ACL Primary Repair Has Limited Indications and Outcomes Inferior to ACL Reconstruction.

ACL primary repair literature does not convincingly show non-inferiority to the gold-standard of ACL reconstruction using a graft. Primary repair has narrow indications, typically Sherman Type I tear pattern representing femoral avulsion good tissue quality. In addition, recent research shows greater post-operative laxity in repairs deemed successful in comparison to laxity in patients having reconstruction. Our primary point is worth repeating: In contrast to ACL primary repair, ACL reconstruction is the gold standard for ACL tears.

Carbon Monoxide-Related Vision Loss in an Acute Burn Patient.

Carbon monoxide poisoning can occur as part of smoke exposure in the burn population. Here we report the case of a 32-year-old, previously healthy male, with carbon monoxide-related blindness after smoke exposure in an apartment fire. Cerebral hypoperfusion was diagnosed using magnetic resonance imaging of the brain, and the patient was diagnosed with cortical visual impairment. He was treated with hyperbaric oxygen therapy following which he had partial recovery of his vision. There is a paucity of information regarding this phenomenon and its treatment.

Candida auris in the burn unit: a prolonged biphasic outbreak.

Candida auris is an emerging pathogen responsible for healthcare-associated infections and outbreaks. This organism has a high tolerance to both high temperatures and high salinity. We describe our experience with a C. auris outbreak in an 8-bed inpatient burn unit at an academic medical center.

Editorial Commentary: Biceps Management During Rotator Cuff Tear: Confounding Variables Result in Unclear Indications.

Is "killing the biceps" during rotator cuff repair a capital crime or a lawful act? One of the most passionately debated topics in shoulder surgery is what to do with the biceps during rotator cuff repair: save it, tenotomize it, or perform tenodesis. Results of repair are not very successful, and given that repair of massive rotator cuff tears shows a 40% to 57% failure rate, there is renewed interest in sparing the biceps tendon as a humeral head depressor-or so that it may be used as a local graft for revision rotator cuff repair. The literature regarding tenodesis versus biceps sparing during rotator cuff repair is controversial. There are so many confounding variables affecting rotator cuff repair outcomes (tear size, comorbidities, age, tissue quality, etc.) that we do not believe that anything less than a randomized, prospective study that matches groups is likely to provide a conclusive verdict.

Computational Pathology Assessments of Cardiac Stromal Remodeling: Clinical Correlates and Prognostic Implications in Heart Transplantation.

Both overt and indolent inflammatory insults in heart transplantation can accelerate pathologic cardiac remodeling, but there are few tools for monitoring the speed and severity of remodeling over time. To address this need, we developed an automated computational pathology system to measure pathologic remodeling in transplant biopsy samples in a large, retrospective cohort of n=2167 digitized heart transplant biopsy slides. Biopsy images were analyzed to identify the pathologic stromal changes associated with future allograft loss or advanced allograft vasculopathy. Biopsy images were then analyzed to assess which historical allo-inflammatory events drive progression of these pathologic stromal changes over time in serial biopsy samples. The top-5 features of pathologic stromal remodeling most strongly associated with adverse outcomes were also strongly associated with histories of both overt and indolent inflammatory events. Our findings identify previously unappreciated subgroups of higher- and lower-risk transplant patients, and highlight the translational potential of digital pathology analysis.

Endoluminal Biopsy for Vein of Galen Malformation.

