Evidence for secondary thrombotic microangiopathy in COVID-19

The causes of coagulopathy associated with COVID-19 disease are poorly understood. We aimed to investigate the relationship between markers of endothelial activation, intravascular hemolysis, coagulation, and organ damage in COVID-19 patients and study their association with disease severity and mortality. We conducted a retrospective study of 181 hospitalized COVID-19 patients randomly selected with equal distribution of survivors and non-survivors. Patients who died had significantly lower ADAMTS13 activity, significantly higher LDH, schistocytes and von Willebrand Factor levels compared to patients discharged alive. Only 30% of patients with an initial ADAMTS13 activity <43% survived vs. 60% with ADAMTS13 [≥]43% who survived. In conclusion, COVID-19 may manifest as a TMA-like illness in a subset of hospitalized patients. Presence of schistocytes on admission may warrant a work-up for TMA. These findings indicate the need for future investigation to study the relationship between endothelial and coagulation activation and the efficacy of TMA treatments in COVID-19.

Whole-body magnetic resonance imaging in myxoid liposarcoma: A useful adjunct for the detection of extra-pulmonary metastatic disease.

Myxoid liposarcomas (MLS) are a subgroup of soft-tissue sarcomas which have a propensity for extra-pulmonary metastases. Conventional radiological staging of soft-tissue sarcomas consists of chest radiographs (CXR) and thoracic computed tomography (CT) for possible chest metastases, supplemented by magnetic resonance imaging (MRI) for local disease. The optimal radiological modality to detect extra-pulmonary metastases for systemic staging has not been proven. We reviewed the efficacy of Whole-Body MRI (WBMRI) for this purpose. 33 WBMRI and simultaneous CT scans were performed in 28 patients suffering from MLS between 2007 and 2015. 38 metastases were identified in seven patients via WBMRI. Osseous lesions predominated (spine, pelvis, chest-wall and long bones), followed by soft-tissue and abdominal lesions. Of the 29 soft-tissue or osseous metastases that were within the field-of-view of the simultaneous CT scans, five soft-tissue and zero osseous metastases were identified using CT. Metastatic disease was detected in three patients solely using WBMRI, which directly influenced their management. WBMRI is a useful adjunct in the detection of extra-pulmonary metastatic disease, which directly alters patient management. WBMRI has demonstrated an ability to identify more sites of metastatic disease compared to CT. WBMRI should be used in two situations. Firstly, at diagnosis where ablative treatment will be required e.g. amputation, when the diagnosis of occult metastasis would change treatment planning. Secondly, at diagnosis of relapse to confirm if it is a solitary site of relapse prior to consideration of metastectomy.

The outcome of resection of the distal ulna for tumour without soft-tissue or prosthetic reconstruction.

In patients with a tumour affecting the distal ulna it is difficult to preserve the function of the wrist following extensive local resection. We report the outcome of 12 patients (nine female, three male) who underwent excision of the distal ulna without local soft-tissue reconstruction. In six patients, an aggressive benign tumour was present and six had a malignant tumour. At a mean follow-up of 64 months (15 to 132) the mean Musculoskeletal Tumour score was 64% (40% to 93%) and the mean DASH score was 35 (10 to 80). The radiological appearances were satisfactory in most patients. Local recurrence occurred in one patient with benign disease and two with malignant disease. The functional outcome was thus satisfactory at a mean follow-up in excess of five years, with a relatively low rate of complications. The authors conclude that complex reconstructive soft-tissue procedures may not be needed in these patients.

The outcome of patients sustaining a proximal femur fracture who suffer from alcohol dependency.

There are many negative health consequences associated with alcohol dependency. Fractures of the proximal femur carry significant morbidity and mortality. This study examines the outcomes in patients with alcohol dependency, who sustain a fracture of the proximal femur. Twenty-eight consecutive alcohol dependent patients who suffered a fracture of the proximal femur were identified over a three year period. Data were collected on demographics, co-morbidity, surgical factors, mobility and mortality. The median age of patients was 61 years. The median weekly alcohol intake was 158 units. Thirteen patients sustained an extra-capsular fracture and 15 an intra-capsular proximal femoral fracture. Twenty-two fractures were treated with internal fixation and six with arthroplasty. The overall mortality rate was 29% at a median of 15 months post fracture. The failure rate of intra-capsular fractures fixed with cannulated screws was 56% at a median time of 43 days. All patients had a reduction in mobility compared to their pre-operative function. The reduction in mobility was greatest in patients with intra-capsular fractures treated with cannulated screw fixation. Alcohol dependent patients sustaining a fracture of the proximal femur are significantly younger than non-alcohol dependent patients sustaining the same injury. Despite the younger age at presentation the one year mortality rate of this group was high (29%). The high rate of complications with fracture fixation and high one year mortality suggest that hemiarthroplasty may be the best treatment option for intra-capsular fractures in this patient group.

