Analysis, identification and visualization of subgroups in genomics.

MOTIVATION: Cancer is a complex and heterogeneous disease involving multiple somatic mutations that accumulate during its progression. In the past years, the wide availability of genomic data from patients' samples opened new perspectives in the analysis of gene mutations and alterations. Hence, visualizing and further identifying genes mutated in massive sets of patients are nowadays a critical task that sheds light on more personalized intervention approaches. RESULTS: Here, we extensively review existing tools for visualization and analysis of alteration data. We compare different approaches to study mutual exclusivity and sample coverage in large-scale omics data. We complement our review with the standalone software AVAtar ('analysis and visualization of alteration data') that integrates diverse aspects known from different tools into a comprehensive platform. AVAtar supplements customizable alteration plots by a multi-objective evolutionary algorithm for subset identification and provides an innovative and user-friendly interface for the evaluation of concurrent solutions. A use case from personalized medicine demonstrates its unique features showing an application on vaccination target selection. AVAILABILITY: AVAtar is available at: https://github.com/sysbio-bioinf/avatar. CONTACT: hans.kestler@uni-ulm.de, phone: +49 (0) 731 500 24 500, fax: +49 (0) 731 500 24 502.

Navigating our way through a hospital ransomware attack: ethical considerations in delivering acute orthopaedic care.

Ransomware attacks on healthcare systems are becoming more prevalent globally. In May 2021, Waikato District Health Board in New Zealand was devastated by a major attack that crippled its information technology system. The Department of Orthopaedic Surgery faced a number of challenges to the way they delivered care including, patient assessment and investigations, the deferral of elective surgery, and communication and patient confidentiality. These issues are explored through the lens of the four key principles of medical ethics in the hope that they will provide some guidance to future departments who may experience such attacks.

Medium-term outcomes of a cohort of revision rotator cuff repairs.

BACKGROUND: There are limited medium- and long-term studies investigating clinical outcomes following revision rotator cuff surgery. The aim of the current study was to analyze the medium-term pain and functional outcomes of a cohort of revision rotator cuff repairs. METHODS: This was a multicenter, prospective cohort study of revision rotator cuff repairs undertaken between March 2009 and December 2010. Pain, function (Flex-SF), and postoperative data were collected at baseline; 6, 12, and 24 months; and 5 years. RESULTS: A total of 125 revision rotator cuff repairs were included in this study. Average improvement in Flex-SF and pain from baseline to 5 years was 8.5 (P < .001) and 2.1 points, respectively (P < .001). The improvement was not as pronounced as those who underwent primary repair. Significantly lower pain scores were seen in nonsmokers (P < .001) and in those who underwent tenotomy rather than tenodesis (2 vs. 3.5, P < .05) for a damaged long head of biceps. Significantly higher function scores were seen in those with only 1 tendon involved (P < .05). The patient-reported retear rate was 32.6%, and the reoperation rate was 34.7%. CONCLUSION: Revision rotator cuff repair provides significant improvement in both pain and function at 5 years postoperation, though not as good as primary repair. Superior clinical outcomes are seen in nonsmokers, those with only 1 tendon affected, and those who undergo tenotomy instead of tenodesis for a damaged long head of biceps tendon.

Three-dimensional ultrasound of the neonatal brain: technical approach and spectrum of disease.

Brain pathology is an important cause of morbidity and mortality in neonates, especially in the premature population. While conventional two-dimensional neurosonography is traditionally used for screening, diagnosis and monitoring of brain disorders such as germinal matrix hemorrhage, periventricular leukomalacia and hydrocephalus, three-dimensional ultrasonography has gained popularity in a variety of clinical applications in recent years. Three-dimensional ultrasonography is not yet widely utilized in pediatric imaging but is a potentially powerful tool for evaluating the neonatal brain. Three-dimensional neurosonography allows imaging of the entire brain in a single volumetric sweep and offers the capability of reconstructing images in the axial plane and performing volumetric analyses that are unavailable in conventional two-dimensional neurosonography. The purpose of this article is two-fold: (1) to present the technical aspects of three-dimensional neurosonography and (2) to illustrate the potential applications of three-dimensional neurosonography in the context of commonly encountered neonatal neuropathology.

Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

A Diagnosis Not to Miss: A Case of Fitz-Hugh-Curtis Syndrome.

