Benchmarking weakly-supervised deep learning pipelines for whole slide classification in computational pathology

Artificial intelligence (AI) can extract visual information from histopathological slides and yield biological insight and clinical biomarkers. Whole slide images are cut into thousands of tiles and classification problems are often weakly-supervised: the ground truth is only known for the slide, not for every single tile. In classical weakly-supervised analysis pipelines, all tiles inherit the slide label while in multiple-instance learning (MIL), only bags of tiles inherit the label. However, it is still unclear how these widely used but markedly different approaches perform relative to each other.We implemented and systematically compared six methods in six clinically relevant end-to-end prediction tasks using data from N=2980 patients for training with rigorous external validation. We tested three classical weakly-supervised approaches with convolutional neural networks and vision transformers (ViT) and three MIL-based approaches with and without an additional attention module. Our results empirically demonstrate that histological tumor subtyping of renal cell carcinoma is an easy task in which all approaches achieve an area under the receiver operating curve (AUROC) of above 0.9. In contrast, we report significant performance differences for clinically relevant tasks of mutation prediction in colorectal, gastric, and bladder cancer. In these mutation prediction tasks, classical weakly-supervised workflows outperformed MIL-based weakly-supervised methods for mutation prediction, which is surprising given their simplicity. This shows that new end-to-end image analysis pipelines in computational pathology should be compared to classical weakly-supervised methods. Also, these findings motivate the development of new methods which combine the elegant assumptions of MIL with the empirically observed higher performance of classical weakly-supervised approaches. We make all source codes publicly available at https://github.com/KatherLab/HIA, allowing easy application of all methods to any similar task.     

Risk factors for acute kidney injury in vancomycin and piperacillin/tazobactam combination therapy: A retrospective study

IntroductionCombined use of vancomycin (VCM) and piperacillin/tazobactam (PIPC/TAZ) has been reported to increase the incidence of acute kidney injury (AKI). However, the risk factors associated with AKI after VCM and PIPC/TAZ (VPT) administration have not yet been identified. Therefore, we retrospectively assessed patients treated with VPT to investigate the risk factors for AKI development.MethodsThe study involved patients who were treated with VPT from January 1, 2016 to March 31, 2020. The patients were divided into the AKI or non-AKI group. The clinical characteristics of patients and antimicrobial therapy were compared between the groups. Their association with AKI risk was evaluated using multivariate logistic regression analysis.ResultsIn total, 182 patients were included, with 118 in the non-AKI group and 64 in the AKI group. Therefore, the incidence of AKI was 35.2 %. The initiation of VPT combination therapy on the same day and concomitant use of vasopressors were associated with an increased risk of AKI (odds ratio [OR] 2.55, 95 % confidential interval [CI] 1.20–5.44 and OR 3.22, 95 % CI 1.31–7.89, respectively).ConclusionOur findings suggest that the concomitant use of vasopressors and initiating VPT combination therapy on the same day are likely risk factors for AKI development.     

A therapeutic regimen of ceftazidime-avibactam for a critical patient receiving prolonged intermittent renal replacement therapy

The present report firstly described a critically ill patient receiving a dosing regimen of ceftazidime-avibactam (CAZ-AVI) (1.875g q24h) to eliminate multidrug-resistant Klebsiella pneumoniae and a scheduled time for prolonged intermittent renal replacement therapy (PIRRT) every 48h (6h-session beginning 12h after the previous dosage on hemodialysis day). This dosing regimen for CAZ-AVI and a scheduled time for PIRRT allowed pharmacodynamic parameters of ceftazidime and avibactam to have little difference on hemodialysis and non-hemodialysis days so that we can maintain a relatively stable drug concentration. Our report highlighted not only the importance of dosing regimens in patients with PIRRT but also the significance of hemodialysis time points during the dosing interval. The innovative therapeutic plan proved to be suitable for patients infected with Klebsiella pneumoniae when on PIRRT according to the trough plasma concentrations of ceftazidime and avibactam which were maintained above the minimum inhibitory concentration during the dosing interval.     