BACKGROUND AND OBJECTIVES: Vein of Galen malformation (VOGM), the result of arteriovenous shunting between choroidal and/or subependymal arteries and the embryologic prosencephalic vein, is among the most severe cerebrovascular disorders of childhood. We hypothesized that in situ analysis of the VOGM lesion using endoluminal tissue sampling (ETS) is feasible and may advance our understanding of VOGM genetics, pathogenesis, and maintenance. METHODS: We collected germline DNA (cheek swab) from patients and their families for genetic analysis. In situ VOGM "endothelial" cells (ECs), defined as CD31+ and CD45-, were obtained from coils through ETS during routine endovascular treatment. Autologous peripheral femoral ECs were also collected from the access sheath. Single-cell RNA sequencing of both VOGM and peripheral ECs was performed to demonstrate feasibility to define the transcriptional architecture. Comparison was also made with a published normative cerebrovascular transcriptome atlas. A subset of VOGM ECs was reserved for future DNA sequencing to assess for somatic and second-hit mutations. RESULTS: Our cohort contains 6 patients who underwent 10 ETS procedures from arterial and/or venous access during routine VOGM treatment (aged 12 days to ∼6 years). No periprocedural complications attributable to ETS occurred. Six unique coil types were used. ETS captured 98 ± 88 (mean ± SD; range 17-256) experimental ECs (CD31+ and CD45-). There was no discernible correlation between cell yield and coil type or route of access. Single-cell RNA sequencing demonstrated hierarchical clustering and unique cell populations within the VOGM EC compartment compared with peripheral EC controls when annotated using a publicly available cerebrovascular cell atlas. CONCLUSION: ETS may supplement investigations aimed at development of a molecular-genetic taxonomic classification scheme for VOGM. Moreover, results may eventually inform the selection of personalized pharmacologic or genetic therapies for VOGM and cerebrovascular disorders more broadly.

Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers.

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

Safety and Adverse Events During Primary Care Paramedic Interfacility Transfer of Stable STEMI Patients.

OBJECTIVE: Current guidelines recommend that patients presenting with ST-elevation myocardial infarction (STEMI) to hospitals not capable of performing primary percutaneous coronary intervention (PCI) be transferred to a PCI-capable hospital if reperfusion can be accomplished within 120 min. Most STEMI patients are accompanied by an advanced care paramedic (ACP, equivalent to EMT-P), nurse, or physician who can manage complications should they arise. In our region, stable STEMI patients are transported by primary care paramedics (PCPs, similar scope of practice to advanced EMT) in cases where a nurse, physician, or ACP paramedic is not available. Our goal was to describe adverse events and need for advanced interventions among initially stable STEMI patients during interfacility transfer by PCPs. METHODS: We reviewed ambulance and hospital records of initially stable STEMI patients (as determined by first set of vital signs documented by paramedics) transferred to a PCI-capable hospital by PCPs between March 1, 2014, and December 31, 2019. We identified whether pre-determined adverse clinical events occurred during the transport as well as the potential need for advanced care interventions not within the PCP scope of practice. Adverse events upon arrival in the PCI lab were also identified. RESULTS: Of 346 STEMI patients transferred, 179 met inclusion criteria. The mean age of included patients was 61 years (SD 12.1) and 74.9% (134/179) were male. Median transport interval was 36 min (IQR 3.0). During transport, 47/179 (26.0%) patients experienced pre-defined adverse events; for 16/47 (34%), one or more adverse events was major. Three patients met criteria for ACP interventions. One patient suffered a cardiac arrest and was promptly resuscitated with defibrillation by the PCPs. CONCLUSIONS: We found PCP-interfacility transport of initially stable STEMI patients was safe and associated with a moderate proportion of adverse events, the majority of which did not require an advanced care intervention. These findings may help decision-making to avoid delays transferring stable patients to PCI-capable centers.

Endovascular balloon usage in endoscopic third ventriculostomy for hydrocephalus during a national shortage: case series and technical note.

Endoscopic third ventriculostomy (ETV) is a well-established surgical technique for treating hydrocephalus. Many providers have transitioned to utilizing the specialized Neuroballoon for the stoma dilation in ETV; however, these devices are intermittently unavailable during supply chain shortages. We present the experience of employing cardiac angioplasty and neurovascular balloons as substitutes for the Neuroballoon in 3 patients. The scepter balloon (Microvention), priced at $1800 compared to the standard $300 Neuroballoon (Integra), proved effective, but its pliability presented technical challenges. The substantial cost differential compared to a Neuroballoon ($300) raises economic considerations. The Cardiac TREK balloon (Abbott) was similarly effective, while also being easier to manage endoscopically and cheaper at $158. These experiences support the viability of non-neuroendoscopic specialized balloons as alternatives for ETV dilation of the floor of tuber cinereum.

