding and chemoresistance and invasiveness of human OS cells. Loss-of-function experiments verified tumor suppressive functions of these miRNAs at endogenous levels of expression. Using RNA immunoprecipitation (RIP) assays, we identify direct targets of miR-16-1-3p and miR-16-2-3p in OS cells. Moreover, validation experiments identified FGFR2 as a direct target for miR-16-1-3p and miR-16-2-3p. Overall, our findings underscore the importance of passenger strand miRNAs, at least some, in osteosarcomagenesis.

Minocycline Effectively Protects the Rabbit's Spinal Cord From Aortic Occlusion-Related Ischemia.

OBJECTIVES: To identify the minocycline anti-inflammatory and antiapoptotic mechanisms through which it is believed to exert spinal cord protection during aortic occlusion in the rabbit model. DESIGN: An animal model of aortic occlusion-related spinal cord ischemia. Randomized study with a control group and pre-ischemia and post-ischemia escalating doses of minocycline to high-dose minocycline in the presence of either hyperglycemia, a pro-apoptotic maneuver, or wortmannin, a specific phosphatidylinositol 3-kinase antagonist. SETTING: Tertiary medical center and school of medicine laboratory. PARTICIPANTS: Laboratory animals-rabbits. INTERVENTIONS: Balloon obstruction of infrarenal aorta introduced via femoral artery incision. RESULTS: Severe hindlimb paralysis (mean Tarlov score 0.36±0.81 out of 3) was observed in all the control group animals (9 of 11 with paraplegia and 2 of 11 with paraparesis) compared with 11 of 12 neurologically intact animals (mean Tarlov score 2.58±0.90 [p = 0.001 compared with control]) in the high-dose minocycline group. This protective effect was observed partially during a state of hyperglycemia and was completely abrogated by wortmannin. Minocycline administration resulted in higher neurologic scores (p = 0.003) and a shift to viable neurons and more apoptotic-stained nuclei resulting from reduced necrosis (p = 0.001). CONCLUSIONS: In a rabbit model of infrarenal aortic occlusion, minocycline effectively reduced paraplegia by increasing the number of viable neurons in a dose-dependent manner. Its action was completely abrogated by inhibiting the phosphatidylinositol 3-kinase pathway and was inhibited partially by the pro-apoptotic hyperglycemia maneuver, indicating that the activation of cell salvage pathways and mitochondrial sites are possible targets of minocycline action in an ischemic spinal cord.

[CLIMBING HIGHER--COMMON INJURIES IN ROCK CLIMBERS].

Rock climbing is becoming an increasingly popular sport in Israel with more and more climbing walls being built in the cities and new routes being traced on cliffs around the country. Our account describes the case of a 15 years old climber with chronic pain (without trauma) in the 3rd finger of the right hand. A stress fracture, involving the proximal interphalangeal joint (SH3) of the middle phalanx, was diagnosed. The fracture healed following two months of rest with gradual return to activity. As this sport becomes more common, there is an increasing need for knowledge about the characteristic injuries, their diagnosis and treatment. Although considered an extreme sport, most of the injuries are overuse injuries, mainly to the upper limbs. Finger flexor tendon pulley rupture being one of the most common. Diagnosis is based on history, physical examination and ultrasonography. Conservative treatment is successful for most injuries, while more complicated cases require surgical intervention.

Home Versus Hospital Rehabilitation of Older Adults Following Hip Fracture Yields Similar Patient-Reported Outcome Measures.

