A spectroscopic liquid biopsy for the earlier detection of multiple cancer types.

BACKGROUND: A rapid, low-cost blood test that can be applied to reliably detect multiple different cancer types would be transformational. METHODS: In this large-scale discovery study (n = 2092 patients) we applied the Dxcover® Cancer Liquid Biopsy to examine eight different cancers. The test uses Fourier transform infrared (FTIR) spectroscopy and machine-learning algorithms to detect cancer. RESULTS: Area under the receiver operating characteristic curve (ROC) values were calculated for eight cancer types versus symptomatic non-cancer controls: brain (0.90), breast (0.76), colorectal (0.91), kidney (0.91), lung (0.91), ovarian (0.86), pancreatic (0.84) and prostate (0.86). We assessed the test performance when all eight cancer types were pooled to classify 'any cancer' against non-cancer patients. The cancer versus asymptomatic non-cancer classification detected 64% of Stage I cancers when specificity was 99% (overall sensitivity 57%). When tuned for higher sensitivity, this model identified 99% of Stage I cancers (with specificity 59%). CONCLUSIONS: This spectroscopic blood test can effectively detect early-stage disease and can be fine-tuned to maximise either sensitivity or specificity depending on the requirements from different healthcare systems and cancer diagnostic pathways. This low-cost strategy could facilitate the requisite earlier diagnosis, when cancer treatment can be more effective, or less toxic. STATEMENT OF TRANSLATIONAL RELEVANCE: The earlier diagnosis of cancer is of paramount importance to improve patient survival. Current liquid biopsies are mainly focused on single tumour-derived biomarkers, which limits test sensitivity, especially for early-stage cancers that do not shed enough genetic material. This pan-omic liquid biopsy analyses the full complement of tumour and immune-derived markers present within blood derivatives and could facilitate the earlier detection of multiple cancer types. There is a low barrier to integrating this blood test into existing diagnostic pathways since the technology is rapid, simple to use, only minute sample volumes are required, and sample preparation is minimal. In addition, the spectroscopic liquid biopsy described in this study has the potential to be combined with other orthogonal tests, such as cell-free DNA, which could provide an efficient route to diagnosis. Cancer treatment can be more effective when given earlier, and this low-cost strategy has the potential to improve patient prognosis.

Recurrent neural networks for time domain modelling of FTIR spectra: application to brain tumour detection.

Attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) spectroscopy alongside machine learning (ML) techniques is an emerging approach for the early detection of brain cancer in clinical practice. A crucial step in the acquisition of an IR spectrum is the transformation of the time domain signal from the biological sample to a frequency domain spectrum via a discrete Fourier transform. Further pre-processing of the spectrum is typically applied to reduce non-biological sample variance, and thus to improve subsequent analysis. However, the Fourier transformation is often assumed to be essential even though modelling of time domain data is common in other fields. We apply an inverse Fourier transform to frequency domain data to map these to the time domain. We use the transformed data to develop deep learning models utilising Recurrent Neural Networks (RNNs) to differentiate between brain cancer and control in a cohort of 1438 patients. The best performing model achieves a mean (cross-validated score) area under the receiver operating characteristic (ROC) curve (AUC) of 0.97 with sensitivity of 0.91 and specificity of 0.91. This is better than the optimal model trained on frequency domain data which achieves an AUC of 0.93 with sensitivity of 0.85 and specificity of 0.85. A dataset comprising 385 patient samples which were prospectively collected in the clinic is used to test a model defined with the best performing configuration and fit to the time domain. Its classification accuracy is found to be comparable to the gold-standard for this dataset demonstrating that RNNs can accurately classify disease states using spectroscopic data represented in the time domain.

Tranexamic Acid Associated With Less Wound Complications in Ankle and Hindfoot Surgery: Level III, Retrospective Cohort Study.

