Reflex Testing Research Articles

Early Detection of Peripheral Neuropathy by Assessment of Sudomotor Function

Chronic hyperglycemia in both type 1 and type 2 diabetes commonly lead to diabetic peripheral neuropathy (DPN) which commonly affects small nerve fibers, including autonomic sudomotor nerves, of the lower limbs. DPN results from nerve damage leading to gradual onset of foot pain, tingling, numbness, muscle weakness, extreme sensitivity to touch, and heat intolerance. Peripheral neuropathy is associated with increased all-cause mortality and morbidities such as foot ulcers, poor wound healing, local and systemic infection, limb amputation, and painful neuropathic symptoms. DPN is also typically diagnosed during later stages when disease progression has already led to irreversible nerve damage and associated severe symptoms. As such, early detection of peripheral neuropathy is important in implementing early interventions and can help preserve nerve function and prevent serious complications of DPN. Non-invasive methods of testing for early DPN rely on assessment of sudomotor nerve function. One method includes quantitative sudomotor axon reflex test (QSART) which measures postganglionic sympathetic function via iontophoresis which allows quantification of sweat production, and by extension, autonomic function. In general, QSART provides a non-invasive, reproducible, and precise evaluation of autonomic function in both controls and diabetics. It can be used to evaluate a large number of autonomic diseases, and the quantitative data it generates provides a measure of the extent and location of the peripheral neuropathy in each individual. Another assessment method includes the sympathetic skin response (SSR) test which measures the change in electrical potential of the skin which itself comes from activated eccrine sweat glands. The SSR test has a well-established protocol, and the results are easily-measured, and the results are quantifiable. It can be used reliably in the diagnosis of numerous autonomic disorders including DPN where a diminished or absent response correlate with sudomotor nerve damage. SudoCheck by VitalScan is an FDA-cleared, non-invasive autonomic sdomotor assessment tool that combines QSART, SSR, BIA, and EIS to provide rapid results with a specificity of 95% and a sensitivity of 80%. It was created to enable a precise evaluation of sweat gland function, and by extension, the presence and progression of diabetic peripheral neuropathy including early sub-clinical disease

The Importance of Evaluating Sudomotor Function in the Diagnosis of Cardiac Autonomic Neuropathy.

Cardiac autonomic neuropathy (CAN) is a disorder affecting the autonomic nerves that regulate the cardiovascular system, leading to irregular heart rate and blood pressure control. It is commonly associated with diabetes mellitus but can also result from other conditions such as autoimmune disorders, chronic kidney disease, alcohol abuse, and certain medications. Screening for CAN is essential, particularly in individuals with poor glycemic control, cardiovascular risk factors, or complications. Early identification of CAN is vital for timely intervention to prevent or manage cardiovascular complications effectively. Regular screening helps detect CAN before symptoms emerge, enabling early intervention to slow or halt its progression. This study examined the relationship between sudomotor function and cardiovascular reflex tests. This was a cross-sectional study conducted between June 2019 and June 2020. The study included 271 subjects aged 18 years and above who provided informed consent, were diagnosed with type 2 diabetes mellitus (T2DM), and were overweight or obese. Exclusion criteria encompassed patients with other types of diabetes, pregnant women, those with recent neoplasm diagnoses, stroke sequelae, history of myocardial infarction, or pelvic limb amputations. The assessment of cardiac autonomic neuropathy involved conducting an electrocardiogram and evaluating the QTc interval in the morning before taking medication. Additionally, cardiovascular reflex tests (CART) were conducted, including assessments of heart rate variability during deep breathing, the Valsalva maneuver, and changes in orthostatic position. Simultaneously, the diagnosis of CAN was assessed by performing a sweat test using a Sudoscan assessment (Impeto Medical, Moulineaux, France). Results: More than half of the participants (52%, n=143) were female. Significant differences in statistical measures were noted between females and males regarding age, systolic blood pressure, fasting blood glucose, A1c level, total cholesterol, triglycerides, gamma-glutamyl transferase, and bilirubin levels. Within the CAN-diagnosed group (CAN+), 40.92% were classified as mild cases (n=90), 47.27% as moderate cases (n=104), and 11.81% as severe cases (n=26). Among the CAN+ group, 54% (n=119) were women. Electrochemical skin conductance was lower in the CAN+ group than the CAN- group in hands (67.34±15.51 μS versus 72.38±12.12 μS, p=0.008) and feet (73.37±13.38 μS versus 82.84 ±10.29 μS, p<0.001). The Sudoscan-CAN score significantly correlated with Ewing scores (r= 0.522, p<0.001). In multiple linear regression analysis, the Sudoscan-CAN score remained significantly associated with age, high BMI, long-standing diabetes, and Ewing score. Sudoscan demonstrates potential in identifying patients with an increased risk of CAN. Its integration into clinical practice can improve patient outcomes through early detection, risk stratification, and personalized treatment approaches. Its non-invasive, portable, and user-friendly features render it suitable for utilization in outreach programs or resource-constrained settings as part of screening efforts designed to pinpoint high-risk individuals for additional assessment.