The increase in hip fractures (HF) due to aging of the population and the rise in attractiveness of services provided at home following the COVID-19 pandemic, emphasize the need to compare outcomes of home versus hospital HF rehabilitation. To date, studies comparing the 2 services have focused primarily on clinical outcomes rather than patient-reported outcomes (PROs). This longitudinal observational study evaluated PROs of older adults with HF in the 2 settings. The SF36 questionnaire was used to measure PROs 3 times after surgery. The first PRO was retrospective and reflected pre-fracture health status. Descriptive statistics and mixed-effect logistic regression were used. Of 86 patients participating in the study, 41 had home rehabilitation and 45 had hospital rehabilitation. In both groups, the mental and physical scores plummeted 2 weeks after the HF, compared to pre-fracture status. The difference in improvement from pre-fracture status to recovery in both groups, were not significantly (P < .05) different, except for the pain domain. PROs of home versus hospital rehabilitation were similar, suggesting that rehabilitation at home can be as effective as hospital rehabilitation for suitable patients. This knowledge can improve quality of care in an aging global population.

Is It Safe to Resume Direct Oral Anticoagulants upon Discharge after Hip Fracture Surgery? A Retrospective Study.

This study aimed to examine the incidence rate of early reoperations following hip fracture surgery and determine the safety of resuming direct oral anticoagulants. Many orthopedic surgeons are reluctant to resume chronic anticoagulation therapy for patients after surgical intervention for hip fractures. One of the main reasons is the potential for reoperation in the case of surgical complications. We conducted a retrospective cohort study at an Academic Level I trauma center, reviewing the records of 425 geriatric patients (age > 60) who underwent hip fracture surgery between 2018 and 2020, including a subgroup treated with direct oral anticoagulants prior to hospitalization. The study assessed the incidence rate of complications requiring early reoperation. Out of the 425 patients, only nine (2%) required reoperation within a month after discharge, with two (0.5%) on chronic anticoagulation therapy. None of the reoperations were urgent, and all were performed at least 24 h after re-admission. The findings revealed a very low incidence rate of reoperations in patients who underwent hip fracture surgery, with no reoperations performed within 24 h of re-admission. Consequently, we believe that resuming chronic direct oral anticoagulants is a safe and effective approach when discharging patients after hip fracture surgery.

The Suitability of Measuring Patient-Reported Outcomes in Older Adults Following a Hip Fracture Using the Short-Form 36 Questionnaire: A Qualitative Description Approach.

Hip-fractures (HF) in older adults are associated with poor outcomes and high costs. Measuring quality-of-care of HF patients has focused on clinical definitions rather than on measuring outcomes that are meaningful to the patient. Healthcare systems worldwide are increasingly interested in patient-reported outcome measures (PROs). The Short-form (SF36) questionnaire is a recommended measure among older adults however it's comprehensiveness and uniqueness for specific patients after a HF is not clear. The aims of this study were to: understand the perspective of the older adults experience following HF, to assess the suitability of the SF36 as a PRO for HF and to determine the best timing for questioning. A qualitative description approach was used. This took place in 2 large academic medical-centers in Israel. The inquiry was done in 2 parts by semi-structured interview. A total 15 HF patients were interviewed. Categories and themes emerging from their responses were similar to the 8 domains of the SF36 questionnaire, but the participants added clarity regarding their own needs for setting goals. In the second part, participants agreed that the SF36 reflected common issues and served as an adequate measure for personal-goal setting. The study encourages patient-centered care in older adults recovering from HF, providing evidence that the SF36 is a suitable tool for measuring PROs in HF patients. Healthcare systems focus on clinical-outcome indicators and do not reflect how the patient views his outcomes. This study provides evidence that care should be customized for each person.

Perception of Goals and Expected Outcomes in Older Hip Fracture Patients and Their Medical Staff: A Cross Sectional Study.