INTRODUCTION: The purpose of this study was to determine whether total ankle arthroplasty (TAA) and ankle/hindfoot fusion patients receiving tranexamic acid (TXA) exhibit fewer wound complications. METHODS: A retrospective review was conducted of 212 patients (217 feet) undergoing TAA (n = 72), ankle (n = 36), tibiotalocalcaneal (n = 20), pantalar (n = 1), or hindfoot fusion (ie, subtalar = 47, double = 33, and triple = 8) between 2015 and 2020 by a fellowship-trained foot and ankle surgeon at an academic medical center. Demographics, medical history, complications, and union status were compared between TXA (n = 101) and non-TXA (n = 116) cohorts. The mean follow-up was 1.24 years (range, 0.25 to 4.68). RESULTS: The TXA group had significantly less postoperative infections (5.9% versus 15.5%, P = 0.025). Within a subgroup analysis of ankle/hindfoot fusions, the TXA group exhibited significantly more Charcot neuroarthropathy (20.7% versus 5.7%, P = 0.006) and shorter follow-up duration (0.96 versus 1.30 years, P = 0.030); however, TXA was associated with shorter time to fusion (146 versus 202 days, P = 0.049) and fewer revision surgeries (8.6% versus 21.8%, P = 0.036). Subgroup analysis excluding feet with Charcot also demonstrated less postoperative infections (4.5% versus 14.4%, P = 0.020). Subgroup analysis of TAAs showed fewer cases of superficial infections (2.3% versus 27.6%, P = 0.002) and delayed wound healing (25.6% versus 48.3%, P = 0.047) in the TXA cohort. DISCUSSION: TXA use in ankle/hindfoot surgery was correlated with a reduction in superficial infections and radiographic time to union. The use of TXA in TAA correlated with fewer superficial infections and cases of delayed wound healing. Thus, in addition to other areas of orthopaedics, TXA seems to be beneficial in hindfoot and ankle surgery. DATA AVAILABILITY AND TRIAL REGISTRATION NUMBERS: All data were obtained from our institution's medical records. This study is not associated with a clinical trial.

Clinical validation of a spectroscopic liquid biopsy for earlier detection of brain cancer.

Background: Diagnostic delays impact the quality of life and survival of patients with brain tumors. Earlier and expeditious diagnoses in these patients are crucial to reduce the morbidities and mortalities associated with brain tumors. A simple, rapid blood test that can be administered easily in a primary care setting to efficiently identify symptomatic patients who are most likely to have a brain tumor would enable quicker referral to brain imaging for those who need it most. Methods: Blood serum samples from 603 patients were prospectively collected and analyzed. Patients either had non-specific symptoms that could be indicative of a brain tumor on presentation to the Emergency Department, or a new brain tumor diagnosis and referral to the neurosurgical unit, NHS Lothian, Scotland. Patient blood serum samples were analyzed using the Dxcover® Brain Cancer liquid biopsy. This technology utilizes infrared spectroscopy combined with a diagnostic algorithm to predict the presence of intracranial disease. Results: Our liquid biopsy approach reported an area under the receiver operating characteristic curve of 0.8. The sensitivity-tuned model achieves a 96% sensitivity with 45% specificity (NPV 99.3%) and identified 100% of glioblastoma multiforme patients. When tuned for a higher specificity, the model yields a sensitivity of 47% with 90% specificity (PPV 28.4%). Conclusions: This simple, non-invasive blood test facilitates the triage and radiographic diagnosis of brain tumor patients while providing reassurance to healthy patients. Minimizing time to diagnosis would facilitate the identification of brain tumor patients at an earlier stage, enabling more effective, less morbid surgical and adjuvant care.

Rapid Spectroscopic Liquid Biopsy for the Universal Detection of Brain Tumours.