Diffuse pigmented villonodular synovitis (diffuse-type giant cell tumour) of the foot and ankle.

Pigmented villonodular synovitis (PVNS) is a rare benign disease of the synovium of joints and tendon sheaths, which may be locally aggressive. We present 18 patients with diffuse-type PVNS of the foot and ankle followed for a mean of 5.1 years (2 to 11.8). There were seven men and 11 women, with a mean age of 42 years (18 to 73). A total of 13 patients underwent open or arthroscopic synovectomy, without post-operative radiotherapy. One had surgery at the referring unit before presentation with residual tibiotalar PVNS. The four patients who were managed non-operatively remain symptomatically controlled and under clinical and radiological surveillance. At final follow-up the mean Musculoskeletal Tumour Society score was 93.8% (95% confidence interval (CI) 85 to 100), the mean Toronto Extremity Salvage Score was 92 (95% CI 82 to 100) and the mean American Academy of Orthopaedic Surgeons foot and ankle score was 89 (95% CI 79 to 100). The lesion in the patient with residual PVNS resolved radiologically without further intervention six years after surgery. Targeted synovectomy without adjuvant radiotherapy can result in excellent outcomes, without recurrence. Asymptomatic patients can be successfully managed non-operatively. This is the first series to report clinical outcome scores for patients with diffuse-type PVNS of the foot and ankle.

Five-year survival of nonagenerian patients undergoing total hip replacement in the United Kingdom.

Between January 2000 and December 2007, 31 patients 90 years of age or older underwent total hip replacement at our hospital. Their data were collected prospectively. The rate of major medical complications was 9%. The surgical re-operation rate was 3%. The requirement for blood transfusion was 71% which was much higher than for younger patients. The 30-day, one-year and current mortality figures were 6.4% (2 of 31), 9.6% (3 of 31) and 55% (17 of 31), respectively, with a mean follow-up for the 14 surviving patients of six years. Cox's regression analysis revealed no significant independent predictors of mortality. Only 52% of patients returned immediately to their normal abode, with 45% requiring a prolonged period of rehabilitation. This is the first series to assess survival five years after total hip replacement for patients in their 90th year and beyond. Hip replacement in the extreme elderly should not be discounted on the grounds of age alone, although the complication rate exceeds that for younger patients. It can be anticipated that almost half of the patients will survive five years after surgery.

One-year outcome for elderly patients with displaced intracapsular fractures of the femoral neck managed non-operatively.

The outcome of patients with a displaced intracapsular femoral neck fracture treated non-operatively was assessed at 1 year and compared with patients managed operatively over the same time period. Data were collected prospectively for 102 consecutive patients. 80 patients underwent hemiarthroplasty and 22 were managed non-operatively. Patients were managed non-operatively if they were felt to have an unacceptably high risk of death within the perioperative period despite medical optimisation. Non-operative management entailed active early mobilisation without bed rest or traction. Patients managed non-operatively had a greater 30-day mortality compared with operatively managed patients. Deaths were due to pre-existing medical conditions or events, which had occurred at the time of hip fracture. No patient in the non-operative treatment group developed pneumonia, pressure sores or thrombo-embolic events. Patients treated non-operatively, who survived 30 days after fracture, had a mortality rate over the following year comparable with those who had undergone surgery. At 1 year, all non-operatively managed patients were able to transfer without pain and 6 of the 11 surviving patients were able to mobilise with walking aids. At 1 year, the majority of surviving non-operatively managed patients were living in their own homes. Surgical intervention is the treatment of choice for the majority of elderly patients with a displaced intracapsular femoral neck fracture. However, in patients with life-threatening medical co-morbidity, non-operative treatment with early mobilisation can yield acceptable results.

The St. Leger total knee replacement: a 10-year clinical and radiological assessment.

The St. Leger total knee replacement (Zynergy Orthopaedics Ltd, Rotherham, UK) was developed as a cheaper alternative to similar implants of its time. Between October 1993 and June 1999, 144 St. Leger total knee replacements were implanted into 114 patients. Seventy-three patients (99 knees) were recalled for assessment (mean follow-up of 10.2 years). Eighteen patients had had their prostheses revised, 11 had died and 12 were lost to follow-up. Functional Score showed 90% poor results and the Objective Knee Score showed 31% poor results. Radiological assessment identified 12 arthroplasties that had failed and 58 that required close follow. Kaplan-Meier cumulative survivorship was 87% at 10 years. The St. Leger knee replacement did not perform as well as others of the same generation and was not worth the initial financial savings.

Effects of upper-limb immobilisation on driving safety.