Background: Goal-oriented patientcare is a key element in qualityhealthcare. Medical-caregiver's (MC) are expected to generate a shared decision-making process with patients regarding goals and expected health-outcomes. Hip-fracture patients (HFP) are usually older-adults with multiple health-conditions, necessitating that agreed-upon goals regarding the rehabilitation process, take these conditions into consideration. This topic has yet to be investigated by pairing and comparing the perception of expected outcomes and therapeutic goals of multidisciplinary MCs and their HF patient's. Our aim was to assess in a quantitative method whether HFPs and their multidisciplinary MCs agree upon target health-outcomes and their most important goals as they are reflected in the SF12 questionnaire. Methods: This was a cross-sectional, multi-center, study of HFPs and their MCs. Patients and MCs were asked to rate their top three most important goals for rehabilitation from the SF12 eight subscales: physical functioning, physical role limitation, bodily pain, general health, vitality, social functioning, emotional role limitation and mental health, and indicate their expected outcome. Descriptive statistics and mixed effect logistic-regression were used to compare concordance of the ratings. Agreement between patients and MCs was assessed using interclass coefficients (ICCs). Results: A total of 378 ratings were collected from 52 patients, 12 nurses, 12 physicians and 6 paramedical personnel. Each patient had between 3 and 9 raters. Patients considered physical functioning and physical role limitation more important than did MCs. Physicians and nurses emphasized the importance of bodily pain while patients referred to it as relatively less significant. The total ICC was low (2%) indicating poor agreement between MCs and patients. With the exception of physical-functioning, MCs predicted a less optimistic outcome in all of the SF12's subscales in comparison to HFPs. Conclusion: Effective intervention in HFPs requires constructive communication between MCs and patients. The study suggests that caregivers have an insufficient understanding of the expectations of HFPs. More effective communication channels are required in order to better understand HFPs' needs and expectations.

Utilising patient-reported outcomes for goal-directed therapy of hip fracture patients: a sequential controlled trial.

BACKGROUND: Hip fracture patients (HFPs) frequently have multiple underlying conditions, necessitating that agreed-upon goals take these complications into consideration. Communication regarding goals between medical-personnel and patients is not always effective. Patient-reported outcomes (PROs) can outline personal goals and help promote quality health care in HFPs. Few studies have been published on this topic. The study's aim was to outline the process of using PROs for goal-directed therapy among HFPs. METHODS: This sequential controlled trial was conducted among HFPs from two medical centres. The control and the intervention group received integrative rehabilitation. PROs were measured in both groups using the SF36 questionnaire three times postsurgery: 24-48 hours, 2 weeks and 3 months. During the first round of questioning, only the intervention group was asked 'what matters most to you?' during the rehabilitative process. Accordingly, agreed-upon goals that were determined by the SF36's eight topics and were incorporated into the HFP's rehabilitative process. A Likert scale of 1-5, '1' indicating no-achievement and '5' full-achievement, was used to assess the goal achievement 4-6 months post-fracture. RESULTS: 84 HFPs participated in the study: 40 and 44 in the intervention and control group, respectively. In both groups, PROs declined after the HF, then improved somewhat 3 months later, but did not return to prefracture scores. Among the intervention group, 39% reached their specific goals (Likert level 5). Patients who achieved their goals had better PROs in comparison to others. The intervention group indicated PROs helped them articulate their desires and introduced them to new areas of care. CONCLUSIONS: Shifting from asking 'what's the matter?' to 'what matters most to you?' can improve the understanding of HFPs' own priorities, promote quality outcomes and enhance patient-centred care. Using PROs as a guide for goal-directed therapy can create a more inclusive process that includes the patients' most important health determinants and needs.

Rapid Classification of Sarcomas Using Methylation Fingerprint: A Pilot Study.