Fitz-Hugh-Curtis syndrome is a rare disease attributed to complications of pelvic inflammatory disease secondary to chlamydia or gonorrhea infections. Patients generally complain of vague abdominal pain that is often acute in onset, with or without genitourinary complaints. We present a case of Fitz-Hugh-Curtis syndrome with a young female who presents with a complaint of right upper quadrant abdominal pain for 2 months' duration. She initially had no genitourinary complaints. She underwent a diagnostic laparoscopy and cholecystectomy during which adhesions from the lateral liver to the abdominal wall were visualized. The cholecystectomy did not relieve her pain. She later complained of abnormal vaginal bleeding for 15 days one month prior to her admission, unbeknownst to the medical team on admission. A chlamydia DNA probe test was positive, and the diagnosis of Fitz-Hugh-Curtis syndrome was made.

HIV Symptom Clusters are Similar Using the Dimensions of Symptom Occurrence and Distress.

CONTEXT: People living with HIV infection (PLWH) in the United States continue to experience a high symptom burden despite improvements in antiretroviral therapy. OBJECTIVES: The purpose of this study was to determine if the number and types of symptom clusters differed based on whether symptom occurrence rates or distress ratings were used to create the clusters. METHODS: Data from 2,000 patients with complete symptom occurrence rates and distress scores on the 20-item HIV Symptom Index from their first ambulatory clinic visit at one of six national HIV centers of excellence in the Center for AIDS Research Network of Integrated Clinical Systems were used in these analyses. Exploratory factor analysis was used to create the symptom clusters. RESULTS: The same four symptom clusters (i.e., gastrointestinal, psychological, pain, body image) were identified using occurrence rates and distress ratings. For both dimensions of the symptom experience, the psychological, pain, and body image clusters each had the same symptoms. For the gastrointestinal cluster, four symptoms loaded on the occurrence dimension and six symptoms loaded on the distress dimension. CONCLUSION: The number and types of symptom clusters were relatively similar across the occurrence and distress dimensions of the symptom experience. Symptom clusters in PLWH may provide insights into the development of targeted interventions for multiple co-occurring symptoms.

Do Age, Demographics, and Tear Characteristics Affect Outcomes After Rotator Cuff Repair? Results of Over 2000 Rotator Cuff Repairs at 5-Year Follow-up.

Background: The New Zealand Rotator Cuff Registry represents the largest prospective cohort of rotator cuff repairs. Despite this, there are limited medium- to long-term data of rotator cuff repair outcomes. Purpose: To (1) analyze the pain and functional outcomes of a large cohort of primary rotator cuff repairs and (2) evaluate the effect of patient factors and tear characteristics on medium-term outcomes. Study Design: Cohort study; Level of evidence, 2. Methods: This was a multicenter, multisurgeon prospective cohort study of rotator cuff repairs from March 2009 until December 2010. Surgical data were collected by the operating surgeon. Primary outcome measures were the Flexilevel Scale of Shoulder Function (FLEX-SF) and a pain score, collected at baseline, 6, 12, and 24 months, and 5 years. Univariate and multivariate analyses were carried out. Results: Overall, 2533 primary rotator cuff repairs were analyzed with 81% follow-up at 5 years. The mean age of the cohort was 56 years. In the 2052 patients with final follow-up data, improvement on the FLEX-SF continued until 24 months postoperatively and remained high at 5 years. Mean improvement in FLEX-SF from baseline to 5 years was 15 points. Patients aged >70 years had lower FLEX-SF scores but no significant difference in improvement compared with patients ≤70 years. The mean anteroposterior tear size was 2.2 cm, and on multivariate analysis, tears >4 cm had worse 5-year FLEX-SF scores. If the affected tendon was easily reducible, there was no difference in FLEX-SF score for retracted or larger tears compared with smaller tears. The reoperation rate was 6.2%. Conclusion: Results indicated that rotator cuff repairs provide a sustained clinical improvement out past 5 years. Most functional improvement and pain relief occurred within the first 6 months, but improvement continued out to 24 months. Most population groups did well after rotator cuff repairs, including those >70 years. Tear size >4 cm and tendon reducibility correlated with outcome. Even patients with large tear sizes had clinically significant improvement in FLEX-SF scores after repair.

Testing for non-random mating: evidence for ancestry-related assortative mating in the Framingham heart study.