BACKGROUND: To support the early detection and diagnosis of brain tumours we have developed a rapid, cost-effective and easy to use spectroscopic liquid biopsy based on the absorbance of infrared radiation. We have previously reported highly sensitive results of our approach which can discriminate patients with a recent brain tumour diagnosis and asymptomatic controls. Other liquid biopsy approaches (e.g., based on tumour genetic material) report a lower classification accuracy for early-stage tumours. In this manuscript we present an investigation into the link between brain tumour volume and liquid biopsy test performance. METHODS: In a cohort of 177 patients (90 patients with high-grade glioma (glioblastoma (GBM) or anaplastic astrocytoma), or low-grade glioma (astrocytoma, oligoastrocytoma and oligodendroglioma)) tumour volumes were calculated from magnetic resonance imaging (MRI) investigations and patients were split into two groups depending on MRI parameters (T1 with contrast enhancement or T2/FLAIR (fluid-attenuated inversion recovery)). Using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy coupled with supervised learning methods and machine learning algorithms, 90 tumour patients were stratified against 87 control patients who displayed no symptomatic indications of cancer, and were classified as either glioma or non-glioma. RESULTS: Sensitivities, specificities and balanced accuracies were all greater than 88%, the area under the curve (AUC) was 0.98, and cancer patients with tumour volumes as small as 0.2 cm3 were correctly identified. CONCLUSIONS: Our spectroscopic liquid biopsy approach can identify gliomas that are both small and low-grade showing great promise for deployment of this technique for early detection and diagnosis.

Early diagnosis of brain tumours using a novel spectroscopic liquid biopsy.

Early diagnosis of brain tumours is challenging and a major unmet need. Patients with brain tumours most often present with non-specific symptoms more commonly associated with less serious diagnoses, making it difficult to determine which patients to prioritize for brain imaging. Delays in diagnosis affect timely access to treatment, with potential impacts on quality of life and survival. A test to help identify which patients with non-specific symptoms are most likely to have a brain tumour at an earlier stage would dramatically impact on patients by prioritizing demand on diagnostic imaging facilities. This clinical feasibility study of brain tumour early diagnosis was aimed at determining the accuracy of our novel spectroscopic liquid biopsy test for the triage of patients with non-specific symptoms that might be indicative of a brain tumour, for brain imaging. Patients with a suspected brain tumour based on assessment of their symptoms in primary care can be referred for open access CT scanning. Blood samples were prospectively obtained from 385 of such patients, or patients with a new brain tumour diagnosis. Samples were analysed using our spectroscopic liquid biopsy test to predict presence of disease, blinded to the brain imaging findings. The results were compared to the patient's index brain imaging delivered as per standard care. Our test predicted the presence of glioblastoma, the most common and aggressive brain tumour, with 91% sensitivity, and all brain tumours with 81% sensitivity, and 80% specificity. Negative predictive value was 95% and positive predictive value 45%. The reported levels of diagnostic accuracy presented here have the potential to improve current symptom-based referral guidelines, and streamline assessment and diagnosis of symptomatic patients with a suspected brain tumour.

Enhanced Characterization of Pyrene Binding in Mixed Cyclodextrin Systems via Fluorescence Spectroscopy.

Although significant effort has been expended to analyze the binding of pyrene in ß-cyclodextrin and γ-cyclodextrin, little has been published on the binding of this guest in ß-cyclodextrin derivatives (methyl-ß-cyclodextrin and 2-hydroxypropyl-ß-cyclodextrin) or in mixtures of such derivatives, despite the fact that these derivatives are known to have different supramolecular properties that facilitate unique modes of complexation. Reported herein is a detailed spectroscopic investigation of the binding of pyrene in ß-cyclodextrin derivatives and in binary mixtures of cyclodextrins. Py values, defined as the ratio of representative vibronic bands in the fluorescence emission of pyrene, were used to measure changes in the pyrene microenvironment in the presence of the cyclodextrin hosts, and indicated that unmodified ß-cyclodextrin is unique in providing a fully hydrophobic environment for pyrene through the use of two cyclodextrins to bind a single pyrene guest. By comparison, both γ-cyclodextrin and modified ß-cyclodextrin analogues bind pyrene in a less hydrophobic environment through 1:1 binding stoichiometries that allow for continued interactions between the incompletely encapsulated pyrene guest and the aqueous solvent system. Binary mixtures of cyclodextrins were also explored and reinforce the unique properties of the unmodified ß-cyclodextrin host. Graphical Abstract The unique binding geometries of pyrene in beta-cyclodextrin and its derivatives leads to measurable fluorescence emission signals, whose information can be used to elucidate the highly structurally dependent binding geometries and stoichiometries.