Adjusting the distance.

This paper describes the anxiety evoked in a patient threatened by invasion or engulfment by his object on the one hand, and the fears of isolation and abandonment on the other. The author illustrates the patient's strugles to find a distance between himself and his object he can tolerate. The analyst has also to cope with the anxieties evoked by the patient's projections, and find a distance between himself and his patient that enables him to think and work.

"Home Field Advantage": The Presence of a "Home" Neurosurgical Residency Training Program is Associated With Improved Match Outcomes.

BACKGROUND AND OBJECTIVES: Competition for neurosurgical residency training positions remains fierce. The support provided by applicants' home neurosurgery residency training programs (NRTP) is suspected to play a key role in the National Resident Matching Program (NRMP) process. We sought to evaluate the impact of the presence of an Accreditation Council for Graduate Medical Education-accredited NRTP at medical students' home institutions has on NRMP match outcomes. METHODS: Our cross-sectional observational study examined all US allopathic senior student Electronic Residency Application Service applications to a single NRTP from 2016 to 2022. RESULTS: We analyzed a total of 1650 Electronic Residency Application Service applications to a single NRTP, of which 1432 (86.8%) were from schools with an Accreditation Council for Graduate Medical Education-accredited NRTP (NRTP+) and 218 (13.2%) were from schools without a residency (NRTP-). NRTP+ applicants matched a higher rate on both pooled analysis (80.8% vs 71.6%, P = .002) and paired analysis ( P = .02) over the seven-cycle study period. This difference was present before (82.4% vs 73.9%, P = .01) and after (77.2% vs 65.6%, P = .046) the COVID-19 pandemic. Cohorts were overall similar; however, NRTP+ applicants had more publication experiences (19.6 ± 19.0 vs 13.1 ± 10.2, P < .001) and were more likely to complete a research gap year (RGY) (25.8% vs 17.0%, P = .004). Completing a RGY was associated with an increased likelihood of matching for NRTP+ applicants but not for NRTP- applicants: NRTP+: 84.9% vs 78.1% ( P = .0056); NRTP-: 70.3% vs 70.9% ( P = .94). CONCLUSION: The presence of a NRTP at a medical student's home institution is associated with improved NRMP match outcomes. This held true both before and after the COVID-19 pandemic. Applicants from schools with a NRTP had more publication experiences and were more likely to complete a RGY. Completion of a RGY is associated with an increased likelihood of matching only for students with an affiliated NRTP.

Global Economic Evaluation of the Reported Costs of Deep Brain Stimulation.

INTRODUCTION: Despite the known benefits of deep brain stimulation (DBS), the cost of the procedure can limit access and can vary widely. Our aim was to conduct a systematic review of the reported costs associated with DBS, as well as the variability in reporting cost-associated factors to ultimately increase patient access to this therapy. METHODS: A systematic review of the literature for cost of DBS treatment was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase databases were queried. Olsen & Associates (OANDA) was used to convert all reported rates to USD. Cost was corrected for inflation using the US Bureau of Labor Statistics Inflation Calculator, correcting to April 2022. RESULTS: Twenty-six articles on the cost of DBS surgery from 2001 to 2021 were included. The median number of patients across studies was 193, the mean reported age was 60.5 ± 5.6 years, and median female prevalence was 38.9%. The inflation- and currency-adjusted mean cost of the DBS device was USD 21,496.07 ± USD 8,944.16, the cost of surgery alone was USD 14,685.22 ± USD 8,479.66, the total cost of surgery was USD 40,942.85 ± USD 17,987.43, and the total cost of treatment until 1 year of follow-up was USD 47,632.27 ± USD 23,067.08. There were no differences in costs observed across surgical indication or country. CONCLUSION: Our report describes the large variation in DBS costs and the manner of reporting costs. The current lack of standardization impedes productive discourse as comparisons are hindered by both geographic and chronological variations. Emphasis should be put on standardized reporting and analysis of reimbursement costs to better assess the variability of DBS-associated costs in order to make this procedure more cost-effective and address areas for improvement to increase patient access to DBS.

