First Time In Humans Research Articles

A Virtual In Vivo Dissection and Analysis of Socioaffective Symptoms Related to Cerebellum-Midbrain Reward Circuitry in Humans.

Emerging research in nonhuman animals implicates cerebellar projections to the ventral tegmental area (VTA) in appetitive behaviors, but these circuits have not been characterized in humans. Here, we mapped cerebello-VTA white matter connectivity in a cohort of men and women using probabilistic tractography on diffusion imaging data from the Human Connectome Project. We uncovered the topographical organization of these connections by separately tracking from parcels of cerebellar lobule VI, crus I/II, vermis, paravermis, and cerebrocerebellum. Results revealed that connections between the cerebellum and VTA predominantly originate in the right cerebellar hemisphere, interposed nucleus, and paravermal cortex and terminate mostly ipsilaterally. Paravermal crus I sends the most connections to the VTA compared with other lobules. We discovered a mediolateral gradient of connectivity, such that the medial cerebellum has the highest connectivity with the VTA. Individual differences in microstructure were associated with measures of negative affect and social functioning. By splitting the tracts into quarters, we found that the socioaffective effects were driven by the third quarter of the tract, corresponding to the point at which the fibers leave the deep nuclei. Taken together, we produced detailed maps of cerebello-VTA structural connectivity for the first time in humans and established their relevance for trait differences in socioaffective regulation.

Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: Relevance for psychedelic research

The serotonin 2A (5-HT2A) receptor is an important target for drug development and the main receptor through which classical psychedelics elucidate their hallucinogenic effects. The 5-HT2A receptor antagonist ketanserin has frequently been used as a tool to block the receptor.Here, we establish the dose-occupancy relation of ketanserin and the cerebral 5-HT2A receptor in healthy participants by conducting a positron emission tomography (PET) study. 120-min PET scans using the 5-HT2A receptor agonist radiotracer [11C]Cimbi-36 were conducted at baseline and after oral doses of either 10, 20, or 40 mg of ketanserin; each participant underwent one or two scans after ketanserin administration. Occupancy was defined as the percent change in neocortex binding potential (BPND), estimated using the simplified reference tissue model (SRTM) with the cerebellum as reference region.Peroral ketanserin intake resulted in a plasma concentration-related increase in cerebral 5-HT2A receptor occupancy with the highest plasma ketanserin concentrations measured after ∼2 h. The relation between mean plasma ketanserin concentrations and 5-HT2A receptor occupancy conformed to a single-site binding model with an estimated EC50 (95 % CI) of 2.52 (0.75; 8.1) ng/mL, which corresponds to a peroral dose of ketanserin of approximately 10 mg.These data elucidate for the first time in humans the cerebral pharmacodynamics of ketanserin, both benefitting its use as a pharmacological tool for probing brain function and adding to its potential for therapeutic use in rescuing a bad psychedelic experience.

Intra-rater and inter-rater reliability of robotic arthrometer DYNEELAX®.

The purpose of our study was to test the intra-rater and inter-rater reliability of the DYNEELAX® arthrometer in healthy subjects. Since rotational laxity will be measured for the first time in humans, indications for normative values will also be presented. Knee anterior laxity and rotational laxity using a DYNEELAX® arthrometer were assessed in 73 subjects (39 females and 34 males). An intraclass correlation coefficient was calculated to evaluate the intra-rater and inter-rater reliability of the DYNEELAX®. An intraclass correlation coefficient for intra-rater reliability ranges from 0.631 (95% confidence interval; [CI]: 0.47-0.75) to 0.699 (95% CI: 0.56-0.80) and from 0.916 (95% CI: 0.87-0.95) to 0.94 (95% CI: 0.91-0.96) for anterior knee laxity and rotational knee laxity, respectively. An intraclass correlation coefficient for inter-rater reliability ranges from 0.578 (95% CI: 0.40-0.71) to 0.646 (95% CI: 0.44-0.78) and from 0.822 (95% CI: 0.57-0.91) to 0.933 (95% CI: 0.89-0.96) for anterior knee laxity and rotational knee laxity, respectively. The DYNEELAX® arthrometer has good to excellent intra-rater and inter-rater reliability for rotational knee laxity and moderate intra-rater reliability for anterior knee laxity in healthy subjects. Future studies should investigate the clinical significance of anterior and rotational laxity measured with the DYNEELAX® arthrometer in patients with knee pathology, as both laxities are critical for assessing the integrity of the intra-articular structures of the knee in clinical practice. Level IV.

