Invasive lobular carcinoma of the breast; clinicopathologic profile and response to neoadjuvant chemotherapy over a 15-year period.

INTRODUCTION: Invasive lobular carcinoma (ILC) accounts for 5-15% of invasive breast cancers. Typical ILC is oestrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative. Atypical biomarker profiles (ER- and HER2+, ER+ and HER2+ or triple negative) appear to differ from typical ILCs. This study compared subtypes of ILC in terms of clinical and pathological parameters, and response to neoadjuvant chemotherapy (NACT) according to biomarker profile. METHODS: All patients with ILC treated in a single centre from January 2005 to December 2020 were identified from a prospectively maintained database. Clinicopathologic and outcome data was collected and analysed according to tumour biomarker profile. RESULTS: A total of 582 patients with ILC were treated. Typical ILC was observed in 89.2% (n = 519) and atypical in 10.8% (n = 63). Atypical ILCs were of a higher grade (35% grade 3 vs 9.6% grade 3, p < 0.001). A larger proportion of atypical ILC received NACT (31.7% vs 6.9% p < 0.001). Atypical ILCs showed a greater response to NACT (mean RCB (Residual Cancer Burden Score) 2.46 vs mean RCB 3.41, p = 0.0365), and higher pathological complete response rates (15% vs 0% p = 0.017). Despite this, overall 5-year disease-free survival (DFS) was higher in patients with typical ILC (91% vs 83%, p = 0.001). CONCLUSIONS: Atypical ILCs have distinct characteristics. They are more frequently of a higher grade and demonstrate a superior response to NACT. Despite the latter, atypical ILCs have a worse 5-year DFS which should be taken into consideration in terms of prognostication and may assist patient selection for NACT.

On the role of dysferlin in striated muscle: membrane repair, t-tubules and Ca2+ handling.

Dysferlin is a 237 kDa membrane-associated protein characterised by multiple C2 domains with a diverse role in skeletal and cardiac muscle physiology. Mutations in DYSF are known to cause various types of human muscular dystrophies, known collectively as dysferlinopathies, with some patients developing cardiomyopathy. A myriad of in vitro membrane repair studies suggest that dysferlin plays an integral role in the membrane repair complex in skeletal muscle. In comparison, less is known about dysferlin in the heart, but mounting evidence suggests that dysferlin's role is similar in both muscle types. Recent findings have shown that dysferlin regulates Ca2+ handling in striated muscle via multiple mechanisms and that this becomes more important in conditions of stress. Maintenance of the transverse (t)-tubule network and the tight coordination of excitation-contraction coupling are essential for muscle contractility. Dysferlin regulates the maintenance and repair of t-tubules, and it is suspected that dysferlin regulates t-tubules and sarcolemmal repair through a similar mechanism. This review focuses on the emerging complexity of dysferlin's activity in striated muscle. Such insights will progress our understanding of the proteins and pathways that regulate basic heart and skeletal muscle function and help guide research into striated muscle pathology, especially that which arises due to dysferlin dysfunction.

Case of metastatic clear cell odontogenic carcinoma with response to chemoimmunotherapy.

Our patient initially presented with 6 months of left jaw pain and gingival bleeding, leading to the discovery of a radiolucent left maxillary mass on dental evaluation. A biopsy confirmed clear cell odontogenic carcinoma, and the patient was treated with definitive surgery and radiation for localised disease. Unfortunately, the patient was found to have pulmonary metastases 3 months after initial management and was subsequently treated with a combination of cytotoxic chemotherapy and immunotherapy with a partial response. To our knowledge, this is the first case demonstrating the successful use of chemoimmunotherapy in metastatic clear cell odontogenic carcinoma.

Conserved Noncoding Elements Evolve Around the Same Genes Throughout Metazoan Evolution.