Pediatric non-galenic pial arteriovenous fistula's characteristics and outcomes: a systematic review.

INTRODUCTION: Pediatric non-galenic pial arteriovenous fistulas (pAVFs) are rare vascular malformations that are characterized by a pial arterial-venous connection without an intervening capillary bed. Outcomes and treatment strategies for pAVFs are highly individualized, owing to the rarity of the disease and lack of large-scale data guiding optimal treatment approaches. METHODS: We performed a systematic review of pediatric patients (< 18 years at diagnosis) diagnosed with a pAVF by digital subtraction angiogram (DSA). The demographics, treatment modalities, and outcomes were documented for each patient and clinical outcome data was collected. Descriptive information stratified by outcome scores were classified as follows: 1 = excellent (no deficit and full premorbid activity), 2 = good (mild deficit and full premorbid activity), 3 = fair (moderate deficit and impaired activity), 4 = poor (severe deficit and dependent on others), 5 = death. RESULTS: A total of 87 studies involving 231 patients were identified. Median age at diagnosis was 3 years (neonates to 18 years). There was slight male preponderance (55.4%), and 150 subjects (81.1%*) experienced excellent outcomes after treatment. Of the 189 patients treated using endovascular approaches, 80.3% experienced excellent outcomes and of the 15 patients surgically treated subjects 75% had an excellent outcome. The highest rate of excellent outcomes was achieved in patients treated with Onyx (95.2%) and other forms of EvOH (100%). High output heart failure and comorbid vascular lesions tended to result in worse outcomes, with only 54.2% and 68% of subjects experiencing an excellent outcome, respectively. *Outcomes were reported in only 185 patients. CONCLUSION: pAVFs are rare lesions, necessitating aggregation of patient data to inform natural history and optimal treatment strategies. This review summarizes the current literature on pAVF in children, where children presenting with heart failure as a result of high flow through the lesion were less likely to experience an excellent outcome. Prospective, large-scale studies would further characterize pediatric pAVFs and enable quantitative analysis of outcomes to inform best treatment practices.

Preresidency research output among US neurological surgery residents.

OBJECTIVE: Research productivity is often used to evaluate candidates for neurosurgery residency. Official annual reports describe the mean total number of research products of successful applicants for each match cycle; however, the average number of indexed publications, the highest-valued research product, is not reported separately from other research products. The primary objectives of this study were to describe the distribution of preresidency indexed publication quantity among successful neurosurgery applicants from 2017 to 2021 and determine whether any change in publication quantity across application cycles existed. Secondary objectives included determining the rate at which the average publication quantity is increasing across application cycles, whether this increase is driven by high-output applicants alone, and if a performance ceiling has been reached. METHODS: US doctor of medicine seniors applying to the senior author's institution between 2017 and 2021 and who successfully matched into any US neurosurgery program were included. Publication quantities were extracted using Scopus. Additional variables were extracted from residency applications. Mean (SD) and median (IQR) publication quantities were used to describe the distribution and compare across years. Applicants were ranked by descending publication count and divided into quartiles. Averages within each quartile were compared with respective quartiles across years. Averages of the top 10% most productive applicants were compared across years to determine if a performance ceiling existed. RESULTS: Overall, 93.2% of matched applicants were captured. The mean and median total numbers of publications for applicants who matched from 2017 to 2021 were 5.6 ± 8.3 and 3.0 (1.0, 7.0), respectively. The mean and median numbers of publications increased from 3.7 ± 5.3 and 2.0 (0.0, 5.0) in 2016-2017 to 8.1 ± 10.0 and 5.0 (2.0, 11.0) in 2020-2021 (p < 0.001). The distribution of publication quantity was right-skewed. Multivariable analysis determined the application year to be independently and positively correlated with publication quantity (ß 1.07 [95% CI 0.71-1.42], p < 0.001). All quartiles observed an increased average number of publications across years (p < 0.001). The mean and median numbers for the top 10% increased from 15.8 ± 8.7 and 13.0 (10.8, 15.5) in 2016-2017, respectively, to 31.3 ± 16.0 and 25.0 (21.0, 35.5) in 2020-2021 (p < 0.001). CONCLUSIONS: Indexed publications account for a small portion of the total research products that successful neurosurgery candidates list on applications. A high number of publications is not necessary for candidates to match, with approximately 50% of all applicants who successfully matched having ≤ 5 publications and 25% having ≤ 2 publications. The average preresidency publication quantity has been increasing yearly among neurosurgery applicants. This increase was present across the applicant pool. Additionally, no performance ceiling was observed.