Targeted therapeutic options in early and metastatic NSCLC-overview.

The complex therapeutic strategy of non-small cell lung cancer (NSCLC) has changed significantly in recent years. Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation. In oncogenic-addictive metastatic NSCLC, primarily in adenocarcinoma, the range of targeted therapies is expanding, with which the expected overall survival increases significantly, measured in years. By 2021, the FDA and EMA have approved targeted agents to inhibit EGFR activating mutations, T790 M resistance mutation, BRAF V600E mutation, ALK, ROS1, NTRK and RET fusion. In 2022, the range of authorized target therapies was expanded. With therapies that inhibit KRASG12C, EGFR exon 20, HER2 and MET. Until now, there was no registered targeted therapy for the KRAS mutations, which affect 30% of adenocarcinomas. Thus, the greatest expectation surrounded the inhibition of the KRAS G12C mutation, which occurs in ∼15% of NSCLC, mainly in smokers and is characterized by a poor prognosis. Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1. In EGFR exon 20 insertion mutation of lung adenocarcinoma, amivantanab was registered for progression after platinum-based chemotherapy. Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.

Measurement of ctDNA Tumor Fraction Identifies Informative Negative Liquid Biopsy Results and Informs Value of Tissue Confirmation.

Liquid biopsy (LBx) for tumor profiling is increasingly used, but concerns remain regarding negative results. A lack of results may truly reflect tumor genomics, or it may be a false negative that would be clarified by tissue testing. A method of distinguishing between these scenarios could help clarify when follow-on tissue testing is valuable. Here we evaluate circulating tumor DNA (ctDNA) tumor fraction (TF), a quantification of ctDNA in LBx samples, for utility in identifying true negative results. We assessed concordance between LBx and tissue-based results, stratified by ctDNA TF, in a real-world genomic dataset of paired samples across multiple disease types. We also evaluated the frequency of tissue results identifying driver alterations in patients with lung cancer after negative LBx in a real-world clinicogenomic database. The positive percent agreement and negative predictive value between liquid and tissue samples for driver alterations increased from 63% and 66% for all samples to 98% and 97% in samples with ctDNA TF ≥1%. Among 505 patients with lung cancer with no targetable driver alterations found by LBx who had subsequent tissue-based profiling, 37% had a driver, all of which had ctDNA TF <1%. Patients with lung cancer with negative LBx and ctDNA TF ≥1% are unlikely to have a driver detected on confirmatory tissue testing; such informative negative results may benefit instead from prompt treatment initiation. Conversely, negative LBx with ctDNA TF <1% will commonly have a driver identified by follow-up tissue testing and should be prioritized for reflex testing.

Abstract 3751: Diagnostic assessment of Filamin A (FLNA) as a serum biomarker for identification of benign prostatic hyperplasia vs aggressive prostate cancer in a prospective Mexican cohort