Conserved noncoding elements (CNEs) are DNA sequences located outside of protein-coding genes that can remain under purifying selection for up to hundreds of millions of years. Studies in vertebrate genomes have revealed that most CNEs carry out regulatory functions. Notably, many of them are enhancers that control the expression of homeodomain transcription factors and other genes that play crucial roles in embryonic development. To further our knowledge of CNEs in other parts of the animal tree, we conducted a large-scale characterization of CNEs in more than 50 genomes from three of the main branches of the metazoan tree: Cnidaria, Mollusca, and Arthropoda. We identified hundreds of thousands of CNEs and reconstructed the temporal dynamics of their appearance in each lineage, as well as determining their spatial distribution across genomes. We show that CNEs evolve repeatedly around the same genes across the Metazoa, including around homeodomain genes and other transcription factors; they also evolve repeatedly around genes involved in neural development. We also show that transposons are a major source of CNEs, confirming previous observations from vertebrates and suggesting that they have played a major role in wiring developmental gene regulatory mechanisms since the dawn of animal evolution.

The Impact of a Pandemic on a Military Oral and Maxillofacial Pathology Biopsy Service.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) and the resulting societal reaction presented new challenges to the medical community by limiting patient access to care in 2020 and 2021. The Navy Postgraduate Dental School (NPDS) oral and maxillofacial pathology biopsy service is dependent on in-office physician or dentist appointments and patient biopsies. The purpose of this study was to understand the regulatory and societal impacts of COVID-19 restrictions on biopsy service submissions by assessing NPDS biopsy submission quantities and disease distribution. MATERIALS AND METHODS: All NPDS oral and maxillofacial pathology biopsy submissions from calendar years 2015 to 2016 and 2019 to 2021 were evaluated, and patient demographics and biopsy diagnoses were recorded in a biopsy registry. Data collected included age, sex, biopsy site, and diagnosis. Data from 2015, 2016, and 2019 were defined as pre-COVID and 2020 and 2021 as COVID. Biopsy reports for each year were organized in quarters. Diagnoses were categorized as malignant, pre-malignant, or benign. Categorical and continuous data were evaluated and presented as counts with percentages and means or medians with standard deviations, respectively. Significant differences in proportions or means were assessed using chi-square analysis or Student t-test, respectively. Cases were aggregated by quarter and year and assessed for temporal trends using linear regression analysis. RESULTS: The study evaluated 9,351 biopsy submission reports. The annual pre-COVID count mean (± standard deviation) and yearly counts for 2020 and 2021 were 2,063 ± 33.3, 1,421, and 1,742, respectively. The mean (± standard deviation) percentage of diagnoses classified as malignant from pre-COVID, 2020, and 2021 were 2.46 ± 0.005%, 3.59%, and 3.04%, respectively. Case counts and representation as a percentage of all biopsy diagnoses for Human Papillomavirus (HPV)-associated squamous cell carcinoma increased significantly during COVID compared to pre-COVID years (P < .05). CONCLUSIONS: Overall, preventative COVID-19 health measures and protocols resulted in a reduction in biopsy submission frequency, particularly during the second quarter (April to June) of 2020. However, case counts for malignant biopsies remained consistent between pre-COVID and COVID time intervals, suggesting that the identification and analysis of cases requiring follow-on care were unaffected by COVID-19 protocols.

What is the best treatment for hypotension in healthy dogs during anaesthesia maintained with isoflurane?

Hypotension is a common and potentially life-threatening complication of general anaesthesia in dogs. Due to the combination of cardiovascular side effects of many anaesthetic, sedative and analgesic drugs used peri-operatively hypotension is frequently reported even in healthy dogs undergoing elective procedures. Several treatment options for hypotension have been advocated. Potential treatments include rapid administration of either crystalloid or colloid fluids; pharmacological treatments to increase cardiac output and/or systemic vascular resistance; or reduction in the delivery of the volatile anaesthetic agents. This critical appraisal considers the current evidence for which treatment is the best option for treating hypotension in healthy euvolemic dogs undergoing general anaesthesia maintained with isoflurane. Fourteen relevant studies were appraised, including 12 laboratory studies and two small clinical trials. One study demonstrated that reduction in the delivery of isoflurane may correct hypotension, but this treatment may not always be feasible. In general, rapid administration of fluids did not increase blood pressure and failed to correct hypotension. Synthetic colloids demonstrated some efficacy, but results were inconsistent between studies and large volumes may be required. Infusion of dopamine appears to be the most reliable pharmacological option consistently increasing blood pressure, cardiac output and correcting hypotension.