The effect of massage therapy on pain after surgery: A comprehensive meta-analysis

BackgroundFindings on the usefulness of massage therapy (MT) in postoperative pain management are often inconsistent among studies.ObjectivesThis study’s aim is to conduct a meta-analysis of randomized controlled trials (RCT) to clarify the effects of massage therapy in the treatment of postoperative pain.MethodsThree databases (PubMed, Embase, and Cochrane Central Register of Controlled Trials) were searched for RCTs published from database inception through January 26, 2021. The primary outcome was pain relief. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. The random-effect model was used to calculate the effect sizes and standardized mean difference (SMD) with 95 % confidential intervals (CIs) as a summary effect. The heterogeneity test was conducted through I². Subgroup and sensitivity analyses were used to explore the source of heterogeneity. Possible publication bias was assessed using visual inspection of funnel plot asymmetry.ResultsThe analysis included 33 RCTs and showed that MT is effective in reducing postoperative pain (SMD, −1.32; 95 % CI, −2.01 to −0.63; p = 0.0002; I² = 98.67 %). A similar significant effect was found for both short (immediate assessment) and long terms (assessment performed 4–6 weeks after the MT). Remarkably, we found neither the duration per session nor the dose had an impact on the effect of MT and there seemed to be no difference in the effects of different MT types. In addition, MT seemed to be more effective for adults. Furthermore, MT had better analgesic effects on cesarean section and heart surgery than orthopedic surgery.LimitationsPublication bias is possible due to the inclusion of studies in English only. Additionally, the included studies were extremely heterogeneous. Double-blind research on MT is difficult to implement, and none of the included studies is double-blind. There was some heterogeneity and publication bias in the included studies. In addition, there is no uniform evaluation standard for the operation level of massage practitioners, which may lead to research implementation bias.ConclusionsMT is effective in reducing postoperative pain in both short and long terms.     

Integrating informatics into undergraduate nursing education: A case study using a spiral learning approach

A gap in informatics expertise amongst nursing students, practising staff and faculty has been noted globally, which reduces the potential for nurses to utilise technology to enhance patient care. National nursing education strategies and recommendations from professional associations have identified digital health as an area that needs investment. This case study describes how health informatics is being integrated into a Bachelor of Nursing programme in the United Kingdom. An international collaboration with a US-UK Fulbright Specialist Scholar enabled individual learning units corresponding to key health informatics competencies to be designed and incorporated into a pedagogic framework grounded in the spiral learning approach. This approach is proposed as one way to integrate informatics into nursing education, so students can become competent clinicians that are able to deliver technology enabled care in the health service.     

Skin Cancer in Solid Organ Transplant Recipients: A Review for the Nondermatologist

Solid organ transplant recipients (SOTRs) are at increased risk for the development of skin cancer compared with the general population, which requires consistent monitoring and management from a multidisciplinary team. The aim of this review is to provide a comprehensive overview for nondermatologist clinicians, outlining skin cancer diagnosis, treatment pearls, and skin cancer prevention strategies as they relate to SOTRs. A comprehensive search of the literature was conducted through the MEDLINE database with search terms including organ transplantation, transplant recipient, skin cancer, cutaneous neoplasms, management, and therapies. The search was limited to the English language and dates ranging from January 1, 2011, to December 28, 2021. All studies were reviewed for inclusion. Skin cancer will develop in more than half of SOTRs at some point in their life, most often nonmelanoma skin cancer such as basal cell carcinoma or squamous cell carcinoma. Melanoma and rarer cutaneous malignant neoplasms, such as Merkel cell carcinoma and Kaposi sarcoma, are also more frequent among SOTRs. A multidisciplinary effort at skin cancer screening and patient education is invaluable to prevent skin cancer–related morbidity and mortality in this population of patients. Reduction in immunosuppressive medications and surgical intervention are effective therapeutic approaches, and more novel systemic therapies including G protein–coupled receptor inhibitors and immune checkpoint inhibitors are possible options when traditional treatment approaches are not feasible. Checkpoint inhibitor therapy, however, comes with the risk of allograft rejection. With a growing and aging SOTR population, it is essential that SOTRs have support from dermatologists and nondermatologists alike in skin cancer prevention and treatment.     