Abstract Prostate cancer (PCa) exhibits a significant health risk to aging men, in which effective diagnosis of high gleason (Gleason &amp;gt;7) cancers is of critical need. Currently, the main screening tool utilized for detection of prostate cancer is prostate specific antigen (PSA), however, PSA exhibits limited utility in men with benign prostatic hyperplasia (BPH) due to inherent elevated PSA as the result of an enlarged prostate, resulting in increasing unnecessary biopsies. In Mexico, there is currently a higher incidence of aggressive PCa due to the risk within the overall population as well as the need for increased screening tools. Since, there is a critical unmet need to evaluate novel PCa diagnostic test that could serve as a reflex test within the screening paradigm, we evaluated the recently developed test, pSTATEdx, which measures the cleaved portion of Filamin A (FLNA) via IP-MRM mass spectrometry in conjunction with the patients age, to determine the overall risk of aggressive prostate cancer. In the current study, we analyzed a prospective cohort from Mexico City and Guadalajara evaluating 34 BPH and 44 PCa in men exhibiting symptoms with PSA levels between 4-10 ng/mL, who were all referred for 12 core prostate biopsies due to suspicion of prostate cancer. Additionally, we assessed 41 non-diseased men as controls who had PSA below 1.5 ng/mL, who were not assessed further. Comparison of non-diseased controls with BPH/PCa men exhibited an AUC of 0.99, PPV 0.96, NPV 0.89, OR 118, and P value 2 e-20, thus demonstrating that pSTATEdx had significant utility in assessing prostate health independent of PSA. In comparison with previously published data, FLNA mean levels were 24 ng/mL in previously published American study cohort and 55 ng/mL in the Mexican BPH/PCa cohort with a P value of &amp;lt;0.001. Assessment of patient populations revealed that there was superior diagnostic performance of FLNA for patients between PSA 4-7, which represents an increased unmet need for biopsy decision support. Analysis of BPH compared to all PCa exhibited a sensitivity of 0.94 and specificity of 0.53, PPV 0.64, NPV of 0.91, and OR of 16.4. Diagnostic analysis of BPH compared to high gleason PCa exhibited a sensitivity of 1, specificity of 0.21, PPV 0.38, NPV of 1, and OR of inf in this pilot study. This assessment revealed promising insight that aggressive PCa was not missed using pSTATEdx. pSTATEdx demonstrated diagnostic utility in prevention of unnecessary biopsies in the Mexican population as a reflex test to those patients with PSA levels between 4-7 as well as demonstrated that aggressive prostate cancers were not missed with the risk score. Additional studies are planned in the future to expand the utility of pSTATEdx in Latin America. Citation Format: Arturo Rodriguez, Arturo Mendoza, Matthew Rosenburg, José de J. Castaneda, Alejandro A. Melgar, Bernardo Ciseros, Adrian G. Gangemi, Nischal M. Chand, Poornima Tekumalla, Greg Miller, Anjan Thakurta, Diego Banuelos, Juan J. Real, Diego A. Joya, Alejandro Romero, Juan D. Farias, Eduardo Cabeza, Hector H. Remess, Julio J. Delgado, Hector M. Sanchez, Ignacio Barragan, Mabel Rodriguez, Barbara Garcia, David A. Sanchez, Juan Izquierdo, Elizabeth M. Lopez, Juan Hanao, Jeronimo G. Frusch, Niven R. Narain, Michael A. Kiebish. Diagnostic assessment of Filamin A (FLNA) as a serum biomarker for identification of benign prostatic hyperplasia vs aggressive prostate cancer in a prospective Mexican cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3751.

The Association of Race, Ethnicity, and Insurance Status with the Visual Acuity of Retinoblastoma Survivors in the IRIS® Registry

ABSTRACT Purpose To identify sociodemographic factors associated with the visual outcomes of retinoblastoma survivors. Methods Retrospective cohort study using a US-based clinical data registry. All individuals < 18 years of age with a history of retinoblastoma in the Intelligent Research in Sight (IRIS®) Registry (1/1/2013–12/31/2020). The primary outcome was visual acuity below the threshold for legal blindness (20/200 or worse) in at least one eye. Multivariable logistic regression was used to evaluate the association between visual outcomes and age, sex, laterality, race, ethnicity, type of insurance, and geographic location. Results This analysis included 1545 children with a history of retinoblastoma. The median length of follow-up was 4.1 years (IQR, 2.2–5.9 years) and the median age at most recent clinical visit was 12 years (IQR, 8–16 years). Retinoblastoma was unilateral in 54% of cases. Poor vision in at least one eye was identified in 78% of all children and poor vision in both eyes in 17% of those with bilateral disease. Poor visual outcomes were associated with unilateral diagnosis (OR, 1.55; 95% CI,1.13–2.12; p = .007), Black race (OR, 2.03; 95% CI, 1.19–3.47; p = .010), Hispanic ethnicity (OR, 1.65; 95% CI, 1.16–2.37; p = .006), and non-private insurance (OR, 1.47; 95% CI, 1.02–2.10; p = .037). Conclusions Poor visual outcomes appear to be more common among Black, Hispanic, and publicly insured children with a history of retinoblastoma, raising concerns regarding healthcare inequities. Primary care physicians should ensure that young children receive red reflex testing during routine visits and consider retinoblastoma in the differential diagnosis of abnormal eye exams.

Clinical study of esodeviations in children

Esotropia or convergent strabismus is a common type of squint in children. The esodeviation, the refractive error and the amblyopia should be examined and treated early to achieve good cosmetic correction and to improve Visual acuity.A meticulous history of 25 children up to age of 12 years who presented with esodeviations was taken including the age of onset, duration and previous treatment. They were examined for amount and type of deviation by cover test, hirschberg corneal reflex test, Prism bar cover test and evaluated for refractive error under full cycloplegic correction, for Binocular Single Vision, diplopia, suppression and amblyopia by Worth four-dot test and RAF ruler. Ocular movements and fundus findings were recorded.11 male and 14 female children with esodeviations with age of presentation varying from 9 months to 12 years were evaluated for type of esotropia. In our study the most common type seen in 12 cases (48%) is refractive accommodative esotropia with high hypermetropia. Non-refractive accommodative esotropia greater for near with high AC/A ratio in 5 patients (20%), Partially accommodative (mixed) esotropia in 2 cases, acquired non-accommodative esotropia seen in 2 patients. 1 case each is seen in Infantile esotropia, in Sensory esotropia, in child with Duane’s retraction syndrome (DRS) and in child having cerebral visual impairment (CVI).Our study aimed to diagnose and manage the various types of esodeviations at an early age so as to maintain binocular alignment and a good Visual acuity to avoid progression to amblyopia.