Doctors are frequently asked by patients whether it is safe to drive with an upper limb immobilised in a cast. In the literature there are no objective measurements of the effects of upper-limb immobilisation upon driving performance. Eight healthy volunteers performed four 20-min driving circuits in a driving simulator (STISIM 400W), circuits 1 and 4 without immobilisation and circuits 2 and 3 with immobilisation. Immobilisation involved a lightweight below-elbow cast with the thumb left free. Volunteers were randomised to right or left immobilisation for circuit 2, and the contralateral wrist was immobilised for circuit 3. Circuits included urban and rural environments and specific hazards (pedestrians crossing, vehicles emerging from a concealed entrance, traffic lights changing suddenly, avoidance of an oncoming vehicle in the driver's carriageway). Limb immobilisation led to more cautious rural and urban driving, with less adjustment of speed and lateral road position than when unrestricted. However when responding to hazards immobilisation caused less safe driving, with higher speeds, a greater proximity to the hazard before action was taken and less steering adjustment. The effects of restriction upon performance were more prevalent and severe with right-arm immobilisation. Upper-limb immobilisation appears to have little effect on the ability to drive a car unchallenged, but to adversely affect responses to routine hazards. Advice on ability to drive safely should be cautious, as the impact of immobilisation appears to be more subtle and wide ranging than previously thought.

Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells.

Somatic mosaicism has been observed previously in the lymphocyte population of patients with Fanconi anemia (FA). To identify the cellular origin of the genotypic reversion, we examined each lymphohematopoietic and stromal cell lineage in an FA patient with a 2815-2816ins19 mutation in FANCA and known lymphocyte somatic mosaicism. DNA extracted from individually plucked peripheral blood T cell colonies and marrow colony-forming unit granulocyte-macrophage and burst-forming unit erythroid cells revealed absence of the maternal FANCA exon 29 mutation in 74.0%, 80.3%, and 86.2% of colonies, respectively. These data, together with the absence of the FANCA exon 29 mutation in Epstein-Barr virus-transformed B cells and its presence in fibroblasts, indicate that genotypic reversion, most likely because of back mutation, originated in a lymphohematopoietic stem cell and not solely in a lymphocyte population. Contrary to a predicted increase in marrow cellularity resulting from reversion in a hematopoietic stem cell, pancytopenia was progressive. Additional evaluations revealed a partial deletion of 11q in 3 of 20 bone marrow metaphase cells. By using interphase fluorescence in situ hybridization with an MLL gene probe mapped to band 11q23 to identify colony-forming unit granulocyte-macrophage and burst-forming unit erythroid cells with the 11q deletion, the abnormal clone was exclusive to colonies with the FANCA exon 29 mutation. Thus, we demonstrate the spontaneous genotypic reversion in a lymphohematopoietic stem cell. The subsequent development of a clonal cytogenetic abnormality in nonrevertant cells suggests that ex vivo correction of hematopoietic stem cells by gene transfer may not be sufficient for providing life-long stable hematopoiesis in patients with FA.

Alpha-fetoprotein and beta-human chorionic gonadotropin: their clinical significance as tumour markers.

Tumour markers can aid in areas such as diagnosis, surveillance of recurrence, staging and prognosis. This article focuses on 2 tumour markers, alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG). These tumour markers have been examined for their utility as prognostic indicators in 2 different manners. First, the marker level at diagnosis has been studied to determine if it is prognostic of outcome presumably because of its relation to tumour bulk or to the biological nature of the tumour. A more recent trend has been to investigate tumour marker decline. The finding of a delayed rate of decline suggests a poorer response of the malignancy to chemotherapy. The major focus of the article will be on marker decline of AFP and HCG as prognostic tools in peripheral and central nervous system (CNS) germ cell tumours (GCTs) and hepatic tumours (hepatoblastoma and hepatocellular carcinoma). The articles reviewed here suggest that HCG and AFP can correlate with survival if examined in specific ways, and could potentially be used to tailor treatment for individual patients. One group of authors presents data on patients with GCTs suggesting that satisfactory marker regression is an independent prognostic factor for survival. In a study of hepatoblastoma, data demonstrate that both the magnitude and rate of decline are associated with survival. Marker decline studies in hepatocellular carcinoma do not exist and marker levels at diagnosis do not appear to have a role in potential therapeutic changes. However, data on fucosylated subtype of AFP, Lens culinaris agglutinin A reactive AFP, has shown prognostic significance in hepatocellular carcinoma. The data for CNS GCTs are limited and studies examining serial cerebrospinal fluid HCG/AFP are ongoing. In some diseases, issues relating to timing of marker sampling when examining marker decline need to be studied in greater detail. Hopefully, marker decline studies can be duplicated in the other diseases, to document a potential role in determining outcome. Further studies are needed to test the ability to alter therapy in attempts to improve survival while decreasing toxicity to patients.

Sequence variation in the Fanconi anemia gene FAA.