Acute Flaccid Myelitis: A Clinical Overview for 2019

Acute flaccid myelitis (AFM) is characterized by flaccid paralysis of one or more limbs, often following a viral illness, with magnetic resonance imaging findings consistent with inflammation of the spinal cord gray matter. It is unclear whether all patients with AFM will have full recovery of neurologic function. Since 2014, there have been several clusters of AFM in the United States, with a 3-fold increase in reported AFM cases recorded in 2018 compared with the previous year. Epidemiological evidence supports a temporal association between respiratory enteroviral illness, particularly with enteroviruses D68 and A71, and clustering of AFM cases. However, causality has yet to be established. Treatment of AFM is primarily supportive. Adjunctive therapies such as intravenous immunoglobulin, corticosteroids, plasmapheresis, and fluoxetine have not been found to improve long-term outcomes. Further research is urgently needed to characterize and optimize management of this emerging, yet poorly understood, condition.     

Superiority of high sensitivity cardiac troponin T vs. I for long-term prognostic value in patients with chest pain; data from the Akershus cardiac Examination (ACE) 3 study

BackgroundCardiac troponins (cTn) are essential in the diagnostic assessment of non-ST-segment-elevation acute coronary syndrome (NSTE-ACS). Elevated concentrations of cTnT and cTnI predict cardiovascular events in non-acute settings, but the individual troponin isotype association with long-term mortality in patients with suspected unstable angina pectoris (UAP) is less clear.MethodsPatients hospitalized with chest pain between June 2009 and December 2010 were included in the Akershus Cardiac Examination 3 Study and followed for median 6.6 (IQR 6.2-7.1) years. The index diagnosis was adjudicated by an independent committee as NSTE-myocardial infarction (NSTEMI), UAP or non-ACS. Blood samples were collected within 24 h of admission and analyzed with high sensitivity assays for cTnT (hs-cTnT, Roche) and cTnI (hs-cTnI, Singulex).ResultsOf 402 patients included, 74 (18%) were classified as NSTEMI, 88 (22%) UAP and 240 (60%) non-ACS. hs-cTnI concentrations were detectable in all patients (median 3 [IQR 1–11] ng/L), while hs-cTnT concentrations were above the level of blank in 205 (51%) (median 3 [IQR 3–16] ng/L). In patients with UAP, both log₂-transformed hs-cTnT and hs-cTnI were associated with all-cause mortality in analyses that adjusted for other risk factors: HR 2.40 [95% CI 1.75–3.30], p < 0.001 and HR 1.44 [1.14–1.81], p = 0.002. There were no significant sex-dependent differences in the association between hs-cTnT or hs-cTnI and outcome. Time dependent receiver-operating characteristics area under the curve was 0.85 (95% CI 0.79–0.92) for hs-cTnT and 0.74 (0.64–0.84) for hs-cTnI, p = 0.008 for difference between values.ConclusionsHigher concentrations of hs-cTnT and hs-cTnI were both associated with all-cause mortality in patients with UAP, but the association with outcome was stronger for hs-cTnT than for hs-cTnI.     

Weight-based versus non-weight-based diltiazem dosing in the setting of atrial fibrillation with rapid ventricular response

PurposeThere is conflicting evidence to support the superiority of weight-based (WB) dosing of intravenous (IV) diltiazem over non-weight-based (NWB) dosing strategies in the management of atrial fibrillation (AFib) with rapid ventricular response (RVR).MethodsA retrospective review evaluated patients presenting to the emergency department (ED) in AFib with RVR and receiving IV diltiazem from 2015 to 2018. Those receiving a NWB dose were compared with those receiving a WB dose based on actual body weight (ABW). Secondary analyses evaluated safety profiles of the regimens and compared response in groups defined by ABW or ideal body weight (IBW).ResultsA total of 371 patients were included in the analysis. No significant difference was observed in achieving a therapeutic response (66.5% vs. 73.1%, p = 0.18) or adverse events between the groups. Patients receiving a WB dose were significantly more likely to have a HR < 100 bpm than those receiving a NWB dose (40.9% vs. 53.5%, p = 0.01). When groups were defined by IBW, WB dosing was associated with a significantly higher incidence of achieving a therapeutic response (62.7% vs. 74.3%, p = 0.02).ConclusionIn patients presenting with AF with RVR, there was no significant difference in achieving a therapeutic response between the two strategies. A WB dosing approach did result in a greater proportion of patients with a HR < 100 bpm. The utilization of IBW for WB dosing may result in an increased achievement of a therapeutic response.     