Sarcoma classification is challenging and can lead to treatment delays. Previous studies used DNA aberrations and machine-learning classifiers based on methylation profiles for diagnosis. We aimed to classify sarcomas by analyzing methylation signatures obtained from low-coverage whole-genome sequencing, which also identifies copy-number alterations. DNA was extracted from 23 suspected sarcoma samples and sequenced on an Oxford Nanopore sequencer. The methylation-based classifier, applied in the nanoDx pipeline, was customized using a reference set based on processed Illumina-based methylation data. Classification analysis utilized the Random Forest algorithm and t-distributed stochastic neighbor embedding, while copy-number alterations were detected using a designated R package. Out of the 23 samples encompassing a restricted range of sarcoma types, 20 were successfully sequenced, but two did not contain tumor tissue, according to the pathologist. Among the 18 tumor samples, 14 were classified as reported in the pathology results. Four classifications were discordant with the pathological report, with one compatible and three showing discrepancies. Improving tissue handling, DNA extraction methods, and detecting point mutations and translocations could enhance accuracy. We envision that rapid, accurate, point-of-care sarcoma classification using nanopore sequencing could be achieved through additional validation in a diverse tumor cohort and the integration of methylation-based classification and other DNA aberrations.

Paraneoplastic syndrome due to angiomatoid fibrous histiocytoma: a known presentation of an uncommon diagnosis in a rare site and age.

A woman in her 70s presented with a small subcutaneous retrosacrococcygeal mass and a history of elevated erythrocyte sedimentation rate present for several years. It was misdiagnosed as an inflammatory process of unclear origin. She underwent further investigation with the appearance of weight loss and weakness. A sacrococcygeal mass was noted on CT scan. A core needle biopsy was inconclusive for chordoma versus myoepithelioma. Wide surgical resection of the tumour including the coccygeal bone was performed. Following surgery, all the systemic symptoms resolved with normalisation of inflammatory markers. The pathological examination showed a relatively circumscribed multinodular myxoid tumour with lymphatic tissue cuff. Pan-sarcoma fusion analysis detected an EWSR1 (Exon7)-CREB1 (Exon7) fusion gene. The lesion was diagnosed as angiomatoid fibrous histiocytoma with paraneoplastic syndrome presentation of several years' duration.

Modified Transhumeral Amputation: A Case Report.

CASE: A 7-year-old boy presented with osteosarcoma of the ulna that required a transhumeral amputation. The patient completed neoadjuvant chemotherapy before surgery. To prevent bone overgrowth and improved prosthetic fitting, a modified amputation was performed with acute shortening and distal epiphysis preservation. CONCLUSION: In this modified amputation, bone overgrowth was not seen and repeated surgeries for stump shaping were prevented. The modified technique enabled length for the prosthetic elbow and a wide stump for better fitting. In cases of transhumeral amputation in children, the modified technique should be considered.

Fragility fracture management and FLS models in South Africa and Israel.

Osteoporosis is a common disease of the elderly. Many patients at high risk are neither identified nor treated. A Fracture Liaison Service is a coordinated model of care for secondary fracture prevention. Several national quality indicators have been published in each country to improve surgical treatment and osteoporosis medical treatment. Fracture Liaison Services in both countries have been created by local clinicians with different models depending on the medical geographic locations of patients and the local setup. The objective of this review is to describe the national guidelines and the current clinical treatment models for fragility fractures in South Africa and Israel. Successes and barriers to successful implementation have been identified and are summarized.

The role of routine imaging procedures in the detection of relapse of patients with Hodgkin lymphoma and aggressive non-Hodgkin lymphoma.

Despite improved initial therapies, a subgroup of patients with aggressive non-Hodgkin (A-NHL) and Hodgkin lymphomas (HL) will relapse after first remission. The optimal follow-up strategy for the detection of relapse has not been clarified and periodic imaging is not recommended in most written guidelines. We identified 125 patients with HL and A-NHL diagnosed between January 1993 and September 2008 who relapsed at least 1 month after the end of initial therapy. We assessed whether relapse was detected based on clinical signs or periodic computed tomography (CT), [(18)F] fluorodeoxyglucose positron emission tomography (PET), or combined PET/CT and whether the mode of detection influenced the pattern and outcome of relapsed disease. Overall, most relapses (62%) were diagnosed clinically especially in A-NHL and in patients with extranodal involvement at diagnosis (p < 0.05); however, relapses of HL occurring after 2001 when PET/CT became available were more commonly detected by routine imaging (p < 0.05). Imaging-detected relapse was not associated with improved survival. While clinical exam remains the most common mode of detecting relapse, our results suggest a potential role for routine PET/CT surveillance in HL patients; however, survival does not appear to be affected by mode of detection.