Impact of fludrocortisone on the outcomes of subarachnoid hemorrhage patients: A retrospective analysis.

BACKGROUND: Whether the use of fludrocortisone affects outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We conducted a retrospective analysis of 78 consecutive patients with a ruptured aSAH at a single academic center in the United States. The primary outcome was the score on the modified Rankin scale (mRS, range, 0 [no symptoms] to 6 [death]) at 90 days. The primary outcome was adjusted for age, hypertension, aSAH grade, and time from aSAH onset to aneurysm treatment. Secondary outcomes were neurologic and cardiopulmonary dysfunction events. RESULTS: Among 78 patients at a single center, the median age was 58 years [IQR, 49 to 64.5]; 64 % were female, and 41 (53 %) received fludrocortisone. The adjusted common odds ratio, aOR, of a proportional odds regression model of fludrocortisone use with mRS was 0.33 (95 % CI, 0.14-0.80; P = 0.02), with values <1.0 favoring fludrocortisone. Organ-specific dysfunction events were not statistically different: delayed cerebral ischemia (22 % vs. 39 %, P = 0.16); cardiac dysfunction (0 % vs. 11 %; P = 0.10); and pulmonary edema (15 % vs. 8 %; P = 0.59). CONCLUSIONS: The risk of disability or death at 90 days was lower with the use of fludrocortisone in aSAH patients.

Failing to Make the Grade: Conventional Cardiac Allograft Rejection Grading Criteria Are Inadequate for Predicting Rejection Severity.

BACKGROUND: Cardiac allograft rejection is the leading cause of early graft failure and is a major focus of postheart transplant patient care. While histological grading of endomyocardial biopsy samples remains the diagnostic standard for acute rejection, this standard has limited diagnostic accuracy. Discordance between biopsy rejection grade and patient clinical trajectory frequently leads to both overtreatment of indolent processes and delayed treatment of aggressive ones, spurring the need to investigate the adequacy of the current histological criteria for assessing clinically important rejection outcomes. METHODS: N=2900 endomyocardial biopsy images were assigned a rejection grade label (high versus low grade) and a clinical trajectory label (evident versus silent rejection). Using an image analysis approach, n=370 quantitative morphology features describing the lymphocytes and stroma were extracted from each slide. Two models were constructed to compare the subset of features associated with rejection grades versus those associated with clinical trajectories. A proof-of-principle machine learning pipeline-the cardiac allograft rejection evaluator-was then developed to test the feasibility of identifying the clinical severity of a rejection event. RESULTS: The histopathologic findings associated with conventional rejection grades differ substantially from those associated with clinically evident allograft injury. Quantitative assessment of a small set of well-defined morphological features can be leveraged to more accurately reflect the severity of rejection compared with that achieved by the International Society of Heart and Lung Transplantation grades. CONCLUSIONS: Conventional endomyocardial samples contain morphological information that enables accurate identification of clinically evident rejection events, and this information is incompletely captured by the current, guideline-endorsed, rejection grading criteria.

Rare subclonal sequencing of breast cancers indicates putative metastatic driver mutations are predominately acquired after dissemination.