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy. The gene for FA complementation group A (FAA) recently has been cloned. The cDNA is predicted to encode a polypeptide of 1,455 amino acids, with no homologies to any known protein that might suggest a function for FAA. We have used single-strand conformational polymorphism analysis to screen genomic DNA from a panel of 97 racially and ethnically diverse FA patients from the International Fanconi Anemia Registry for mutations in the FAA gene. A total of 85 variant bands were detected. Forty-five of the variants are probably benign polymorphisms, of which nine are common and can be used for various applications, including mapping studies for other genes in this region of chromosome 16q. Amplification refractory mutation system assays were developed to simplify their detection. Forty variants are likely to be pathogenic mutations. Seventeen of these are microdeletions/microinsertions associated with short direct repeats or homonucleotide tracts, a type of mutation thought to be generated by a mechanism of slipped-strand mispairing during DNA replication. A screening of 350 FA probands from the International Fanconi Anemia Registry for two of these deletions (1115-1118del and 3788-3790del) revealed that they are carried on about 2% and 5% of the FA alleles, respectively. 3788-3790del appears in a variety of ethnic groups and is found on at least two different haplotypes. We suggest that FAA is hypermutable, and that slipped-strand mispairing, a mutational mechanism recognized as important for the generation of germ-line and somatic mutations in a variety of cancer-related genes, including p53, APC, RB1, WT1, and BRCA1, may be a major mechanism for FAA mutagenesis.

Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise.

BACKGROUND: Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials. METHODS AND RESULTS: We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction < or = 0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n = 145) or carvedilol (n = 133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P = .014) or by a global assessment of progress judged either by the patient (P = .002) or by the physician (P < .001). In addition, treatment with carvedilol was associated with a significant increase in ejection fraction (P < .001) and a significant decrease in the combined risk of morbidity and mortality (P = .029). In contrast, carvedilol therapy had little effect on indirect measures of patient benefit, including changes in exercise tolerance or quality-of-life scores. The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure. CONCLUSIONS: These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor.

Implementation of the Patient Self-Determination Act in a community hospital.

After extensive staff/community education, a New Jersey community hospital survey found good compliance with the Patient Self-Determination Act, but only 14.8 percent of patients had completed advance directives, and there was infrequent physician documentation.

Limited usefulness of exercise testing and thallium scintigraphy in evaluation of ambulatory patients several months after recovery from an acute coronary event: implications for management of stable coronary heart disease. Multicenter Myocardial Ischemia Research Group.

OBJECTIVES: This study evaluated the value of noninvasive testing to predict cardiac events in patients with stable coronary disease after hospital admission (and risk stratification) for an acute coronary event. BACKGROUND: Exercise testing with thallium perfusion imaging identifies patients with obstructive coronary artery disease and has been used to stratify patients after myocardial infarction. Its usefulness for predicting cardiac events in patients with stable coronary disease after recovery from an acute coronary event was explored. METHODS: Nine hundred thirty-six patients were enrolled 1 to 6 months after hospital admission for a coronary event. Patients underwent exercise treadmill testing with planar thallium-201 scintigraphy and were followed up for an average of 23 months (range 6 to 43). End points were 1) unstable angina requiring hospital admission, nonfatal myocardial infarction or cardiac death; 2) nonfatal infarction or cardiac death; or 3) cardiac death alone. RESULTS: Twelve patients died of cardiac causes (1.2%); 32 had a nonfatal myocardial infarction (3.4%); and 79 patients (8.4%) developed unstable angina in the first year. Exercise testing improved proportional hazards models constructed from clinical variables for all three end points (p < 0.05). The perfusion scan further improved models for the end points (nonfatal infarction or cardiac death and cardiac death alone, p < 0.05). However, the exercise test with or without thallium added little to the overall prediction of primary events (area under the receiver operating curve increased from 0.649 to 0.663), and only 2% to 13% of patients with abnormal results either had a nonfatal infarction or died. CONCLUSIONS: Thallium-201 scintigraphy and exercise testing variables identify patients at risk for subsequent cardiac events. However, the poor predictive performance of these tests in this group of patients with stable coronary disease severely limits their usefulness. These results suggest a limited role for exercise and thallium testing in predicting cardiac events in patients with known coronary disease.

Early emergent coronary bypass after failed angioplasty.

Emergency CABG for failed coronary angioplasty was required in 3.3 percent of 1,625 consecutive patients undergoing angioplasties. Twenty-six percent of the patients died in the perioperative period. Efforts must be concentrated on identifying PTCA failure prior to cardiogenic shock.

Early emergent coronary bypass after failed angioplasty.

Emergency CABG for failed coronary angioplasty was required in 3.3 percent of 1,625 consecutive patients undergoing angioplasties. Twenty-six percent of the patients died in the perioperative period. Efforts must be concentrated on identifying PTCA failure prior to cardiogenic shock.