The influence of subclavian ansae stimulation on cardiac hemodynamics and electrophysiology in atrial fibrillation- exploring a novel target for neuromodulation in atrial fibrillation (SAS-AF study)

Abstract Background Sympathetic nervous system activation plays a significant role in arrhythmia development and maintenance.Neuromodulation techniques such as stellate ganglion block and sympathectomy, are limited by off-target side effects and complex targeting.The Subclavian Ansae (SA,a nerve cord encircling the subclavian artery) may be an intravascular site allowing specific targeting of the cardiac afferent sympathetic system.Preclinical studies have revealed increased sympathetic tone upon selective SA stimulation. Objective We sought to define for the first time in Humans the functional anatomy and physiology of Subclavian Ansae via a percutaneous approach. Methods A prior cadaveric study defined the anatomical course of the subclavian ansae, encircling the subclavian arteries and connecting the middle cervical ganglia to inferior cervical ganglia/stellate.Patients undergoing catheter ablation for paroxysmal atrial fibrillation(pAF) under general anesthesia were prospectively recruited for the study. Subclavian Ansae stimulation (SAS) was performed on the left and/or the right (L/SAS ± R/SAS) within the subclavian artery using the TactiCath Ablation Catheter introduced via a femoral arterial sheath. Stimulation parameters included up to 70 V output, 10 Hz frequency, and pulse width of 2-4ms for 20-30s. Test pulses ensured no cardiac capture during stimulation. Participants discontinued antiarrhythmic agents at least 4-5 half-lives prior to the procedure. Invasive arterial blood pressure(BP), heart rate (HR), and electrophysiological parameters were recorded in response to selective stimulation. An increase of ten percent or more in either arterial blood pressure(BP) or heart rate(HR) from the initial baseline measurements was deemed a positive response. Results 15 patients (62±11 years, 9 males, pAF duration 51±24 months) underwent the simulation protocol prior to their clinical AF ablation procedure. A positive hemodynamic response was observed in nine patients, and among them, arrhythmia was inducible in 3 patients (atrial fibrillation in 2 patients and repeated runs of atrial ectopy in 1 patient) in response to SAS. Mean sinus cycle length(CL) decreased(chronotropic) after stimulation,particularly with a significant change observed in response to R/SAS. Additionally,L/SAS led to a notable increase in mean systolic (SBP) and diastolic(DBP) blood pressure (inotropic). While the mean right atrial effective refractory period (ERP) did not significantly decrease after stimulation, there was a demonstrable difference in interatrial conduction time(dromotropy). Six patients, including the initial 3 subjected to low-energy stimulation (up to 12V), did not exhibit an adrenergic response. Conclusion This study represents the first successful application of selective SAS in humans. A heterogeneity in electrophysiological modulation by SAS exists, including laterality.The SA is a potential important target for targeted autonomic neuromodulation therapy

In-field use of I-VED electrical impedance sensor for assessing post-dive decompression stress in humans

Purpose: Ultrasound imaging is commonly used in decompression research to assess venous gas emboli (VGE) post-dive, with higher loads associated with increased decompression sickness risk. This work examines, for the first time in humans, the performance of a novel electrical impedance spectroscopy technology (I-VED), on possible detection of post-dive bubbles presence and arterial endothelial dysfunction that may be used as markers of decompression stress. Methods: I-VED signals were recorded in scuba divers who performed standardized pool dives before and at set time points after their dives at 35-minute intervals for about two hours. Two distinct frequency components of the obtained signals, Low-Pass Frequency-LPF: 0-0.5 Hz and Band-Pass Frequency-BPF: 0.5-10 Hz, are extracted and respectively compared to VGE presence and known flow-mediated dilation trends for the same dive profile for endothelial dysfunction. Results: Subjects with VGE counts above the median for all subjects were found to have an elevated average LPF compared to subjects with lower VGE counts, although this was not statistically significant (p=0.06), as well as significantly decreased BPF standard deviation post-dive compared to pre-dive (p=0.008). Conclusions: I-VED was used for the first time in humans and operated to provide qualitative in-vivo electrical impedance measurements that may contribute to the assessment of decompression stress. Compared to ultrasound imaging, the proposed method is less expensive, not operator-dependent and compatible with continuous monitoring and application of multiple probes. This study provided preliminary insights; further calibration and validation are necessary to determine I-VED sensitivity and specificity.