BACKGROUND: Evolutionary models of breast cancer progression differ on the extent to which metastatic potential is pre-encoded within primary tumors. Although metastatic recurrences often harbor putative driver mutations that are not detected in their antecedent primary tumor using standard sequencing technologies, whether these mutations were acquired before or after dissemination remains unclear. METHODS: To ascertain whether putative metastatic driver mutations initially deemed specific to the metastasis by whole exome sequencing were, in actuality, present within rare ancestral subclones of the primary tumors from which they arose, we employed error-controlled ultra-deep sequencing (UDS-UMI) coupled with FFPE artifact mitigation by uracil-DNA glycosylase (UDG) to assess the presence of 132 "metastasis-specific" mutations within antecedent primary tumors from 21 patients. Maximum mutation detection sensitivity was ~1% of primary tumor cells. A conceptual framework was developed to estimate relative likelihoods of alternative models of mutation acquisition. RESULTS: The ancestral primary tumor subclone responsible for seeding the metastasis was identified in 29% of patients, implicating several putative drivers in metastatic seeding including LRP5 A65V and PEAK1 K140Q. Despite this, 93% of metastasis-specific mutations in putative metastatic driver genes remained undetected within primary tumors, as did 96% of metastasis-specific mutations in known breast cancer drivers, including ERRB2 V777L, ESR1 D538G, and AKT1 D323H. Strikingly, even in those cases in which the rare ancestral subclone was identified, 87% of metastasis-specific putative driver mutations remained undetected. Modeling indicated that the sequential acquisition of multiple metastasis-specific driver or passenger mutations within the same rare subclonal lineage of the primary tumor was highly improbable. CONCLUSIONS: Our results strongly suggest that metastatic driver mutations are sequentially acquired and selected within the same clonal lineage both before, but more commonly after, dissemination from the primary tumor, and that these mutations are biologically consequential. Despite inherent limitations in sampling archival primary tumors, our findings indicate that tumor cells in most patients continue to undergo clinically relevant genomic evolution after their dissemination from the primary tumor. This provides further evidence that metastatic recurrence is a multi-step, mutation-driven process that extends beyond primary tumor dissemination and underscores the importance of longitudinal tumor assessment to help guide clinical decisions.

Cost considerations for vestibular schwannoma screening and imaging: a systematic review.

Vestibular schwannomas (VS) account for approximately 8% of all intracranial neoplasms. Importantly, the cost of the diagnostic workup for VS, including the screening modalities most commonly used, has not been thoroughly investigated. Our aim is to conduct a systematic review of the published literature on costs associated with VS screening. A systematic review of the literature for cost of VS treatment was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The terms "vestibular schwannoma," "acoustic neuroma," and "cost" were queried using the PubMed and Embase databases. Studies from all countries were considered. Cost was then corrected for inflation using the US Bureau of Labor Statistics Inflation Calculator, correcting to April 2022. The search resulted in an initial review of 483 articles, of which 12 articles were included in the final analysis. Screening criteria were used for non-neurofibromatosis type I and II patients who complained of asymmetric hearing loss, tinnitus, or vertigo. Patients included in the studies ranged from 72 to 1249. The currency and inflation-adjusted mean cost was $418.40 (range, $21.81 to $487.03, n = 5) for auditory brainstem reflex and $1433.87 (range, $511.64 to $1762.15, n = 3) for non-contrasted computed tomography. A contrasted magnetic resonance imaging (MRI) scan was found to have a median cost of $913.27 (range, $172.25-$2733.99; n = 8) whereas a non-contrasted MRI was found to have a median cost of $478.62 (range, $116.61-$3256.38, n = 4). In terms of cost reporting, of the 12 articles, 1 (8.3%) of them separated out the cost elements, and 10 (83%) of them used local prices, which include institutional costs and/or average costs of multiple institutions. Our findings describe the limited data on published costs for screening and imaging of VS. The paucity of data and significant variability of costs between studies indicates that this endpoint is relatively unexplored, and the cost of screening is poorly understood.

Inferring super-resolution tissue architecture by integrating spatial transcriptomics with histology.

Spatial transcriptomics (ST) has demonstrated enormous potential for generating intricate molecular maps of cells within tissues. Here we present iStar, a method based on hierarchical image feature extraction that integrates ST data and high-resolution histology images to predict spatial gene expression with super-resolution. Our method enhances gene expression resolution to near-single-cell levels in ST and enables gene expression prediction in tissue sections where only histology images are available.