Rapid analysis of disease state in liquid human serum combining infrared spectroscopy and "digital drying".

In recent years, the diagnosis of brain tumors has been investigated with attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy on dried human serum samples to eliminate spectral interferences of the water component, with promising results. This research evaluates ATR-FTIR on both liquid and air-dried samples to investigate "digital drying" as an alternative approach for the analysis of spectra obtained from liquid samples. Digital drying approaches, consisting of water subtraction and least-squares method, have demonstrated a greater random forest (RF) classification performance than the air-dried spectra approach when discriminating cancer vs control samples, reaching sensitivity values higher than 93.0% and specificity values higher than 83.0%. Moreover, quantum cascade laser infrared (QCL-IR) based spectroscopic imaging is utilized on liquid samples to assess the implications of a deep-penetration light source on disease classification. The RF classification of QCL-IR data has provided sensitivity and specificity amounting to 85.1% and 75.3% respectively.

Chronic Esophagitis and Gastritis After Ingestion of Box Jellyfish (Class Cubozoa).

This is a case report of chronic esophagitis and gastritis following the ingestion of box jellyfish (Alatina alata) by a 12-year old boy with severe autism spectrum disorder and pica. Biopsies taken at esophagogastroduodenoscopy at two months post ingestion revealed histological evidence of esophagitis and gastritis, which resolved after treatment with H2 receptor agonist and proton pump inhibitor.

Author Correction: A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals.

Neurofibrillary tangles are a pathological hallmark of Alzheimer's disease, and their levels correlate with the severity of cognitive dysfunction in humans. However, experimental evidence suggests that soluble tau species cause cognitive deficits and memory impairment. Our recent study suggests that caspase-2 (Casp2)-catalyzed tau cleavage at aspartate 314 mediates synaptic dysfunction and memory impairment in mouse and cellular models of neurodegenerative disorders. Δtau314, the C-terminally-truncated cleavage products, are soluble and present in human brain. In addition, levels of Δtau314 proteins are elevated in the brain of the cognitively impaired individuals compared to the cognitively normal individuals, indicating a possible role for Δtau314 proteins in cognitive deterioration. Here we show that (1) Δtau314 proteins are present in the inferior temporal gyrus of human brains; (2) Δtau314 proteins are generated from all six tau splicing isoforms, (3) levels of both Casp2 and Δtau314 proteins are elevated in cognitively impaired individuals compared to cognitively normal individuals, and (4) levels of Δtau314 proteins show a modest predictive value for dementia. These findings advance our understanding of the characteristics of Δtau314 proteins and their relevance to cognitive dysfunction and shed light on the contribution of Casp2-mediated Δtau314 production to cognitive deterioration.

Developing infrared spectroscopic detection for stratifying brain tumour patients: glioblastoma multiforme vs. lymphoma.

Over a third of brain tumour patients visit their general practitioner more than five times prior to diagnosis in the UK, leading to 62% of patients being diagnosed as emergency presentations. Unfortunately, symptoms are non-specific to brain tumours, and the majority of these patients complain of headaches on multiple occasions before being referred to a neurologist. As there are currently no methods in place for the early detection of brain cancer, the affected patients' average life expectancy is reduced by 20 years. These statistics indicate that the current pathway is ineffective, and there is a vast need for a rapid diagnostic test. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy is sensitive to the hallmarks of cancer, as it analyses the full range of macromolecular classes. The combination of serum spectroscopy and advanced data analysis has previously been shown to rapidly and objectively distinguish brain tumour severity. Recently, a novel high-throughput ATR accessory has been developed, which could be cost-effective to the National Health Service in the UK, and valuable for clinical translation. In this study, 765 blood serum samples have been collected from healthy controls and patients diagnosed with various types of brain cancer, contributing to one of the largest spectroscopic studies to date. Three robust machine learning techniques - random forest, partial least squares-discriminant analysis and support vector machine - have all provided promising results. The novel high-throughput technology has been validated by separating brain cancer and non-cancer with balanced accuracies of 90% which is comparable to the traditional fixed diamond crystal methodology. Furthermore, the differentiation of brain tumour type could be useful for neurologists, as some are difficult to distinguish through medical imaging alone. For example, the highly aggressive glioblastoma multiforme and primary cerebral lymphoma can appear similar on magnetic resonance imaging (MRI) scans, thus are often misdiagnosed. Here, we report the ability of infrared spectroscopy to distinguish between glioblastoma and lymphoma patients, at a sensitivity and specificity of 90.1% and 86.3%, respectively. A reliable serum diagnostic test could avoid the need for surgery and speed up time to definitive chemotherapy and radiotherapy.