Low-Intensity Focused Ultrasound to the Human Dorsal Anterior Cingulate Attenuates Acute Pain Perception and Autonomic Responses.

The dorsal anterior cingulate cortex (dACC) is a critical brain area for pain and autonomic processing, making it a promising noninvasive therapeutic target. We leverage the high spatial resolution and deep focal lengths of low-intensity focused ultrasound (LIFU) to noninvasively modulate the dACC for effects on behavioral and cardiac autonomic responses using transient heat pain stimuli. A N = 16 healthy human volunteers (6 M/10 F) received transient contact heat pain during either LIFU to the dACC or Sham stimulation. Continuous electroencephalogram (EEG), electrocardiogram (ECG), and electrodermal response (EDR) were recorded. Outcome measures included pain ratings, heart rate variability, EDR response, blood pressure, and the amplitude of the contact heat-evoked potential (CHEP).LIFU reduced pain ratings by 1.09 ± 0.20 points relative to Sham. LIFU increased heart rate variability indexed by the standard deviation of normal sinus beats (SDNN), low-frequency (LF) power, and the low-frequency/high-frequency (LF/HF) ratio. There were no effects on the blood pressure or EDR. LIFU resulted in a 38.1% reduction in the P2 CHEP amplitude. Results demonstrate LIFU to the dACC reduces pain and alters autonomic responses to acute heat pain stimuli. This has implications for the causal understanding of human pain and autonomic processing in the dACC and potential future therapeutic options for pain relief and modulation of homeostatic signals.

Paired DBS and TMS Reveals Dentato-Cortical Facilitation Underlying Upper Extremity Movement in Chronic Stroke Survivors

Background Cerebellum shares robust di-synaptic dentato-thalamo-cortical (DTC) connections with the contralateral motor cortex. Preclinical studies have shown that DTC are excitatory in nature. Structural integrity of DTC is associated with better upper extremity (UE) motor function in people with stroke, indicating DTC are important for cerebellar influences on movement. However, there is a lack of understanding of physiologic influence of DTC in humans, largely due to difficulty in accessing the dentate nucleus. Objective Characterize DTC physiology using dentate nucleus deep brain stimulation (DBS) combined with transcranial magnetic stimulation (TMS) in stroke. Methods Nine chronic stroke survivors with moderate-to-severe UE impairment (Fugl-Meyer 13-38) underwent a paired DBS–TMS experiment before receiving experimental dentate nucleus DBS in our first-in-human phase I trial (Baker et al., 2023, Nature Medicine). Conditioning DBS pulses were given to dentate nucleus 1 to 10 ms prior to supra-threshold TMS pulses given to ipsilesional motor cortex. Effects were assessed on motor evoked potentials (MEPs). Size of DBS-conditioned MEPs was expressed relative to TMS MEPs, where values >1 indicate facilitation. Results Dentate nucleus DBS led to facilitation of MEPs at short-latency intervals (3.5 and 5 ms, P = .049 and .021, respectively), a phenomenon we have termed dentato-cortical facilitation (DCF). Higher DCF was observed among patients with more severe UE impairment. Diffusion tensor imaging revealed microstructure of thalamo-cortical portion of DTC was related to higher corticomotor excitability. Conclusions Our in vivo investigation reveals for the first time in humans the intrinsic excitatory properties of DTC, which can serve as a novel therapeutic target for post-stroke motor recovery.