A nationwide survey of facial onset sensory and motor neuronopathy in Japan

The epidemiology and etiology of facial onset sensory and motor neuronopathy (FOSMN), a rare syndrome that initiates with facial sensory disturbances followed by bulbar symptoms, remain unknown. To estimate the prevalence of FOSMN in Japan and establish the characteristics of this disease, we conducted a nationwide epidemiological survey. In the primary survey, we received answers from 604 facilities (49.8%), leading to an estimated number of 35.8 (95% confidential interval: 21.5–50.2) FOSMN cases in Japan. The secondary survey collected detailed clinical and laboratory data from 21 cases. Decreased or absent corneal and pharyngeal reflexes were present in over 85% of the cases. Electrophysiological analyses detected blink reflex test abnormalities in 94.1% of the examined cases. Immunotherapy was administered in 81% of cases and all patients received intravenous immunoglobulin. Among them, 35.3% were judged to have temporary beneficial effects evaluated by the physicians in charge. Immunotherapy tended to be effective in the early stage of disease. The spreading pattern of motor and sensory symptoms differed between cases and the characteristics of the motor-dominant and sensory-dominant cases were distinct. Cases with motor-dominant progression appeared to mimic amyotrophic lateral sclerosis. This is the first nationwide epidemiological survey of FOSMN in Japan. The clinical course of FOSMN is highly variable and motor-dominant cases developed a more severe condition than other types of cases. Because clinical interventions tend to be effective in the early phase of the disease, an early diagnosis is desirable.

HER2-low and tumor infiltrating lymphocytes in triple-negative breast cancer: Are they connected?

Most patients with triple-negative breast cancer (TNBC) are not candidates for targeted therapy, leaving chemotherapy as the primary treatment option. Recently, immunotherapy has demonstrated promising results in TNBC, due to its immunogenicity. In addition, a novel antibody–drug conjugate, namely, trastuzumab-deruxtecan, has shown effectiveness in TNBC patients with low-HER2 expression (HER2-low). These novel treatment options raise the question about the potential association between the density of stromal tumor-infiltrating lymphocytes (sTILs) and the level of HER2 expression. We aimed to evaluate the association between the level of HER2 expression (HER2-low versus HER2-0) and density of sTILs in TNBC patients, and how they impact the response to neoadjuvant chemotherapy (NAC). This was a retrospective multicenter study including all TNBC patients diagnosed between 2018 and 2022. Central pathology review included sTILs percentages and level of HER2 expression. Tumors were reclassified as either HER2-0 (HER2 IHC 0) or HER2-low (IHC 1 + or 2 + with negative reflex test). Various clinicopathologic characteristics, including sTILs density, and response to NAC were compared between HER2-0 and HER2-low cases. In total, 753 TNBC patients were included in this study, of which 292 patients received NAC. Interobserver agreement between the original pathology report and central review was moderate (77% had the same IHC status after reclassification in either HER2-0 or HER2-low; k = 0.45). HER2-low TNBC represented about one third (36%) of the tumors. No significant difference in sTILs density or complete pathologic response rate was found between HER2-0 and HER2-low cases (p = 0.476 and p = 0.339, respectively). The density of sTILs (≥ 10% sTILs vs. < 10%) was independently associated with achieving a pCR (p = 0.011). In conclusion, no significant association was found between HER2-low status and density of sTILs nor response to NAC. Nonetheless, sTILs could be an independent biomarker for predicting NAC response in TNBC patients.

Comparison of Magnetic Resonance Imaging–Based Risk Calculators to Predict Prostate Cancer Risk