A bridge to recovery: Acute amantadine prior to environmental enrichment after brain trauma augments cognitive benefit.

Environmental enrichment (EE) facilitates motor and cognitive recovery after traumatic brain injury (TBI). Historically, EE has been provided immediately and continuously after TBI, but this paradigm does not model the clinic where rehabilitation is typically not initiated until after critical care. Yet, treating TBI early may facilitate recovery. Hence, we sought to provide amantadine (AMT) as a bridge therapy before commencing EE. It was hypothesized that bridging EE with AMT would augment motor and cognitive benefits. Anesthetized adult male rats received a cortical impact (2.8 mm deformation at 4 m/s) or sham surgery and then were housed in standard (STD) conditions where they received intraperitoneal AMT (10 mg/kg or 20 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24 h after surgery and once daily during the 6-day bridge phase or once daily for 19 days for the non-bridge groups (i.e., continuously STD-housed) to compare the effects of acute AMT plus EE vs. chronic AMT alone. Abbreviated EE, which was presented to closer emulate clinical rehabilitation (e.g., 6 h/day), began on day 7 for the AMT bridge and chronic EE groups. Motor (beam-walking) and cognition (acquisition of spatial learning and memory) were assessed on days 7-11 and 14-19, respectively. Cortical lesion volume and hippocampal cell survival were quantified on day 21. EE, whether provided in combination with VEH or AMT, and AMT (20 mg/kg) + STD, benefitted motor and cognition vs. the STD-housed VEH and AMT (10 mg/kg) groups (p < 0.05). The AMT (20 mg/kg) + EE group performed better than the VEH + EE, AMT (10 mg/kg) + EE, and AMT (20 mg/kg) + STD groups in the acquisition of spatial learning (p < 0.05) but did not differ in motor function (p > 0.05). All groups receiving EE exhibited decreased cortical lesion volumes and increased CA3 neuron survival relative to the STD-housed groups (p < 0.05) but did not differ from one another (p > 0.05). The added cognitive benefit achieved by bridging EE with AMT (20 mg/kg) supports the hypothesis that the temporal separation of combinational therapies is more effective after TBI.

In-situ experiment reveals CO2 enriched fluid migration in faulted caprock.

The sealing characteristics of the geological formation located above a CO2 storage reservoir, the so-called caprock, are essential to ensure efficient geological carbon storage. If CO2 were to leak through the caprock, temporal changes in fluid geochemistry can reveal fundamental information on migration mechanisms and induced fluid-rock interactions. Here, we present the results from a unique in-situ injection experiment, where CO2-enriched fluid was continuously injected in a faulted caprock analogue. Our results show that the CO2 migration follows complex pathways within the fault structure. The joint analysis of noble gases, ion concentrations and carbon isotopes allow us to quantify mixing between injected CO2-enriched fluid and resident formation water and to describe the temporal evolution of water-rock interaction processes. The results presented here are a crucial complement to the geophysical monitoring at the fracture scale highlighting a unique migration of CO2 in fault zones.

A Perspective on Developing Modeling and Image Analysis Tools to Investigate Mechanosensing Proteins.

The shift of funding organizations to prioritize interdisciplinary work points to the need for workflow models that better accommodate interdisciplinary studies. Most scientists are trained in a specific field and are often unaware of the kind of insights that other disciplines could contribute to solving various problems. In this paper, we present a perspective on how we developed an experimental pipeline between a microscopy and image analysis/bioengineering lab. Specifically, we connected microscopy observations about a putative mechanosensing protein, obscurin, to image analysis techniques that quantify cell changes. While the individual methods used are well established (fluorescence microscopy; ImageJ WEKA and mTrack2 programs; MATLAB), there are no existing best practices for how to integrate these techniques into a cohesive, interdisciplinary narrative. Here, we describe a broadly applicable workflow of how microscopists can more easily quantify cell properties (e.g., perimeter, velocity) from microscopy videos of eukaryotic (MDCK) adherent cells. Additionally, we give examples of how these foundational measurements can create more complex, customizable cell mechanics tools and models.