Time toxicity associated with early phase clinical trial participation

Early phase cancer clinical trials (EPCTs) involve experimental drugs being used for the first time in humans. These studies are designed for dose determination and safety, and represent the most time intensive of all clinical trials for both clinicians and patients. We sought to quantify the amount of patient time consumed through EPCT participation. A retrospective audit of patients treated in the EPCT unit at Liverpool Hospital, Sydney was carried out from 2013 to 2023. We defined 'time toxicity' (TT) as a composite measure where time-toxic days were considered days with any health care system contact, including clinic visits, infusions, procedures or blood work. A total of 219 patients across 36 EPCTs were included. The median age was 65 years (range 31-81 years). Patients spent a median of 29% (range 4%-100%) of their days in direct contact with the health care system during their study. Protocol-specified visits accounted for the greatest contribution to total TT in 101 (46%) patients. In 7% (n= 16) of patients, unscheduled visits due to either adverse events or cancer-related symptoms accounted for the greatest TT. TT reduced as patients completed additional cycles of treatment. Patients who completed >10 cycles spent 14% of their days interacting with health care systems compared with 35% for those who completed ≤2 cycles. No statistically significant difference in TT was noted between dose-expansion and dose-escalation studies or trials focusing on immune-oncology versus targeted therapy. Our study is the first to report TT in EPCTs with an extended follow-up. Clinicians should be aware of TT when discussing risks and benefits. TT also may not be the appropriate term when describing the time patients invest during EPCTs. Toxicity implies a negative impact, but for many patients, trial participation would be seen as positive. There should be efforts to streamline health care visits to limit TT in EPCTs.

Academia and industry agreement on a feasibility tool for first-time-in-human clinical trial units.

First-time-in-human (FTIH) trials are designed to generate information on the safety, tolerability, as well as the pharmacokinetic and pharmacodynamics profile of new drugs. To ensure the safety of participants, these trials need to be conducted at specifically equipped phase I clinical trial units (CTUs). In accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) and the European Union (EU) regulatory guidelines, one of the aims of the European Regime Accelerator for Tuberculosis (ERA4TB) project is to collaboratively create a feasibility tool, through a partnership between public and private entities, for the validation of CTUs selected to conduct FTIH trials. A feasibility form, encompassing nine sections, was created to gather information on the unit in relation to key attributes of FTIH trials. Collaboratively, industry and academic partners defined the minimal criteria to ensure the adherence of CTUs to the principles of ICH GCP and regulations outlined by the European Medicines Agency (EMA) for the execution of FTIH trials. Subsequently, all CTUs available for the project were assessed for FTIH trial eligibility. The introduction of the certification procedure through the feasibility tool within ERA4TB resulted in the accreditation of the five academic CTUs, which are now prepared to carry out FTIH trials as part of the Consortium. The developed feasibility tool aims to establish open and widely used minimum requirements for the validation of academic CTUs as FTIH units, marking it as the inaugural tool for CTU validation resulting from the collaboration between industry and academia within the ERA4TB project. The established partnership has enabled an innovative and novel way of working.

The Effect of Curcumin on the Recovery of Severe Traumatic Brain Injury: A Double-blind Randomized Controlled Trial

Background and Aim: Traumatic brain injury (TBI) is one of the critical causes of death in trauma patients. In this study, the effect of nanocurcumin on the outcome of severe TBI was investigated for the first time in humans. Methods and Materials/Patients: This randomized, double-blind, and paralleled controlled study included 128 patients aged from 18 to 70 years with severe brain trauma. Patients were randomly assigned to control group (standard care treatment+placebo) and intervention group (standard care treatment+oral nanocurcumin). Changes in the level of consciousness, cerebral edema, kidney function, liver enzymes, sodium and potassium electrolytes, and brain function were followed up and compared until 6 months after discharge. Results: The Mean±SD in the intervention (14.44±31.86 years) and control patients (14.86±33.34 years) had no significant difference (P=0.543). Both groups were similar in terms of gender (P=0.669). The average level of consciousness in the intervention group increased by about 3 units (P=0.004) and more than 2 units (P=0.002) at discharge compared with the control group. By comparing the optimal performance of patients in the first (P=0.389) trimester and second (P=0.309) trimester after discharge, no significant difference was observed between the intervention and control groups. The amount of brain edema caused by severe brain trauma on the seventh day of treatment in the intervention group was lower than that in the control group (P=0.038). Conclusion: Administrating oral nanocurcumin supplement in patients with severe brain trauma along with their routine treatment is effective in improving brain edema and their level of consciousness without causing coagulation, and liver and kidney complications. These findings are not only statistically significant but also clinically vital.