Population stratification leads to a predictable phenomenon-a reduction in the number of heterozygotes compared to that calculated assuming Hardy-Weinberg Equilibrium (HWE). We show that population stratification results in another phenomenon-an excess in the proportion of spouse-pairs with the same genotypes at all ancestrally informative markers, resulting in ancestrally related positive assortative mating. We use principal components analysis to show that there is evidence of population stratification within the Framingham Heart Study, and show that the first principal component correlates with a North-South European cline. We then show that the first principal component is highly correlated between spouses (r = 0.58, p = 0.0013), demonstrating that there is ancestrally related positive assortative mating among the Framingham Caucasian population. We also show that the single nucleotide polymorphisms loading most heavily on the first principal component show an excess of homozygotes within the spouses, consistent with similar ancestry-related assortative mating in the previous generation. This nonrandom mating likely affects genetic structure seen more generally in the North American population of European descent today, and decreases the rate of decay of linkage disequilibrium for ancestrally informative markers.

Lipoprotein(a) as a unique primary risk factor for early atherosclerotic peripheral arterial disease.

Elevated plasma lipoprotein(a) is a relatively common condition that contributes to many cardiovascular diseases. However, the awareness and testing for this condition remain low. Herein, we present a case of an otherwise healthy and active man who developed symptoms of peripheral arterial disease starting at age 49, and was found to have hyper-lipoprotein(a) as his only notable risk factor. Diagnosis was not made until years later, after an extensive workup. Upon further screening, he was also found to have subclinical coronary and carotid artery atherosclerotic disease. The patient was treated with aspirin, statin, niacin and angioplasty to bilateral superficial femoral arteries with good symptom resolution. Early screening of his son also revealed a similarly elevated lipoprotein(a) level. It is important to raise awareness of this condition and its relationship to early-onset peripheral arterial disease so patients and their families can be appropriately identified, counselled and treated.

Genetic diversity, admixture, and hatchery influence in Brook Trout (Salvelinus fontinalis) throughout western New York State.

Although Brook Trout are distributed across most of eastern North America, population numbers have declined in many regions due to habitat loss, climate change, and competition with non-native species. In New York State, Brook Trout habitat has been substantially reduced, with many areas showing complete extirpation of Brook Trout populations, predominantly in the western portion of the state. Small, fragmented populations are at risk of genetic diversity loss, inbreeding depression, and reduced fitness, leading to a greater potential for local extirpation. Genetic monitoring is a practical tool that can facilitate further conservation-decision making regarding small populations. In this study, we used 12 microsatellite loci to examine 3,436 sampled Brook Trout, representing 75 sites from the Allegheny, Erie/Niagara, Genesee, Oswego, Lake Ontario, and Susquehanna drainage basins throughout western New York State. Three Brook Trout hatchery strains were also genetically characterized to evaluate the degree of hatchery introgression between wild populations and hatchery strains stocked in the region. Overall, estimates of genetic diversity varied widely: Allelic richness ranged from 2.23 to 7.485, and expected heterozygosity ranged from 0.402 to 0.766. As observed for Brook Trout in other regions, we found a high degree of genetic differentiation among populations, with all comparisons except one showing significant F ST values. Hatchery introgression was found to be minimal, with estimates ranging from 1.96% to 3.10% of wild individuals exhibiting membership proportions to a hatchery strain cluster exceeding 10% (q ≥ 0.10). Results from this investigation can be used to prioritize management efforts for Brook Trout in western New York State and act as a baseline to monitor future population trends.

CD34+ pigmented fibrous proliferations: the morphologic overlap between pigmented dermatofibromas and Bednar tumors.

Pigmented dermatofibrosarcoma protuberans (DFSP; Bednar tumor) constitutes 5%-10% of all cases of DFSP and shows morphologic features that overlap with melanocytic and fibrous proliferations. We report 2 unusual cases of pigmented fibrous proliferations that demonstrate features of dermatofibromas and DFSP. The first case is that of a 19-year-old man with a 3-year history of a slowly growing pigmented lesion on the right arm. On clinical exam, the lesion was a 7-mm firm pigmented papulonodular lesion. The second case is that of a 31-year-old woman with a 4- to 5-year history of a slowly enlarging, asymptomatic "dark area" on the right buttock. On clinical exam, the lesion was a 2-cm darkly pigmented flat nodule. Morphologically, both lesions are primarily dermal proliferations of spindled cells admixed with pigmented dendritic melanocytes. The lesional cells trap collagen fibers at the periphery and there is basal cell hyperpigmentation. Adnexal structures are effaced, but significant trapping of subcutaneous fat is not present. By immunohistochemistry, both lesions show focal CD34 positivity but are negative for Factor XIIIa and melanocytic markers. Although overlap between standard dermatofibromas and DFSP is well documented in the literature, pigmented fibrous lesions with features of both entities are not well described.