Pharmacological Screening of Kv7.1 and Kv7.1/KCNE1 Activators as Potential Antiarrhythmic Drugs in the Zebrafish Heart.

Long QT syndrome (LQTS) can lead to ventricular arrhythmia and sudden cardiac death. The most common congenital cause of LQTS is mutations in the channel subunits generating the cardiac potassium current IKs. Zebrafish (Danio rerio) have been proposed as a powerful system to model human cardiac diseases due to the similar electrical properties of the zebrafish heart and the human heart. We used high-resolution all-optical electrophysiology on ex vivo zebrafish hearts to assess the effects of IKs analogues on the cardiac action potential. We found that chromanol 293B (an IKs inhibitor) prolonged the action potential duration (APD) in the presence of E4031 (an IKr inhibitor applied to drug-induced LQT2), and to a lesser extent, in the absence of E4031. Moreover, we showed that PUFA analogues slightly shortened the APD of the zebrafish heart. However, PUFA analogues failed to reverse the APD prolongation in drug-induced LQT2. However, a more potent IKs activator, ML-277, partially reversed the APD prolongation in drug-induced LQT2 zebrafish hearts. Our results suggest that IKs plays a limited role in ventricular repolarizations in the zebrafish heart under resting conditions, although it plays a more important role when the IKr is compromised, as if the IKs in zebrafish serves as a repolarization reserve as in human hearts. This study shows that potent IKs activators can restore the action potential duration in drug-induced LQT2 in the zebrafish heart.

The precariousness of living with, and caring for people with, dementia: Insights from the IDEAL programme.

This paper uses precarity as a framework to understand the vulnerabilities experienced by those living with or caring for someone living with dementia. Drawing on qualitative interview data from the Improving the Experience of Dementia and Enhancing Active Life (IDEAL) programme, we attend to our participants' reflections on how they manage the condition and the wider circumstances in which this occurs. To interrogate the utility of precarity, we focus on our participants' descriptions of needs and challenges and set these alongside both the wider contexts in which they seek or offer care (formal and informal) and the sets of values attributed to different ways of living with dementia. Building on the work of Portacolone, our analysis identified four interconnected themes: uncertainty; experiences of support and services; independence and personhood; and cumulative pressures and concerns. We develop this analysis by reviewing how our themes reflect, extend, or depart from previously identified markers of precarity and consider the specific ways in which these markers shape the lives of those living with dementia.

The dilemma of Pituri: a review and case report.

Smokeless tobacco is the term used to describe a range of products found worldwide which individuals use to extract nicotine, but without smoking. Ways of achieving this include chewing, sniffing and placing in areas of the body where tissues are sufficiently thin for absorption to take place such as the oral mucosa or postauricular skin. In Central Australia, Aboriginal groups across a wide area have chewed wild tobacco plants, commonly known as Pituri, for countless generations. As well as inducing a sense of well-being, the habit has strong cultural significance. While some smokeless tobacco products used outside Australia are known to have a detrimental effect on oral health, particularly malignant change, little is known about Pituri. To date, reports of adverse oral outcomes have been elusive. Most Pituri research seems to have focussed on obstetric issues, arguably unexpected as the tobacco seems to be in contact with the mouth for longer than any other body tissues. The following report describes a lesion on the anterior buccal mucosa resulting from prolonged Pituri use. The relevant literature is reviewed. A clinical and ethical management dilemma arises between respecting the associated cultural issues and ignoring an apparent pathological entity. © 2022 Australian Dental Association.

A Rare Case of Monomorphic T-Cell Posttransplant Lymphoproliferative Disorder Presenting as Primary Cutaneous Anaplastic Large Cell Lymphoma, ALK Negative.