Nebulized colistin as the adjunctive treatment for ventilator-associated pneumonia: A systematic review and meta-analysis

PurposeNebulized colistin (NC) is a potential therapy for ventilator-associated pneumonia (VAP); however, the clinical efficacy and safety of NC remain unclear. This study investigated whether NC is an effective therapy for patients with VAP.Materials and methodsWe performed a search in Web of Science, PubMed, Embase, and the Cochrane Library to retrieve randomized controlled trials (RCTs) and observational studies published at any time until February 6, 2023. The primary outcome was clinical response. Secondary outcomes included microbiological eradication, overall mortality, length of mechanical ventilation (MV), length of intensive care unit stay (ICU-LOS), nephrotoxicity, neurotoxicity, and bronchospasm.ResultsSeven observational studies and three RCTs were included. Despite exhibiting a higher microbiological eradication rate (OR,2.21; 95%CI, 1.25–3.92) and the same nephrotoxicity risk (OR,0.86; 95%CI, 0.60–1.23), NC was not significantly different in clinical response (OR,1.39; 95%CI, 0.87–2.20), overall mortality (OR,0.74; 95%CI, 0.50–1.12), MV length (mean difference (MD),-2.5; 95%CI, −5.20–0.19), and the ICU-LOS (MD,-1.91; 95%CI, −6.66–2.84) than by the intravenous antibiotic. Besides, the risk of bronchospasm raised significantly (OR, 5.19; 95%CI, 1.05–25.52) among NC.ConclusionNC was associated with better microbiological outcomes but did not result in any remarkable changes in the prognosis of patients with VAP.     

An automated near-real time computational method for induction and treatment of scar-related ventricular tachycardias

Catheter ablation is currently the only curative treatment for scar-related ventricular tachycardias (VTs). However, not only are ablation procedures long, with relatively high risk, but success rates are punitively low, with frequent VT recurrence. Personalized in-silico approaches have the opportunity to address these limitations. However, state-of-the-art reaction diffusion (R-D) simulations of VT induction and subsequent circuits used for in-silico ablation target identification require long execution times, along with vast computational resources, which are incompatible with the clinical workflow. Here, we present the Virtual Induction and Treatment of Arrhythmias (VITA), a novel, rapid and fully automated computational approach that uses reaction-Eikonal methodology to induce VT and identify subsequent ablation targets. The rationale for VITA is based on finding isosurfaces associated with an activation wavefront that splits in the ventricles due to the presence of an isolated isthmus of conduction within the scar; once identified, each isthmus may be assessed for their vulnerability to sustain a reentrant circuit, and the corresponding exit site automatically identified for potential ablation targeting. VITA was tested on a virtual cohort of 7 post-infarcted porcine hearts and the results compared to R-D simulations. Using only a standard desktop machine, VITA could detect all scar-related VTs, simulating activation time maps and ECGs (for clinical comparison) as well as computing ablation targets in 48 minutes. The comparable VTs probed by the R-D simulations took 68.5 hours on 256 cores of high-performance computing infrastructure. The set of lesions computed by VITA was shown to render the ventricular model VT-free. VITA could be used in near real-time as a complementary modality aiding in clinical decision-making in the treatment of post-infarction VTs.     

A Comparative Study of Treatment Interventions for Patellar Tendinopathy: A Randomized Controlled Trial