Magnetic resonance imaging (MRI)-based risk calculators can replace or augment traditional prostate cancer (PCa) risk prediction tools. However, few data are available comparing performance of different MRI-based risk calculators in external cohorts across different countries or screening paradigms. To externally validate and compare MRI-based PCa risk calculators (Prospective Loyola University Multiparametric MRI [PLUM], UCLA [University of California, Los Angeles]-Cornell, Van Leeuwen, and Rotterdam Prostate Cancer Risk Calculator-MRI [RPCRC-MRI]) in cohorts from Europe and North America. This multi-institutional, external validation diagnostic study of 3 unique cohorts was performed from January 1, 2015, to December 31, 2022. Two cohorts from Europe and North America used MRI before biopsy, while a third cohort used an advanced serum biomarker, the Prostate Health Index (PHI), before MRI or biopsy. Participants included adult men without a PCa diagnosis receiving MRI before prostate biopsy. Prostate MRI followed by prostate biopsy. The primary outcome was diagnosis of clinically significant PCa (grade group ≥2). Receiver operating characteristics for area under the curve (AUC) estimates, calibration plots, and decision curve analysis were evaluated. A total of 2181 patients across the 3 cohorts were included, with a median age of 65 (IQR, 58-70) years and a median prostate-specific antigen level of 5.92 (IQR, 4.32-8.94) ng/mL. All models had good diagnostic discrimination in the European cohort, with AUCs of 0.90 for the PLUM (95% CI, 0.86-0.93), UCLA-Cornell (95% CI, 0.86-0.93), Van Leeuwen (95% CI, 0.87-0.93), and RPCRC-MRI (95% CI, 0.86-0.93) models. All models had good discrimination in the North American cohort, with an AUC of 0.85 (95% CI, 0.80-0.89) for PLUM and AUCs of 0.83 for the UCLA-Cornell (95% CI, 0.80-0.88), Van Leeuwen (95% CI, 0.79-0.88), and RPCRC-MRI (95% CI, 0.78-0.87) models, with somewhat better calibration for the RPCRC-MRI and PLUM models. In the PHI cohort, all models were prone to underestimate clinically significant PCa risk, with best calibration and discrimination for the UCLA-Cornell (AUC, 0.83 [95% CI, 0.81-0.85]) model, followed by the PLUM model (AUC, 0.82 [95% CI, 0.80-0.84]). The Van Leeuwen model was poorly calibrated in all 3 cohorts. On decision curve analysis, all models provided similar net benefit in the European cohort, with higher benefit for the PLUM and RPCRC-MRI models at a threshold greater than 22% in the North American cohort. The UCLA-Cornell model demonstrated highest net benefit in the PHI cohort. In this external validation study of patients receiving MRI and prostate biopsy, the results support the use of the PLUM or RPCRC-MRI models in MRI-based screening pathways regardless of European or North American setting. However, tools specific to screening pathways incorporating advanced biomarkers as reflex tests are needed due to underprediction.

The Degree of Cardiovascular Autonomic Dysfunction is not Different in GBA-Related and Idiopathic Parkinson's Disease Patients: A Case-Control Instrumental Evaluation.

Increased prevalence of cardiovascular autonomic failure might play a key role on Parkinson's disease (PD) progression of glucocerebrosidase gene (GBA)-mutated patients, determining a malignant phenotype of disease in these patients. To objectively characterize, for the first time, the cardiovascular autonomic profile of GBA-mutated patients compared to idiopathic PD patients by means of cardiovascular reflex tests (CRTs). This is a case-control (1 : 2) study on PD patients belonging to well-characterized prospective cohorts. For each PD patient carrying GBA variants, two idiopathic PD patients, matched for sex and disease duration at CRTs, were selected. Patients recruited in these cohorts underwent a complete clinical and instrumental evaluation including specific autonomic questionnaires, CRTs and extensive genetic analysis. A total of 23 GBA-PD patients (19 males, disease duration 7.7 years) were included and matched with 46 non-mutated PD controls. GBA-mutated patients were younger than controls (59.9±8.1 vs. 64.3±7.2 years, p = 0.0257) and showed a more severe phenotype. Despite GBA-mutated patients reported more frequently symptoms suggestive of orthostatic hypotension (OH) than non-mutated patients (39.1% vs 6.5%, p = 0.001), the degree of cardiovascular autonomic dysfunction, when instrumentally assessed, did not differ between the two groups, showing the same prevalence of neurogenic OH, delayed OH and cardiovascular reflex impairment (pathological Valsalva maneuver). GBA-PD patients did not show different instrumental cardiovascular autonomic pattern than non-mutated PD. Our findings suggested that symptoms suggestive of OH should be promptly investigated by clinicians to confirm their nature and improve patient care and management.

The Use of Osteopathic Manipulative Treatment for a Case of Cervical Radiculopathy

Abstract Cervical radiculopathy is a clinical condition related to dysfunction of the cervical spinal nerve roots. Signs and symptoms include unilateral neck, shoulder, or arm pain; paresthesias of the arm, forearm or hand; diminished muscle tendon reflexes, sensory disturbances; and/or muscle weakness. Cervical radiculopathy is primarily a clinical diagnosis with patients reporting a varying degree of pain and/or neurologic dysfunction along a nerve root distribution. In addition to a thorough history, a detailed physical exam including muscle strength testing, deep tendon reflex testing and sensory testing should be performed to determine the nerve root involved and to further help determine a course of action for the patient. The current case report demonstrates the impact of a somatic dysfunction component on underlying pathology of cervical spondylosis, likely driving the symptomatic component of cervical radiculopathy. By eliminating the somatic dysfunction components with the use of osteopathic manipulative treatment, the patient's system was able to function maximally within existing structural limitations and the symptoms resolved.