Development of high-throughput ATR-FTIR technology for rapid triage of brain cancer.

Non-specific symptoms, as well as the lack of a cost-effective test to triage patients in primary care, has resulted in increased time-to-diagnosis and a poor prognosis for brain cancer patients. A rapid, cost-effective, triage test could significantly improve this patient pathway. A blood test using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy for the detection of brain cancer, alongside machine learning technology, is advancing towards clinical translation. However, whilst the methodology is simple and does not require extensive sample preparation, the throughput of such an approach is limited. Here we describe the development of instrumentation for the analysis of serum that is able to differentiate cancer and control patients at a sensitivity and specificity of 93.2% and 92.8%. Furthermore, preliminary data from the first prospective clinical validation study of its kind are presented, demonstrating how this innovative technology can triage patients and allow rapid access to imaging.

A soluble tau fragment generated by caspase-2 is associated with dementia in Lewy body disease.

Lewy body diseases are neurodegenerative disorders characterized by Lewy bodies in the brain. Lewy body dementia (LBD) refers to two forms of Lewy body disease: Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). Tau is a cytoskeletal protein found in neurofibrillary tangles, but not Lewy bodies. The gene encoding tau, MAPT, is a well-established genetic risk factor for LBD; odds ratios of the H1:H2 MAPT haplotypes have been reported in the range of 2 to 4. Despite this genetic association, the mechanism by which tau contributes to dementia is unclear. Recently, a soluble form of tau, Δtau314, which is generated when caspase-2 (Casp2) cleaves tau at Asp314, was reported to be associated with impaired cognition in mice modeling frontotemporal dementia, and with mild cognitive impairment and Alzheimer's disease (AD) in humans. To investigate whether Δtau314 is associated with dementia in Lewy body disease, we compared Δtau314 levels in aqueous extracts from the superior temporal gyrus of pathologically confirmed LBD (n = 21) and non-dementia Parkinson's disease (PD) (n = 12). We excluded subjects with AD or microvascular pathology, which could mask potential associations of Δtau314 with LBD.Using a Δtau314-specific ELISA, we found ~ 2-fold higher levels of Δtau314 in LBD relative to PD (p = 0.009). Additionally, we found ~40% lower levels of soluble total tau and the neuronal marker ß-III-tubulin in LBD. These results suggest that in LBD, there is substantial neuron loss or axonal degeneration in the neocortex but disproportionately high levels of Δtau314 in the surviving neurons.Our results indicate an association between Δtau314 and dementia in Lewy body disease. Cleavage of tau by Casp2 promotes the mislocalization of tau to dendritic spines leading to a reduction in postsynaptic AMPA receptors and excitatory neurotransmission, which suggests a mechanism of the synaptic dysfunction underlying cognitive impairment in LBD. These findings support the potential of Casp2 as a novel drug target for treating LBD.

A soluble truncated tau species related to cognitive dysfunction and caspase-2 is elevated in the brain of Huntington's disease patients.