ABSTRACT: Posttransplant lymphoproliferative disorders are a serious complication of hematopoietic and solid organ transplants secondary to iatrogenic immunosuppression. Most cases present as B-cell proliferations which are often Epstein-Barr virus positive; however, ∼10% of cases are T/NK cell and are less commonly associated with Epstein-Barr virus. Of these, cutaneous T/NK-cell lymphomas are exceedingly rare. We report a case of a 69-year-old male, liver transplant recipient who presented with a tender, bright red papule on the left arm during his annual skin cancer screening. Histopathologic evaluation revealed pleomorphic cells with enlarged nuclei, vesicular chromatin, and frequent mitotic figures, intercalating through the dermis. The tumor formed single strands and small cords without epidermal involvement. A patchy mild mixed inflammatory infiltrate was associated with the tumor. Tumor cells were CD2(+), CD4(+), CD30(+), CD3(-), CD20(-), ALK-1(-), and EBER(-). Molecular studies revealed a monoclonal T-cell receptor gamma gene rearrangement by polymerase chain reaction (PCR); ALK gene rearrangement was negative by fluorescence in situ hybridization (FISH). Taken together, the findings were consistent with an ALK-negative anaplastic large cell lymphoma involving skin, which, given the history of liver transplant, qualified as a monomorphic T-cell posttransplant lymphoproliferative disorder. Follow-up imaging studies showed no evidence of systemic disease, supporting an interpretation of primary cutaneous anaplastic large cell lymphoma.

Accelerated aging of all-inorganic, interface-stabilized perovskite solar cells.

To understand degradation routes and improve the stability of perovskite solar cells (PSCs), accelerated aging tests are needed. Here, we use elevated temperatures (up to 110°C) to quantify the accelerated degradation of encapsulated CsPbI3 PSCs under constant illumination. Incorporating a two-dimensional (2D) Cs2PbI2Cl2 capping layer between the perovskite active layer and hole-transport layer stabilizes the interface while increasing power conversion efficiency of the all-inorganic PSCs from 14.9 to 17.4%. Devices with this 2D capping layer did not degrade at 35°C and required >2100 hours at 110°C under constant illumination to degrade by 20% of their initial efficiency. Degradation acceleration factors based on the observed Arrhenius temperature dependence predict intrinsic lifetimes of 51,000 ± 7000 hours (>5 years) operating continuously at 35°C.

Utility of Cone-Beam CT for Bronchial Artery Embolization and Chemoinfusion: A Single-Institution Retrospective Case Series.

PURPOSE: To describe the technique and document utility of adjunctive cone-beam CT (CBCT) in patients undergoing bronchial artery embolization (BAE) or chemoinfusion (BAC). MATERIALS AND METHODS: Between August 2010 and February 2021, 26 patients (62 bronchial arteries) were evaluated with CBCT in addition to the usual digital subtraction angiography (DSA) during BAE or BAC. 19 patients (43 arteries) underwent BAE for hemoptysis; 7 patients (19 arteries) had BAC for palliation of lung malignancy. Retrospective review of procedural reports and the archived DSA and CBCT images was assessed for (1) whether CBCT findings added unique diagnostic information prior to treatment of target arteries compared to DSA alone; and (2) whether these unique CBCT findings led to modification of embolization or chemoinfusion technique. RESULTS: In 61 of 62 (98%) interrogated bronchial arteries, CBCT provided additional unique diagnostic information over planar DSA, primarily cross-sectional assessment of the spinal canal for spinal arteries. In 46/62 (74%) of the bronchial arteries the unique information did not lead to a change in therapeutic technique. In 15 bronchial arteries (24%), the added information from CBCT led to change in embolization and/or chemoinfusion technique. Embolization of one small unrecognized spinal artery branch (1.6%), which was missed intra-procedurally but retrospectively seen on CBCT led to transient spinal cord ischemia. CONCLUSIONS: These results suggest that adjunctive use of CBCT technique may improve diagnostic confidence from information provided by DSA in nearly all cases of BAE and BAC leading to improved therapeutic targeting or change in technique of embolization or chemoinfusion.

Integrating central nervous system metagenomics and host response for diagnosis of tuberculosis meningitis and its mimics.