Molecular characterization of Cryptosporidium and Giardia in environmental samples and faecal samples from biogas users in Bac Giang, Vietnam

Little is known about Cryptosporidium and Giardia in biogas waste and humans in Vietnam. There is a potential risk of infections during or after using the biogas system. The detected protozoan genotypes are zoonotic pathogens, and contamination of vegetables may relay through runoff to the surface waters and soil. The objective of this study was to understand the role of the environment in the epidemiology of human infections in Bac Giang province, Vietnam, with a focus on investigating the presence of Cryptosporidium spp. genotypes and Giardia assemblages among 239 environmental samples and 94 faecal samples of biogas users. PCR and sequencing analysis were used to identify the occurrence and genotypes of Cryptosporidium and Giardia in these samples. Results showed that 13/333 (3.9 %) and 9/333 (2.7 %) samples were positive for Cryptosporidium oocyst and Giardia cysts, respectively. Characterization revealed the presence of Cryptosporidium scrofarum, C. suis, C. meleagridis, C. bailey and Giardia intestinalis assemblage A and E. C. scrofarum and Giardia assemblage E were identified for the first time in humans in Bac Giang. The current information from the above investigations will be valuable for protozoan source tracking and control interventions against Cryptosporidium and Giardia infection associated with biogas wastes in Vietnam.

Antibody Levels with Cut off Points of 30 IU/ml blood, 50 IU/ml blood, and 80 IU/ ml blood after Employees Administering the Second Dose of the Covid19 Vaccine at Bontang Islamic Hospital (RSIB) in March, May and August 20

Several types of vaccines from the results of phase 3 trials such as mRNA vaccines were developed by American companies, namely Moderna and Pfizer which have been tested for the first time in humans on March 16 2020 in America, Brazil has also been vaccinated with the Sinovac Biotech China covid-19 vaccine in March January 2021 was reported to have an efficacy of 78%, in Turkey 91.25% and in Indonesia 65.3%. The aim of the study was to evaluate antibody (Ab) levels after the second dose of vaccination on day 14, 3 months, 6 months, with cut-off point Ab 30 IU/ml blood; 50 IU/ml of blood and 80 IU/ml of blood after being given the second dose of the covid19 vaccine, as well as factors that influence it such as gender, age and nutritional status. The research method of the Covid19 vaccine intervention study was given two doses, the number of respondents was 93 persons who were selected who had completed the second dose of vaccination and had their antibodies checked on day 14, 3 months and 6 months using the ELISA test method with cut-off point Ab 30 IU/ml blood; 50 IU/ml of blood and 80 IU/ml of blood after being given the second dose of the covid19 vaccine, as well as factors that influence it such as gender, age and nutritional status. The analysis was descriptive and analytic with Chy Square analysis and multinominal logistic regression. Results based on gender the majority were women 58.1%, adult age 92.5%, normal nutritional status 64.5%; 14 days after the second dose of Covid19 vaccination, the Ab level according to the cut-off point is ≥ 30 IU/ml amount 50.5% peoples, titer ≥ 50 IU/ml, the number is 43%; ≥80 IU/ml the number is 31.2%. 3 months Ab ≥ 30IU/ml amount 52.7% ≥ 50IU/ml amount 34.4%, ≥80IU/ml amount 24.7%; 6 months, sex has a significant effect only 6 months after vaccination with levels Ab≥30 IU/ml 66.7%, Ab≥50 IU/ml 50.5%, Ab≥ 80 IU/ml 41.9%peoples. Gender affects Ab levels at 6 months with Ab Cut off Point 30 IU/ml (p value 0.034, OR 0.396.95%CI 0.166-0.941) and Ab50 IU/ml (p value 0.033, OR 0.384.95%CI 0.157-0.936). Nutritional status affected Ab levels on day 14 with an Ab titter of 30IU/ml blood (p value 0.043, OR 2450.95%CI 1021-5880) and at 6 months with an Ab titre of 50IU/ ml blood (p value 0.014, OR 3000, 95% CI 1.233-7.299). The conclusion that BMI has an effect on Ab levels is 50 IU/ml blood, the effect is 8.5%, 6 months the most dominant variable in the formation of antibodies is gender, male good improved Ab days 14, and Female 6 moths was good increased Ab.