Huntington's disease (HD) is a progressive neurodegenerative disease. Involuntary movements, cognitive impairment and psychiatric disturbance are the major clinical manifestations, and gradual atrophy and selective neuronal loss in the striatum and cerebral cortex are the pathologic hallmarks. HD is caused by expanded CAG trinucleotide repeats at the N-terminus of IT15 that encodes the huntingtin (HTT) protein, though the molecular mechanisms through which the mutant HTT (mHTT) exerts toxic effects remain obscure. Members of the caspase family, including caspase-2 (Casp2), play an important role in HD pathogenesis. Genetic ablation of Casp2 ameliorates cognitive and motor deficits of HD mice, though the molecular targets of Casp2 are still unclear. It is well established that the microtubule-associated protein tau potentiates cognitive dysfunction in a variety of neurodegenerative disorders, including HD. Our recent study indicates that Casp2-catalyzed tau cleavage at aspartate 314 (tau 2N4R isoform numbering system) mediates synaptotoxicity, cognitive deficits and neurodegeneration in cellular and mouse models of frontotemporal dementia; further, levels of Δtau314, the soluble, N-terminal cleavage product, are elevated in individuals with mild cognitive impairment and Alzheimer's disease, compared with cognitively normal individuals. Here, we identified the presence of Δtau314 proteins in the striatum (caudate nucleus) and prefrontal cortex (Brodmann's area 8/9) of human subjects, and showed that in both structures, levels of Casp2 and Δtau314 proteins correlate well, and both proteins are higher in HD patients than non-HD individuals. Our findings advance our understanding of the contribution of Casp2-mediated Δtau314 production to HD pathogenesis.

Optimised spectral pre-processing for discrimination of biofluids via ATR-FTIR spectroscopy.

Pre-processing is an essential step in the analysis of spectral data. Mid-IR spectroscopy of biological samples is often subject to instrumental and sample specific variances which may often conceal valuable biological information. Whilst pre-processing can effectively reduce this unwanted variance, the plethora of possible processing steps has resulted in a lack of consensus in the field, often meaning that analysis outputs are not comparable. As pre-processing is specific to the sample under investigation, here we present a systematic approach for defining the optimum pre-processing protocol for biofluid ATR-FTIR spectroscopy. Using a trial-and-error based approach and a clinically relevant dataset describing control and brain cancer patients, the effects of pre-processing permutations on subsequent classification algorithms were observed, by assessing key diagnostic performance parameters, including sensitivity and specificity. It was found that optimum diagnostic performance correlated with the use of minimal binning and baseline correction, with derivative functions improving diagnostic performance most significantly. If smoothing is required, a Sovitzky-Golay approach was the preferred option in this investigation. Heavy binning appeared to reduce classification most significantly, alongside wavelet noise reduction (filter length ≥6), resulting in the lowest diagnostic performances of all pre-processing permutations tested.

A randomized controlled trial to compare component placement in navigated total knee arthroplasty using original and streamlined registration processes.

BACKGROUND: This randomized controlled trial validated a redesigned version of navigated total knee arthroplasty software with a streamlined registration (Smart) against the previous version (Classic). The objectives were to determine if Smart software had the same accuracy of component positioning and whether registration and operative time were reduced. METHODS: A total of 220 patients were recruited and had a navigated total knee arthroplasty performed. With the exception of the software, all patients had the same perioperative care. At 6-week follow-up with an independent arthroplasty service, all patients had a computerized tomography scan. This was assessed by an independent radiologist to measure the mechanical alignment of the components. RESULTS: The mean postoperative mechanical femorotibial angles were equivalent between groups (mean difference -0.2°, 95% confidence interval -0.7° to 0.3°, P = .407). Component positions were similar in both groups. Mean registration time was significantly shorter for the Smart group (2 minutes 30 seconds ± 54 seconds) than the Classic group (3 minutes 23 seconds ± 39 seconds), P < .001. The mean operative time was 72 ± 12 minutes in both groups (P = .855). At 6-week follow-up, both groups had similar clinical outcomes with 96.5% of patients being satisfied or very satisfied. CONCLUSIONS: The study verified that a reduced registration time did not alter the accuracy of component placement. However, despite a shorter registration time, the overall surgical time was not reduced.

Combining random forest and 2D correlation analysis to identify serum spectral signatures for neuro-oncology.