Postoperative extremity compartment syndrome in a cancer center: Incidence and risk factors.

OBJECTIVE: Postoperative compartment syndrome is a reported complication with known patient- and treatment-specific risk factors. Cancer patients carry unique risk factors associated with their underlying disease and long, complex procedures. While elevated serum lactate in traumatic and intensive care settings portends higher risk, no laboratory parameter has demonstrated utility in postoperative risk stratification. Postoperative extremity compartment syndrome in the study institution's cancer population was examined and whether intraoperative serum lactate correlates with postoperative compartment syndrome risk was investigated. METHODS: A 1:2 case-control study was performed, which compared cancer patients with postoperative compartment syndrome to those who underwent similar surgical procedures without this complication. Twelve patients were matched to 24 controls by sex, age, surgical procedures, and duration of surgery. Patient and operative variables were analyzed for prognostic significance. RESULTS: The compartment syndrome rate was 0.09% of all cases (n = 13,491); 0.12% of cases ≥ 3 h' duration (n = 9,979), and 0.25% of cases ≥ 5 h (n = 4,811). Compared with controls, the case group had higher median BMI (31.7 kg/m2 vs. 25.4 kg/m2, P = 0.001), and median intraoperative lactate level (4.05 mmol/L vs. 1.5 mmol/L, P = 0.047). CONCLUSION: Our institutional incidence of postoperative compartment syndrome was similar to that of non-oncologic institutions. While many traditional risk factors did not prove to be influential in our patients, elevated median body mass index and intraoperative serum lactate were identified as risk factors for postoperative compartment syndrome in a cancer population.

Friedrich Disease: A Case Report.

CASE: A 16-year-old girl presented with pain and swelling of the medial edge of the clavicle. She denied previous trauma and was evaluated by multiple physicians for a possible infection or neoplastic lesion. The patient underwent multiple studies and procedures, including blood tests, imaging studies, and biopsy. After 6 months, a diagnosis of osteochondrosis of the medial clavicle was made. After 1 year of observation, the symptoms resolved. CONCLUSIONS: The rarity of Friedrich disease and the scarcity of literature may lead to delayed diagnosis of this pathology. Awareness of medical personnel of this condition may facilitate accurate diagnosis.

A review of sarcopenia: Enhancing awareness of an increasingly prevalent disease.

Sarcopenia is defined as an age associated decline in skeletal muscle mass. The pathophysiology of sarcopenia is multifactorial, with decreased caloric intake, muscle fiber denervation, intracellular oxidative stress, hormonal decline, and enhanced myostatin signaling all thought to contribute. Prevalence rates are as high as 29% and 33% in elderly community dwelling and long-term care populations, respectively, with advanced age, low body mass index, and low physical activity as significant risk factors. Sarcopenia shares many characteristics with other disease states typically associated with risk of fall and fracture, including osteoporosis, frailty, and obesity. There is no current universally accepted definition of sarcopenia. Diagnosing sarcopenia with contemporary operational definitions requires assessments of muscle mass, muscle strength, and physical performance. Screening is recommended for both elderly patients and those with conditions that noticeably reduce physical function. Sarcopenia is highly prevalent in orthopedic patient populations and correlates with higher hospital costs and rates of falling, fracture, and mortality. As no muscle building agents are currently approved in the United States, resistance training and nutritional supplementation are the primary methods for treating sarcopenia. Trials with various agents, including selective androgen receptor modulators and myostatin inhibitors, show promise as future treatment options. Increased awareness of sarcopenia is of great importance to begin reaching consensus on diagnosis and to contribute to finding a cure for this condition.