First Week Of Treatment Research Articles

Blood concentration monitoring and renal function changes during gentamicin administration for infective endocarditis: a retrospective observational study

BackgroundEstablished guidelines for monitoring gentamicin blood concentration are lacking; therefore, we focused on improving pharmacological interventions and ensuring their safety. We aimed to optimize gentamicin administration for infective endocarditis (IE) treatment.MethodsThe study involved adult patients diagnosed with IE and treated with gentamicin from January 2014 to December 2022. Clinical presentation and drug therapy regimen were comprehensively evaluated. We performed a retrospective chart review of the frequency of gentamicin dose adjustments and changes in renal function while on gentamicin. In addition, we attempted to extract risk factors for renal impairment using univariate analysis.ResultsOn average, a 7.1% decline [changed to − 6.7 ± 20.4 (standard deviation) mL/min/1.73 m2] in the estimated glomerular filtration rate was observed after gentamicin administration, but it was statistically insignificant. Notably, 58% of patients required dosage adjustments, with a subset requiring multiple adjustments. Among the cases in which dosage adjustments were made, 61% were within the first week of treatment. There were no patients with gentamicin levels below the target peak concentration. Furthermore, no independent risk factors were identified in patients requiring dose reduction.ConclusionsDose adjustment was necessary in many cases after treatment initiation. The time to dose adjustment varied widely. These findings highlight the importance of consistent blood concentration monitoring in patients of all demographics, at least weekly, and underscore that routine peak concentration assessments may not be essential when a 3 μg/mL target is maintained. This study provides information on monitoring gentamicin blood level, which can improve IE treatment safety.

Metabolic Side Effects from Antipsychotic Treatment with Clozapine Linked to Aryl Hydrocarbon Receptor (AhR) Activation.

Metabolic syndrome (MetS) is the most common adverse drug reaction from psychiatric pharmacotherapy. Neuroreceptor blockade by the antipsychotic drug clozapine induces MetS in about 30% of patients. Similar to insulin resistance, clozapine impedes Akt kinase activation, leading to intracellular glucose and glutathione depletion. Additional cystine shortage triggers tryptophan degradation to kynurenine, which is a well-known AhR ligand. Ligand-bound AhR downregulates the intracellular iron pool, thereby increasing the risk of mitochondrial dysfunction. Scavenging iron stabilizes the transcription factor HIF-1, which shifts the metabolism toward transient glycolysis. Furthermore, the AhR inhibits AMPK activation, leading to obesity and liver steatosis. Increasing glucose uptake by AMPK activation prevents dyslipidemia and liver damage and, therefore, reduces the risk of MetS. In line with the in vitro results, feeding experiments with rats revealed a disturbed glucose-/lipid-/iron-metabolism from clozapine treatment with hyperglycemia and hepatic iron deposits in female rats and steatosis and anemia in male animals. Decreased energy expenditure from clozapine treatment seems to be the cause of the fast weight gain in the first weeks of treatment. In patients, this weight gain due to neuroleptic treatment correlates with an improvement in psychotic syndromes and can even be used to anticipate the therapeutic effect of the treatment.

Skin lesion of external auditory canal in a patient with seborrheic dermatitis.

Patient K. turned to a dermatologist with complaints of periodic itching in the scalp skin, face, auricles, external auditory canals with discomfort and discharge from them. Clinical diagnosis: seborrheic dermatitis. At the otolaryngologist consultation, the patient was diagnosed with bilateral external otitis media with the formation of hyperkeratotic casts in both external auditory canals. Seborrheic dermatitis was treated in two stages. At the first stage, itraconazole 200 mg was prescribed orally 1 time per day for the first week of treatment, then 200 mg orally 1 time per day for the first two days of each month for 3 months and externally on the scalp ketoconazole shampoo 2% 2 times a week for 4 weeks, then 1 time in 2 weeks. At the second stage, isotretinoin was administered orally at a dosage of 10 mg per day in an intermittent mode. A positive clinical result was obtained against the background of the therapy. The patient continues to remain under supervision.

Optimizing tacrolimus dosing in Hispanic renal transplant patients: insights from real-world data.