ObjectivesTo determine the additional effect of dry needling (DN) or percutaneous needle electrolysis (PNE) combined with eccentric exercise (EE) and determine which is the most effective for patients with patellar tendinopathy (PT).DesignBlinded, randomized controlled trial, with follow-up at 10 and 22 weeks.SettingsRecruitment was performed in sport clubs. Diagnosis and intervention were conducted at San Jorge University.ParticipantsPatients (N=48) with PT with pain for at least 3 months between the ages of 18 and 45 years.InterventionsThree interventions were carried out: DN and EE, PNE and EE, and EE with sham needle as the control group.Main Outcome MeasuresDisability was measured using the Victorian Institute of Sports Assessment Questionnaire, patellar tendon. Visual analog scale was used to measure pain over time, the Short Form-36 was used to measure quality of life, and ultrasound was used to measure structural abnormalities.ResultsA total of 48 participants (42 men, 6 women; average age, 32.46y; SD, 7.14y) were enrolled. The improvement in disability and pain in each group between baseline and post-treatment and baseline and follow-up was significant (P≤.05), without differences among groups.ConclusionDN or PNE combined with an EE program has not shown to be more effective than a program of only EE to improve disability and pain in patients with PT in the short (10wk) and medium (22wk) terms. Clinical improvements were not associated with structural changes in the tendon.     

A Target Antigen–Based Approach to the Classification of Membranous Nephropathy

ObjectiveTo describe the clinical and pathological phenotype of membranous nephropathy (MN) associated with M-type-phospholipase–A₂-receptor (PLA₂R), thrombospondin-type-1-domain-containing-7A (THSD7A), semaphorin 3B (SEMA3B), neural-epidermal-growth-factor-like-1-protein (NELL-1), protocadherin 7 (PCDH7), exostosin 1/exostosin 2 (EXT1/EXT2) and neural cell adhesion molecule 1 (NCAM-1) as target antigens.MethodsA retrospective cohort of 270 adult patients with biopsy-proven MN diagnosed between January 2015 and April 2020 was classified as PLA₂R-, THSD7A-, SEMA3B-, NELL-1–, PCDH7-, EXT1/EXT2-, NCAM-1–associated or septuple-negative MN using serologic tests, immunostaining, and/or mass spectrometry. Clinical, biochemical, pathologic, and follow-up data were systematically abstracted from the medical records, including disease activity of conditions traditionally associated with MN and occurring within 5 years of MN diagnosis.ResultsPatients with PLA₂R-associated MN were predominantly middle-aged white men without associated disease. The presence of associated disease did not affect the clinical and pathologic characteristics of PLA₂R-associated MN, suggesting that they were coincidental rather than causally linked. THSD7A-, NELL-1–, PCDH7-, and NCAM-1–associated MN were rare and SEMA3B-associated MN was not discovered in our cohort. EXT1/EXT2-associated MN was primarily diagnosed in younger women with active systemic autoimmunity. A significant proportion of septuple-negative patients had associated malignancy or systemic autoimmunity.ConclusionThe widely used distinction between primary and secondary MN has limitations. We propose a refined terminology that combines the target antigen and associated disease to better classify MN and guide clinical decision making.     

Indirect Comparison of Glucocorticoid-Sparing Agents for Remission Maintenance in Giant Cell Arteritis: A Network Meta-analysis

ObjectiveTo compare and rank the effect of glucocorticoid-sparing agents in giant cell arteritis (GCA), for which several drugs have been evaluated but with a benefit-risk balance that remains uncertain.MethodsThe MEDLINE and Clinical Trials databases were searched up to November 2021; all randomized controlled trials investigating glucocorticoids in GCA were included. The glucocorticoid regimen was dichotomized into short (≤6 months) or prolonged (>6 months) use. Risk of relapse and safety were estimated using network meta-analysis with frequentist random effects models.ResultsOf the 96 records screened, 8 trials were included (572 patients). The trials compared glucocorticoids and a sparing agent: tocilizumab (2 trials), oral methotrexate (3 trials), infliximab (1 trial), etanercept (1 trial), and adalimumab (1 trial). The pooled prevalence of GCA relapse was 52.6% (95% CI, 38.1 to 66.9). The risk of relapse was significantly lower with tocilizumab compared with methotrexate (relative risk [RR], 0.41; 95% CI, 0.17 to 0.97) and prolonged (RR, 0.41; 95% CI, 0.20 to 0.83) and short (RR, 0.32; 95% CI, 0.16 to 0.66) glucocorticoid use. The risk of relapse was not significantly different with methotrexate compared with short (RR, 0.79; 95% CI, 0.48 to 1.31) and prolonged (RR, 0.95; 95% CI, 0.31 to 2.89) glucocorticoid use. The frequency of serious adverse events and serious infection was comparable between the different drugs. The certainty of the evidence was low to very low.ConclusionThis meta-analysis suggests that tocilizumab may be superior to other sparing agents to prevent GCA relapse, but with a low to very low certainty of evidence, and that safety is comparable to the other drugs.RegistrationThe protocol of the meta-analysis is registered in the international prospective register of systematic reviews PROSPERO (https://www.crd.york.ac.uk/prospero/; registration CRD42020112387).     