Fourier transform infrared (FTIR) spectroscopy has long been established as an analytical technique for the measurement of vibrational modes of molecular systems. More recently, FTIR has been used for the analysis of biofluids with the aim of becoming a tool to aid diagnosis. For the clinician, this represents a convenient, fast, non-subjective option for the study of biofluids and the diagnosis of disease states. The patient also benefits from this method, as the procedure for the collection of serum is much less invasive and stressful than traditional biopsy. This is especially true of patients in whom brain cancer is suspected. A brain biopsy is very unpleasant for the patient, potentially dangerous and can occasionally be inconclusive. We therefore present a method for the diagnosis of brain cancer from serum samples using FTIR and machine learning techniques. The scope of the study involved 433 patients from whom were collected 9 spectra each in the range 600-4000 cm(-1). To begin the development of the novel method, various pre-processing steps were investigated and ranked in terms of final accuracy of the diagnosis. Random forest machine learning was utilised as a classifier to separate patients into cancer or non-cancer categories based upon the intensities of wavenumbers present in their spectra. Generalised 2D correlational analysis was then employed to further augment the machine learning, and also to establish spectral features important for the distinction between cancer and non-cancer serum samples. Using these methods, sensitivities of up to 92.8% and specificities of up to 91.5% were possible. Furthermore, ratiometrics were also investigated in order to establish any correlations present in the dataset. We show a rapid, computationally light, accurate, statistically robust methodology for the identification of spectral features present in differing disease states. With current advances in IR technology, such as the development of rapid discrete frequency collection, this approach is of importance to enable future clinical translation and enables IR to achieve its potential.

Neuronal inclusions of α-synuclein contribute to the pathogenesis of Krabbe disease.

Demyelination is a major contributor to the general decay of neural functions in children with Krabbe disease. However, recent reports have indicated a significant involvement of neurons and axons in the neuropathology of the disease. In this study, we have investigated the nature of cellular inclusions in the Krabbe brain. Brain samples from the twitcher mouse model for Krabbe disease and from patients affected with the infantile and late-onset forms of the disease were examined for the presence of neuronal inclusions. Our experiments demonstrated the presence of cytoplasmic aggregates of thioflavin-S-reactive material in both human and murine mutant brains. Most of these inclusions were associated with neurons. A few inclusions were detected to be associated with microglia and none were associated with astrocytes or oligodendrocytes. Thioflavin-S-reactive inclusions increased in abundance, paralleling the development of neurological symptoms, and distributed throughout the twitcher brain in areas of major involvement in cognition and motor functions. Electron microscopy confirmed the presence of aggregates of stereotypic ß-sheet folded proteinaceous material. Immunochemical analyses identified the presence of aggregated forms of α-synuclein and ubiquitin, proteins involved in the formation of Lewy bodies in Parkinson's disease and other neurodegenerative conditions. In vitro assays demonstrated that psychosine, the neurotoxic sphingolipid accumulated in Krabbe disease, accelerated the fibrillization of α-synuclein. This study demonstrates the occurrence of neuronal deposits of fibrillized proteins including α-synuclein, identifying Krabbe disease as a new α-synucleinopathy.

Duloxetine in the management of chronic musculoskeletal pain.

Chronic musculoskeletal pain is among the most frequent painful complaints that healthcare providers address. The bulk of these complaints are chronic low back pain and chronic osteoarthritis. Osteoarthritis is the most common form of arthritis in the United States. It is a chronic degenerative disorder characterized by a loss of cartilage, and occurs most often in older persons. The management of osteoarthritis and chronic low back pain may involve both nonpharmacologic (eg, weight loss, resistive and aerobic exercise, patient education, cognitive behavioral therapy) and pharmacologic approaches. Older adults with severe osteoarthritis pain are more likely to take analgesics than those with less severe pain. The pharmacologic approaches to painful osteoarthritis remain controversial, but may include topical as well as oral nonsteroidal antiinflammatory drugs, acetaminophen, duloxetine, and opioids. The role of duloxetine for musculoskeletal conditions is still evolving.