Abstract LB290: Intracranial, intratumoral drug-releasing microdevices in patients with high grade gliomas may identify biomarkers of drug activity and predict tumor response to systemic chemotherapy

Abstract The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle for the advancement of therapy for high grade gliomas (HGG), and particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial we provide first in human evidence that drug-releasing intratumoral microdevices (IMD) can be safely and effectively used to obtain patient-specific, high throughput molecular and histopathological data to inform selection of drugs based on their observed antitumor effect in situ. The use of IMD is seamlessly integrated in standard surgical practice during tumor resection. None of the six enrolled patients experienced adverse events related to the IMD, and the retrieved tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Molecular analysis of the specimens provided, for the first time in humans, preliminary evidence of the robustness of the readout, with strong correlation between IMD analysis and clinic-radiological responses to temozolomide. We also identified novel transcriptomic and metabolomic biomarkers of response and resistance to a range of targeted and cytotoxic agents used on the IMD. From an investigational aspect, the amount of information obtained with IMD allows unprecedented characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor. Citation Format: Oliver Jonas, Pier Paolo Peruzzi. Intracranial, intratumoral drug-releasing microdevices in patients with high grade gliomas may identify biomarkers of drug activity and predict tumor response to systemic chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB290.

Fetoscopic endoluminal tracheal occlusion with Smart-TO balloon: Study protocol to evaluate effectiveness and safety of non-invasive removal.

One of the drawbacks of fetoscopic endoluminal tracheal occlusion (FETO) for congenital diaphragmatic hernia is the need for a second invasive intervention to reestablish airway patency. The "Smart-TO" (Strasbourg University-BSMTI, France) is a new balloon for FETO, which spontaneously deflates when positioned near a strong magnetic field, e.g., generated by a magnetic resonance image (MRI) scanner. Translational experiments have demonstrated its efficacy and safety. We will now use the Smart-TO balloon for the first time in humans. Our main objective is to evaluate the effectiveness of prenatal deflation of the balloon by the magnetic field generated by an MRI scanner. These studies were first in human (patients) trials conducted in the fetal medicine units of Antoine-Béclère Hospital, France, and UZ Leuven, Belgium. Conceived in parallel, protocols were amended by the local Ethics Committees, resulting in some minor differences. These trials were single-arm interventional feasibility studies. Twenty (France) and 25 (Belgium) participants will have FETO with the Smart-TO balloon. Balloon deflation will be scheduled at 34 weeks or earlier if clinically required. The primary endpoint is the successful deflation of the Smart-TO balloon after exposure to the magnetic field of an MRI. The secondary objective is to report on the safety of the balloon. The percentage of fetuses in whom the balloon is deflated after exposure will be calculated with its 95% confidence interval. Safety will be evaluated by reporting the nature, number, and percentage of serious unexpected or adverse reactions. These first in human (patients) trials may provide the first evidence of the potential to reverse the occlusion by Smart-TO and free the airways non-invasively, as well a safety data.

A randomized trial on the effect of transcutaneous electrical nerve stimulator on glycemic control in patients with type 2 diabetes

Transcutaneous electrical nerve stimulator (TENS) has been demonstrated to be beneficial in glycemic control in animal models, but its application in humans has not been well studied. We randomly assigned 160 patients with type 2 diabetes on oral antidiabetic drugs 1:1 to the TENS study device (n = 81) and placebo (n = 79). 147 (92%) randomized participants (mean [SD] age 59 [10] years, 92 men [58%], mean [SD] baseline HbA1c level 8.1% [0.6%]) completed the trial. At week 20, HbA1c decreased from 8.1% to 7.9% in the TENS group (− 0.2% [95% CI − 0.4% to − 0.1%]) and from 8.1% to 7.8% in the placebo group (− 0.3% [95% CI − 0.5% to − 0.2%]) (P = 0.821). Glycemic variability, measured as mean amplitude of glycemic excursion (MAGE) at week 20 were significantly different in the TENS group vs. the placebo group (66 mg/dL [95% CI 58, 73] vs. 79 mg/dL [95% CI 72, 87]) (P = 0.009). Our study provides the clinical evidence for the first time in humans that TENS does not demonstrate a statistically significant HbA1c reduction. However, it is a safe complementary therapy to improve MAGE in patients with type 2 diabetes.