Overview of Lymphedema for Physicians and Other Clinicians: A Review of Fundamental Concepts

Lymphedema has historically been underrated in clinical practice, education, and scholarship to the detriment of many patients with this chronic, debilitating condition. The mechanical insufficiency of the lymphatic system causes the abnormal accumulation of protein-rich fluid in the interstitium, which triggers a cascade of adverse consequences such as fat deposition and fibrosis. As the condition progresses, patients present with extremity heaviness, itchiness, skin infections, and, in later stages, dermal fibrosis, skin papillomas, acanthosis, and other trophic skin changes. Correspondingly, lymphedema results in psychological morbidity, including anxiety, depression, social avoidance, and a decreased quality of life, encompassing emotional, functional, physical, and social domains. For this review, we conducted a literature search using PubMed and EMBASE and herein summarize the evidence related to the fundamental concepts of lymphedema. This article aims to raise awareness of this serious condition and outline and review the fundamental concepts of lymphedema.     

Developing an empathy educational model (EEM) for undergraduate nursing students: A Delphi Technique

Despite the growing benefits of empathy education for medical students, there is still a lack of formal empathy courses in the Chinese context. To develop an empathy educational model for undergraduate nursing students, the Delphi technique was used in this study. Experts were selected from different regions of China and invited to participate in the three rounds of consultation, via email. The final empathy educational model was comprised of nine themes and 44 subthemes. The nine themes included: a. Bring the learner to the empathic world; b. Introduce the basic knowledge of empathy; c. Master empathy skills; d. Practice empathy; e. Evaluate empathy ability; f. Follow-up support; g. Distribution of educational hours for teaching empathy; h. Forms of empathy training; and i. Student reflection on empathy education. Consensus was achieved among the experts on empathy educational content, using the Delphi Technique, which can provide a reference for the empathy training of university medical students. It is necessary to have the empathy educational model further applied and evaluated, in conjunction with intervention studies, in the future.     

Effects of additive corticosteroid therapy on 90-day survival in patients with community-onset pneumonia

IntroductionSystemic corticosteroid therapy is occasionally used as an additive therapy, especially for patients with severe pneumonia. However, its recommendation for use in patients with pneumonia varies worldwide, and its efficacy is unclear.MethodsAdult Japanese patients hospitalized with community-onset pneumonia between January and December 2012 were analyzed using the Diagnostic Procedure Combination database. The patients were classified into mild-to-moderate and severe groups using the A-DROP (age, dehydration, respiration, orientation, and blood pressure) system. The 90-day survival rate was evaluated between the presence or absence of corticosteroid treatment using the Kaplan-Meier method in the overall, mild-to-moderate and severe groups, respectively. The patients’ clinical characteristics were adjusted between the two groups using the inverse probability of treatment weighting method.ResultsAmong 123,811, 110,534 patients were classified as mild-to-moderate grade (corticosteroid group: 8,465, non-corticosteroid group: 102,069) and 13,277 patients were classified as severe grade (corticosteroid group: 1,338, non-corticosteroid group: 11,939). The 90-day survival rate was higher in the non-corticosteroid group than in the corticosteroid group in patients with pneumonia of overall grade (weighted hazard ratio [HR]: 1.36; P < 0.001) and those with mild-to-moderate grade (weighted HR: 1.46; P < 0.001). However, there were no significant differences in the outcomes between the two groups in those with severe grade (weighted HR: 1.08; P = 0.38).ConclusionsAdditive systemic corticosteroid therapy may be related to poor 90-day prognosis in patients with mild-to-moderate grade community-onset pneumonia, although it may not be positively associated with its prognosis in those with severe grade.