Raising laying hens: housing complexity and genetic strain affect startle reflex amplitude and behavioural response to fear-inducing stimuli.

Individual variation in fearfulness can be modified during ontogeny, and high levels of fear can affect animal welfare. We asked whether early-life environmental complexity and genetic strain affect fear behaviour in young laying hens (pullets). Four replicates of brown (B) and white (W) genetic strains (breeds) of layers were each raised in four environmental treatments (housing): conventional cages (Conv) and different rearing aviaries with increasing space and complexity (Low < Mid < High). We used a startle reflex test (weeks 4 and 14) to measure startle amplitude and autonomic response (i.e. comb temperature). A combination of novel arena (NA) and novel object (NO) tests was used (week 14) to assess NA exploration and alertness, latency to approach the centre and initial NO avoidance and investigation. Housing × strain affected startle amplitude (B-Conv, B-High < B-Low, B-Mid; B > W; no housing effect in W) but not autonomic response. Fear behaviour was affected by housing (NA exploration, investigation: Conv < Low, Mid, High; NO avoidance: Conv, High < Low, Mid), strain (NA alertness: B > W, NO avoidance: W > B) and their interaction (NA centre approach: B-Conv < all other groups). We present evidence for strain-specific fear responses depending on early experience.

Predictive value of heart rate variability and electrochemical skin conductance measurements for cardiovascular autonomic neuropathy persistence in type 2 diabetes and prediabetes: A 3-year follow-up study

ObjectiveThe study aimed to explore risk stratification approaches for cardiovascular autonomic neuropathy (CAN) in individuals with prediabetes and type 2 diabetes (T2DM) over a three-year follow-up period. MethodsParticipants underwent evaluations of autonomic function encompassing cardiovascular autonomic reflex tests (CARTs), baroreflex sensitivity (BRS), heart rate variability (HRV) in time domains (standard deviation of all normal RR intervals (SDNN)) and frequency domains (high frequency/low frequency ratio), and electrochemical skin conductance (ESC). The diagnosis of CAN relied on abnormal CART results. Subjects were categorized into 4 groups, based on their assessment of cardiac autonomic function at 3-year follow-up, relative to the presence or absence of CAN at baseline assessment: Persistent absence of CAN; Resolution of CAN; Progression to CAN; and Persistent CAN. ResultsParticipants with T2DM/prediabetes (n = 91/7) were categorized as: Persistent absence of CAN (n = 25), Resolution of CAN (n = 10), Progression to CAN (n = 18), and Persistent CAN (n = 45) groups. The Persistent absence of CAN group showed significant associations with SDNN. The Resolution of CAN group exhibited notable associations with mean HbA1C (follow-up), while the Progression to CAN group displayed a significant link with baseline estimated glomerular filtration rate. The Persistent CAN group demonstrated significant associations with SDNN and Sudoscan CAN risk score. Screening recommendations involve biennial to annual assessments based on risk levels, aiding in CAN detection and subsequent comprehensive and time-intensive autonomic function tests for confirmation. The study's findings offer improved risk categorization approaches for detecting CAN, which has relevance for shaping public health strategies.

Does the Relationship of the Autonomic Symptoms Questionnaire COMPASS 31 with Cardiovascular Autonomic Tests Differ between Type 1 and Type 2 Diabetes Mellitus?

The aim was to investigate if autonomic symptoms questionnaire Composite Autonomic Symptom Score (COMPASS) 31 has different association with cardiovascular autonomic neuropathy (CAN) and diagnostic performance between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Seventy-nine participants with T1DM and 140 with T2DM completed COMPASS 31 before cardiovascular reflex tests (CARTs) for CAN, and assessment of symptoms, signs, vibration, and thermal perception thresholds for diabetic polyneuropathy (DPN) diagnosis. COMPASS 31 total weighted score (TWS) was similar in the two groups, but significantly associated with confirmed CAN only in T1DM (P=0.0056) and not T2DM group (P=0.1768) and correlated with CARTs score more strongly in T1DM (rho=0.356, P=0.0016) than in T2DM group (rho=0.084, P=0.3218) (P=0.016). Only in T1DM and not T2DM group, the area under the receiver operating characteristic curve (AUC) reached a fair diagnostic accuracy (>0.7) for confirmed CAN (0.73±0.07 vs. 0.61±0.08) and DPN (0.75±0.06 vs. 0.68±0.05), although without a significant difference. COMPASS 31 TWS (cut-off 16.44) reached acceptable diagnostic performance in T1DM, with sensitivity for confirmed CAN 81.2% and sensitivity and specificity for DPN 76.3% and 78%, compared to T2DM group (all <70%). AUC for DPN of orthostatic intolerance domain was higher in T1DM compared to T2DM group (0.73±0.05 vs. 0.58±0.04, P=0.027). COMPASS 31 is more weakly related to CAN in T2DM than in T1DM, with a fair diagnostic accuracy for confirmed CAN only in T1DM. This difference supports a multifactorial origin of symptoms and should be considered when using COMPASS 31.