Apparent diffusion coefficients of 31P metabolites in the human calf muscle at 7 T

PurposeIn this study, we aimed to measure the apparent diffusion coefficients (ADCs) of major phosphorous metabolites in the human calf muscle at 7 T with a diffusion-weighted (DW)-STEAM sequence.MethodsA DW-STEAM sequence with bipolar gradients was implemented at 7 T, and DW MR spectra were acquired in three orthogonal directions in the human calf muscle of six healthy volunteers (TE/TM/TR = 15 ms/750 ms/5 s) at three b-values (0, 800, and 1200 s/mm2). Frequency and phase alignments were applied prior to spectral averaging. Averaged DW MR spectra were analyzed with LCModel, and ADCs of 31P metabolites were estimated.ResultsFour metabolites (phosphocreatine (PCr), adenosine triphosphate (ATP), inorganic phosphate (Pi) and glycerol phosphorylcholine (GPC)) were quantified at all b-values with mean CRLBs below 10%. The ADC values of PCr, ATP, Pi, and GPC were (0.24 ± 0.02, 0.15 ± 0.04, 0.43 ± 0.14, 0.40 ± 0.09) × 10–3 mm2/s, respectively.ConclusionThe ADCs of four 31P metabolites were successfully measured in the human calf muscle at 7 T, among which those of ATP, Pi and GPC were reported for the first time in humans. This study paves the way to investigate 31P metabolite diffusion properties in health and disease on the clinical MR scanner.

Tissue Integration of Calcium Phosphate Compound after Subchondroplasty: 4-Year Follow-Up in a 76-Year-Old Female Patient

Subchondroplasty is a new minimally invasive surgical technique developed to treat bone marrow lesions (BML) and early osteoarthritis (OA). During the procedure, engineered calcium phosphate compound (CPC) is injected. It is claimed by the manufacturer that during the healing process, the CPC is replaced with new bone. The purpose of this study was to verify the replacement of CPC with new bone after subchondroplasty for the first time in humans. A 76-year old woman was referred for resistant medial knee pain. Standing radiographs showed varus knee OA and magnetic resonance imaging (MRI) revealed BML. She was treated with subchondroplasty of medial femoral condyle. Excellent relief of pain was achieved after procedure. Afterwards, the pain worsened, the radiographs confirmed the OA progression and the patient was treated with a total knee arthroplasty (TKA) 4 years after primary procedure. The resected bone was examined histologically and with micro-computed tomography (CT). Histologically, bone trabeculae of subcortical bone were embedded in the amorphous mass. However, no signs of CPC resorption and/or bone replacement have been found with micro-CT. In short term, excellent pain relief could be expected after the subchondroplasty procedure. However, there was no replacement of CPC with bone and the technique probably did not influence the natural process of knee OA.

Reorganization of thalamocortical connections in congenitally blind humans.

Cross-modal plasticity in blind individuals has been reported over the past decades showing that nonvisual information is carried and processed by "visual" brain structures. However, despite multiple efforts, the structural underpinnings of cross-modal plasticity in congenitally blind individuals remain unclear. We mapped thalamocortical connectivity and assessed the integrity of white matter of 10 congenitally blind individuals and 10 sighted controls. We hypothesized an aberrant thalamocortical pattern of connectivity taking place in the absence of visual stimuli from birth as a potential mechanism of cross-modal plasticity. In addition to the impaired microstructure of visual white matter bundles, we observed structural connectivity changes between the thalamus and occipital and temporal cortices. Specifically, the thalamic territory dedicated to connections with the occipital cortex was smaller and displayed weaker connectivity in congenitally blind individuals, whereas those connecting with the temporal cortex showed greater volume and increased connectivity. The abnormal pattern of thalamocortical connectivity included the lateral and medial geniculate nuclei and the pulvinar nucleus. For the first time in humans, a remapping of structural thalamocortical connections involving both unimodal and multimodal thalamic nuclei has been demonstrated, shedding light on the possible mechanisms of cross-modal plasticity in humans. The present findings may help understand the functional adaptations commonly observed in congenitally blind individuals.