ACR white paper on teleradiology practice: a report from the Task Force on Teleradiology Practice.

Teleradiology services are now embedded into the workflow of many radiology practices in the United States, driven largely by an expanding corporate model of services. This has brought opportunities and challenges to both providers and recipients of teleradiology services and has heightened the need to create best-practice guidelines for teleradiology to ensure patient primacy. To this end, the ACR Task Force on Teleradiology Practice has created this white paper to update the prior ACR communication on teleradiology and discuss the current and possible future state of teleradiology in the United States. This white paper proposes comprehensive best-practice guidelines for the practice of teleradiology, with recommendations offered regarding future actions.

Association of DXA-derived bone mineral density and fat mass with African ancestry.

CONTEXT: Both genes and environment have been implicated in determining the complex body composition phenotypes in individuals of European ancestry; however, few studies have been conducted in other race/ethnic groups. OBJECTIVE: We conducted a genome-wide admixture mapping study in an attempt to localize novel genomic regions associated with genetic ancestry. SETTING/PARTICIPANTS: We selected a sample of 842 African-American women from the Women's Health Initiative single nucleotide polymorphism (SNP) Health Association Resource for whom several dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) and fat mass phenotypes were available. METHODS: We derived both global and local ancestry estimates for each individual from Affymetrix 6.0 data and analyzed the correlation of DXA phenotypes with global African ancestry. For each phenotype, we examined the association of local genetic ancestry (number of African ancestral alleles at each marker) and each DXA phenotype at 570 282 markers across the genome in additive models with adjustment for important covariates. RESULTS: We identified statistically significant correlations of whole-body fat mass, trunk fat mass, and all 6 measures of BMD with a proportion of African ancestry. Genome-wide (admixture) significance for femoral neck BMD was achieved across 2 regions ∼3.7 MB and 0.3 MB on chromosome 19q13; similarly, total hip and intertrochanter BMD were associated with local ancestry in these regions. Trunk fat was the most significant fat mass phenotype showing strong, but not genomewide significant associations on chromosome Xp22. CONCLUSIONS: Our results suggest that genomic regions in postmenopausal African-American women contribute to variance in BMD and fat mass existence and warrant further study.

Catalysis-based enantioselective total synthesis of myxothiazole Z, (14S)-melithiazole G and (14S)-cystothiazole F.

A common strategy for the stereoselective and protecting group-free total synthesis of the myxobacterial antibiotics myxothiazole Z, (14S)-melithiazole G and (14S)-cystothiazole F is described featuring an asymmetric organocatalytic transfer hydrogenation, a palladium-catalyzed Stille coupling and a cross-metathesis as the key steps.

Stereoselective synthesis of the C1-C11 and C12-C34 fragments of mycalolide A.

A convergent synthesis of the C1-C11 and C12-C34 fragments of mycalolide A is described. Synthetic highlights include a highly E-selective cross-metathesis between a vinyl-functionalized bis-oxazole unit and a polypropionate side chain to introduce the C19-C20 double bond and an enzymatic desymmetrization of a meso-diol in addition to five stereoselective allylations/crotylations to control the 11 stereogenic centers present in the natural product.

Whose termination is it anyway?

Termination of psychoanalytic treatment presents a complex challenge concerning the application of psychoanalytic theory and technique. The paucity of cases that might provide analysts an opportunity to explore a variety of management approaches demands that practitioners share their experiences in as much detail as possible, but this occurs infrequently outside of seminars and discussion groups. In an effort to "cast a lens" on the termination process, a detailed description and process notes are presented from the closing phase of a 4-year analysis of a man with obsessive compulsive personality and difficulties with urination outside his home. The analyst's countertransference is emphasized, especially during enactments characteristic of this period. Alterations and variations in analytic technique and the demands for practical courses of action within and outside of the treatment are also examined. The issue of "forced" versus "natural" terminations is addressed as a means toward understanding a model of termination as a necessarily co-constructed component of analysis generally.

Enantioselective organocatalytic conjugate reduction of beta-azole-containing alpha,beta-unsaturated aldehydes.

Beta-azole-containing alpha,beta-unsaturated aldehydes were successfully reduced under highly enantioselective organocatalytic transfer hydrogenation conditions. The products were obtained in good yields and up to 94% optical purity. This simple process was successfully applied to the synthesis of the C7-C14 fragment of ulapualide A, a natural product which exhibits promising antitumor activity.