Expanding Broad Molecular Reflex Testing in Non-Small Cell Lung Cancer to Squamous Histology.

Due to the success story of biomarker-driven targeted therapy, most NSCLC guidelines agree that molecular reflex testing should be performed in all cases with non-squamous cell carcinoma (non-SCC). In contrast, testing recommendations for squamous cell carcinoma (SCC) vary considerably, specifically concerning the exclusion of patients of certain age or smoking status from molecular testing strategies. We performed a retrospective single-center study examining the value of molecular reflex testing in an unselected cohort of 316 consecutive lung SCC cases, tested by DNA- and RNA-based next-generation sequencing (NGS) at our academic institution between 2019 and 2023. Clinicopathological data from these cases were obtained from electronic medical records and correlated with sequencing results. In 21/316 (6.6%) cases, we detected an already established molecular target for an approved drug. Among these were seven cases with an EGFR mutation, seven with a KRAS G12C mutation, four with an ALK fusion, two with an EGFR fusion and one with a METex14 skipping event. All patients harboring a targetable alteration were >50 years of age and most of them had >15 pack-years, questioning restrictive molecular testing strategies. Based on our real-world data, we propose a reflex testing workflow using DNA- and RNA-based NGS that includes all newly diagnosed NSCLC cases, irrespective of histology, but also irrespective of age or smoking status.

Laboratory reflex testing strategy for the early identification of primary care patients with multiple myeloma

ObjectivesOur objective was to shorten the screen for multiple myeloma (MM), through reflex testing. Design and MethodsThe clinical laboratory in the public University Hospital of San Juan (Alicante, Spain), serves 234,551 inhabitants. Through an intervention agreed with general practitioners, the Laboratory Information System (LIS) automatically registered serum immunoglobulins (Ig) when serum total proteins (STP) > 80 g/L for the first time in primary care patients. When concomitantly one Ig presented a value above and one below its reference interval, the LIS automatically registered a serum protein electrophoresis (SPEP). When a monoclonal peak in SPEP, immunofixation electrophoresis (IFE) for the typification of monoclonal bands (MB) was performed. If MB were present, a comment in the report explained the intervention. The number of additionally registered Ig, SPEP, IFE, and new diagnosis of MM were counted. The number of days elapsed from the report of elevated STP result to the final MM diagnosis was also counted as median and interquartile range (IQR), and compared to a pre intervention period. Results2071 cases of hyperproteinemia were identified, and had 91 a monoclonal peak, confirmed by IFE. In 35 patients it was a new finding, and 9 were diagnosed with MM, 3 Waldestrom macroglobulinemia, 2 lymphoplasmacytic lymphoma and 21 monoclonal gammopathy of undetermined significance. The number of days elapsed from hyperproteinemia to diagnosis was lower in the intervention period (21.5 vs 119.4) (P < 0.01). As our results show, in addition to shortening the time to diagnosis, an increased rate of detection of plasma cell disorders was observed when using our algorithm. ConclusionsThe above laboratory interventions agreed with clinicians, making use of laboratory technology resulted in early identification of MM.

Postural impairments in unilateral and bilateral vestibulopathy.

Chronic imbalance is a major complaint of patients suffering from bilateral vestibulopathy (BV) and is often reported by patients with chronic unilateral vestibulopathy (UV), leading to increased risk of falling. We used the Central SensoriMotor Integration (CSMI) test, which evaluates sensory integration, time delay, and motor activation contributions to standing balance control, to determine whether CSMI measures could distinguish between healthy control (HC), UV, and BV subjects and to characterize vestibular, proprioceptive, and visual contributions expressed as sensory weights. We also hypothesized that sensory weight values would be associated with the results of vestibular assessments (vestibulo ocular reflex tests and Dizziness Handicap Inventory scores). Twenty HCs, 15 UVs and 17 BVs performed three CSMI conditions evoking sway in response to pseudorandom (1) surface tilts with eyes open or, (2) surface tilts with eyes closed, and (3) visual surround tilts. Proprioceptive weights were identified in surface tilt conditions and visual weights were identified in the visual tilt condition. BVs relied significantly more on proprioception. There was no overlap in proprioceptive weights between BV and HC subjects and minimal overlap between UV and BV subjects in the eyes-closed surface-tilt condition. Additionally, visual sensory weights were greater in BVs and were similarly able to distinguish BV from HC and UV subjects. We found no significant correlations between sensory weights and the results of vestibular assessments. Sensory weights from CSMI testing could provide a useful measure for diagnosing and for objectively evaluating the effectiveness of rehabilitation efforts and future treatments designed to restore vestibular function such as hair cell regeneration and vestibular implants.