Nonoptimal component placement of the human connectome supports variable brain dynamics

Abstract Neural systems are shaped by multiple constraints, balancing region communication with the cost of establishing and maintaining physical connections. It has been suggested that the lengths of neural projections be minimized, reducing their spatial and metabolic impact on the organism. However, long-range connections are prevalent in the connectomes across various species, and thus, rather than rewiring connections to reduce length, an alternative theory proposes that the brain minimizes total wiring length through a suitable positioning of regions, termed component placement optimization. Previous studies in nonhuman primates have refuted this idea by identifying a nonoptimal component placement, where a spatial rearrangement of brain regions in silico leads to a reduced total wiring length. Here, for the first time in humans, we test for component placement optimization. We show a nonoptimal component placement for all subjects in our sample from the Human Connectome Project (N = 280; aged 22–30 years; 138 females), suggesting the presence of constraints—such as the reduction of processing steps between regions—that compete with the elevated spatial and metabolic costs. Additionally, by simulating communication between brain regions, we argue that this suboptimal component placement supports dynamics that benefit cognition.

780 POTENTIAL RELATIONSHIP BETWEEN MITOCHONDRIAL FERRITIN EXPRESSION AND CARDIOTOXICITY IN PATIENTS UNDERGOING ANTHRACYLINE CHEMOTHERAPY

Abstract Background Anthracyclines effectiveness is burdened by numerous side effects, among which cardiotoxicity (CTX) is the one carrying the highest impact on survival. Prevention of CTX is known to be far more effective than its treatment. Nonetheless, present patients stratification does not predict different post-treatment outcomes. The inter-individual variability in the response to treatment likely resides at the molecular level. In this context, mitochondrial ferritin (FtMt) has been studied in preclinical models of doxorubicin-induced cardiotoxicity. Both in cell lines and animal models, overexpression of this protein has been found to be protective against the cytotoxic oxidative damage deriving from anthracycline use. Aim of the study The primary aim of the study was to evaluate – for the first time in humans and in mouse myocardial cells lines – the expression of FtMt and its relationship with the potential development of cardiotoxicity in patients undergoing chemotherapy with anthracyclines. Methods Twenty-nine patients referred to our Oncology Outpatient Clinic to start treatment with anthracyclines – for either lymphoma or breast cancer – were enrolled before treatment initiation. All patients were above 18 years of age and free from any cardiovascular pathology at baseline. Troponin T (TnT), Brain Natriuretic Peptide (NT-proBNP), FtMt and creatinine were evaluated at baseline, before any chemotherapy cycle, at the end of the protocol, at 6 and 12 months from the first cycle. TnT and NT-proBNP were quantified through ECLIA and the expression of FtMt through qRT-PCR performed on peripheral white blood cells. Left ventricular function was evaluated through standard echocardiography at baseline, at the end of chemotherapy, at 6 and 12 months. Furthermore, variations in FtMt expression in response to doxorubicin treatment were studied on mouse primary cardiomyocytes. Results Direct evaluation of FtMt expression in mouse myocardial cells showed higher levels of FtMt in cardiomyocytes exposed to doxorubicin (p=0.0239). In the clinical model FtMt expression was found to be decreased after treatment initiation, with a trend that in the descriptive analysis appeared to be opposite to the one registered for TnT. For any unit of FtMt at baseline, single TnT values after treatment and at one year were found to be decreased of 1,89 ng/L and of 1,57 ng/L, respectively. TnT was the only cardiac parameter showing significant variation following anthracycline administration, with an average increase of 10 ng/L (p<0,0001) and 15,8 ng/L (p=0,0071) in breast cancer and lymphoma patients respectively and remained elevated at follow-up only in the lymphoma group with a difference of 11,35ng/L at 1 year (p=0,0017). No occurrence of CTX – defined according to international guidelines - was found in the population under study. Conclusions Our results confirm that exposure to anthracyclines influences FtMt expression. The study performed on mouse primary cardiomyocytes demonstrate for the first time the ability of cardiac myocytes to increase FtMt expression in response to doxorubicin. In the clinical model any additional unit of FtMt at baseline was associated with a reduction in TnT values at the end of the treatment and at 1 year, potentially indicating a protective role of this protein in this context. The lack of frank cardiotoxicity in this group impeded the evaluation of the prognostic meaning of this event. In the future drugs able to upregulate the expression of this protein should be investigated as potential strategy to prevent anthracycline-induced cardiotoxicity.