The epidemiology of infectious causes of meningitis in sub-Saharan Africa is not well understood, and a common cause of meningitis in this region, Mycobacterium tuberculosis (TB), is notoriously hard to diagnose. Here we show that integrating cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) with a host gene expression-based machine learning classifier (MLC) enhances diagnostic accuracy for TB meningitis (TBM) and its mimics. 368 HIV-infected Ugandan adults with subacute meningitis were prospectively enrolled. Total RNA and DNA CSF mNGS libraries were sequenced to identify meningitis pathogens. In parallel, a CSF host transcriptomic MLC to distinguish between TBM and other infections was trained and then evaluated in a blinded fashion on an independent dataset. mNGS identifies an array of infectious TBM mimics (and co-infections), including emerging, treatable, and vaccine-preventable pathogens including Wesselsbron virus, Toxoplasma gondii, Streptococcus pneumoniae, Nocardia brasiliensis, measles virus and cytomegalovirus. By leveraging the specificity of mNGS and the sensitivity of an MLC created from CSF host transcriptomes, the combined assay has high sensitivity (88.9%) and specificity (86.7%) for the detection of TBM and its many mimics. Furthermore, we achieve comparable combined assay performance at sequencing depths more amenable to performing diagnostic mNGS in low resource settings.

Risk-Based Screening Tools to Optimise HIV Testing Services: a Systematic Review.

PURPOSE OF REVIEW: Effective ways to diagnose the remaining people living with HIV who do not know their status are a global priority. We reviewed the use of risk-based tools, a set of criteria to identify individuals who would not otherwise be tested (screen in) or excluded people from testing (screen out). RECENT FINDINGS: Recent studies suggest that there may be value in risk-based tools to improve testing efficiency (i.e. identifying those who need to be tested). However, there has not been any systematic reviews to synthesize these studies. We identified 18,238 citations, and 71 were included. The risk-based tools identified were most commonly from high-income (51%) and low HIV (<5%) prevalence countries (73%). The majority were for "screening in" (70%), with the highest performance tools related to identifying MSM with acute HIV. Screening in tools may be helpful in settings where it is not feasible or recommended to offer testing routinely. Caution is needed for screening out tools, where there is a trade-off between reducing costs of testing with missing cases of people living with HIV.

Diet-induced Alzheimer's-like syndrome in the rabbit.

INTRODUCTION: Although mouse models of Alzheimer's disease (AD) have increased our understanding of the molecular basis of the disease, none of those models represent late-onset Alzheimer's Disease which accounts for >90% of AD cases, and no therapeutics developed in the mouse (with the possible exceptions of aduhelm/aducanumab and gantenerumab) have succeeded in preventing or reversing the disease. This technology has allowed much progress in understanding the molecular basis of AD. To further enhance our understanding, we used wild-type rabbit (with a nearly identical amino acid sequence for amyloid as in humans) to model LOAD by stressing risk factors including age, hypercholesterolemia, and elevated blood glucose levels (BGLs), upon an ε3-like isoform of apolipoprotein. We report a combined behavioral, imaging, and metabolic study using rabbit as a non-transgenic model to examine effects of AD-related risk factors on cognition, intrinsic functional connectivity, and magnetic resonance-based biomarkers of neuropathology. METHODS: Aging rabbits were fed a diet enriched with either 2% cholesterol or 10% fat/30% fructose. Monthly tests of novel object recognition (NOR) and object location memory (OLM) were administered to track cognitive impairment. Trace eyeblink conditioning (EBC) was administered as a final test of cognitive impairment. Magnetic resonance imaging (MRI) was used to obtain resting state connectivity and quantitative parametric data (R2*). RESULTS: Experimental diets induced hypercholesterolemia or elevated BGL. Both experimental diets induced statistically significant impairment of OLM (but not NOR) and altered intrinsic functional connectivity. EBC was more impaired by fat/fructose diet than by cholesterol. Whole brain and regional R2* MRI values were elevated in both experimental diet groups relative to rabbits on the control diet. DISCUSSION: We propose that mechanisms underlying LOAD can be assessed by stressing risk factors for inducing AD and that dietary manipulations can be used to assess etiological differences in the pathologies and effectiveness of potential therapeutics against LOAD. In addition, non-invasive MRI in awake, non-anesthetized rabbits further increases the translational value of this non-transgenic model to study AD.