Improving the hepatitis C virus care cascade with the in-hospital Reflex tEsting ALarm-C (REAL-C) model.

The World Health Organization (WHO) has set targets to eliminate viral hepatitis, including hepatitis C virus (HCV) infection, by 2030. We present the results of the in-hospital Reflex tEsting ALarm-C (REAL-C) model, which incorporates reflex HCV RNA testing and sending alerts to physicians. We conducted a retrospective study analysing the data of 1730 patients who newly tested positive for anti-HCV between March 2020 and June 2023. Three distinct periods were defined: pre-REAL-C (n = 696), incomplete REAL-C (n = 515) and complete REAL-C model periods (n = 519). The primary outcome measure was the HCV RNA testing rate throughout the study period. Additionally, we assessed the referral rate to the gastroenterology department, linkage time for diagnosis and treatment and the treatment rate. The rate of HCV RNA testing increased significantly from 51.0% (pre-REAL-C) to 95.6% (complete REAL-C). This improvement was consistent across clinical departments, regardless of patients' comorbidities. Among patients with confirmed HCV infection, the gastroenterology referral rate increased from 57.1% to 81.1% after the REAL-C model. The treatment rate among treatment-eligible patients was 92.4% during the study period. The mean interval from anti-HCV positivity to HCV RNA testing decreased from 45.1 to 1.9 days. The mean interval from the detection of anti-HCV positivity to direct-acting antiviral treatment also decreased from 89.5 to 49.5 days with the REAL-C model. The REAL-C model, featuring reflex testing and physician alerts, effectively increased HCV RNA testing rates and streamlined care cascades. Our model facilitated progress towards achieving WHO's elimination goals for HCV infection.

A Behavioral and Electroencephalographic Study of Anesthetic State Induced by MK-801 Combined with Haloperidol, Ketamine and Riluzole in Mice.

Ketamine is an intravenous anesthetic that acts as a channel blocker on the N-methyl- d -aspartate (NMDA) receptor, a glutamate receptor subtype. MK-801 is the most potent compound among noncompetitive NMDA receptor antagonists. Ketamine induces loss of the righting reflex (LORR) in rodents, which is one of the indicators of unconsciousness, whereas high doses of MK-801 produce ataxia, but not LORR. In contrast, we previously reported that MK-801 combined with a low dose of the dopamine receptor antagonist haloperidol-induced LORR in mice. To assess a neurophysiologically distinct brain state and demonstrate unconsciousness, electroencephalograms (EEG) need to be examined together with LORR. Therefore, we herein investigated EEG changes after the systemic administration of MK-801 alone or in combination with haloperidol, and compared them with those induced by ketamine, the glutamate release inhibitor riluzole, and the γ-aminobutyric acid type A receptor agonist propofol. All drugs were intraperitoneally administered to adult male ddY mice (n = 168). General anesthesia was evaluated based on the righting reflex test. Animals who exhibited no righting for more than 30 seconds were considered to have LORR. In a separate group of mice, EEG of the primary visual cortex was recorded before and after the administration of MK-801 (3.0 mg/kg) alone or in combination with haloperidol (0.2 mg/kg), ketamine (150 mg/kg), riluzole (30 mg/kg), or propofol (240 mg/kg). The waveforms recorded were analyzed using EEG power spectra and spectrograms. The high dose of MK-801 alone did not induce LORR, whereas MK-801 combined with haloperidol produced LORR in a dose-dependent manner. Ketamine, riluzole, and propofol also dose-dependently induced LORR. In the EEG study, MK-801 alone induced a significant increase in δ power, while MK-801 plus haloperidol exerted similar effects on not only δ, but also θ and α power during LORR, suggesting that increases in δ, θ, and α power were necessary for LORR. The results obtained on MK-801 plus haloperidol were similar to those on ketamine in the behavioral and EEG studies, except for an increase in γ power by ketamine during LORR. Propofol significantly increased δ, θ, α, and β power during LORR. However, the EEG results obtained using riluzole, which produced a unique pattern of lower amplitude activity spanning most frequencies, markedly differed from those with the other drugs. This study revealed differences in EEG changes induced by various sedatives. The results obtained on MK-801 alone and MK-801 plus haloperidol suggest the importance of dopamine transmission in maintaining the righting reflex.