Tacrolimus, an immunosuppressant used to prevent organ rejection in renal transplant patients, exhibits high inter-patient variability, necessitating therapeutic drug monitoring. Early post-transplant tacrolimus exposure in Hispanics is understudied. Although genotypic information is linked to pharmacokinetic differences, its clinical application remains limited. This study aimed to use a real-world data-driven, pharmacokinetic model-based approach for tacrolimus in Hispanics to determine a suitable initial dose and design an optimal dose titration strategy by simulations to achieve plasma trough concentration target levels of 10-12ng/mL at the earliest. Sparse concentration-time data of tacrolimus were obtained from electronic medical records for self-identified Hispanic subjects following renal transplant. Rich pharmacokinetic literature data was leveraged to estimate structural pharmacokinetic model parameters, which were then fixed in the current analysis. Only apparent clearance was estimated with the sparse tacrolimus data and potential covariates were identified. Simulations of various starting doses and different dose titration strategies were then evaluated. The analysis included 121 renal transplant patients with 2,215 trough tacrolimus concentrations. A two-compartment transit absorption model with allometrically scaled body weight and time-varying hematocrit on apparent clearance adequately described the data. The estimated apparent clearance was 13.7L/h for a typical patient weighing 70kg and at 30% hematocrit, demonstrating a 40% decrease in clearance compared to other patient populations. Model based simulations indicated the best initial dose for the Hispanic population is 0.1mg/kg/day. The proposed titration strategy, with three dose adjustments based on trough levels of tacrolimus, increased the proportion of patients within the target range (10-12ng/mL) more than 2.5-fold and decreased the proportion of patients outside the therapeutic window by 50% after the first week of treatment. Hispanic renal transplant population showed an estimated 40% decrease of apparent clearance in the typical patient compared to other populations with similar characteristics. The proposed dose adjustment attained the target range rapidly and safely. This study advocates for tailored tacrolimus dosing regimens based on population pharmacokinetics to optimize therapy in Hispanic renal transplant recipients.

Psychotic Arousal and the Psychopathology of Acute Schizophrenia: An Exploratory Study of the Experiential Emotional State in Acute Psychosis.

Background: Increasing research data suggest that the dysfunction of emotional brain systems may be an important contributor to the pathophysiology of schizophrenia. However, contemporary psychopathology consistently underestimates the role of emotions in the phenomenology of the disease. Psychotic arousal (PA) is a conceptually defined psychopathological construct aiming to portray the experiential emotional state of acute psychosis. The concept provides an explanatory model for the emergence of psychosis, and the formation and maintenance of delusions based on neurobiological models on the formation of core consciousness and subjectivity. This is the first exploratory study of the major assumptions, endorsed in the project summarized as follows: (1) psychotic arousal is a discrete state, eligible for investigation; (2) abnormal experiential feelings are an integral part of this state; and (3) the state is responsive to antipsychotic intervention during the first weeks of treatment. Methods: We developed the Psychotic Arousal Scale (PAS) accordingly, explored its first psychometric properties and tested its relation to other psychopathological measures. Fifty-five acute schizophrenia patients were evaluated with the PAS, the Positive and Negative Syndrome Scale, the Brown Assessment of Beliefs Scale, the Hamilton Anxiety Scale, and the Calgary Depression Scale. Cronbach α coefficients, t-test analysis, correlations and mixed linear regression models were applied for testing the internal reliability of the scale, associations between parameters and sensitivity to change in three time periods during therapeutic intervention. Results: The results of the study support that (PA) is eligible for investigation as a discrete psychopathological state. Abnormal experiential feelings are an integral part of this state, presenting high affinity with other affective measures; their degree of severity relates to the delusions' conviction and are amenable to antipsychotics early in treatment during the acute psychotic episode. Conclusions: The findings of this exploratory study are connotative of the presence of an emotional arousal permeated by abnormal experiential feelings during acute psychosis, largely overlooked by contemporary psychopathology.

Neonatal high-dose riboflavin treatment channels energy expenditure towards sensorimotor and somatic development and reduces rodent growth and weight gain by modulating NRF-1 in the hypothalamus

Metabolic adaptations early in life can drive energy expenditure towards brain and physical development, with less emphasis on body mass gain and somatic growth. Dietary or pharmacological manipulations can influence these processes, but to date, the effects provided by riboflavin have not been studied. The study aimed to evaluate the effects of neonatal treatment with different doses of riboflavin on sensorimotor and somatic development in rodents. Based on this, the following experimental groups were formed: Control (C, 0 mg/kg), Riboflavin 1 (R1, 1 mg/kg), Riboflavin 2 (R2, 10 mg/kg) and Riboflavin 3 (R3, 100 mg/kg). Treatment with 100 mg/kg riboflavin anticipated the reflex ontogeny of righting, cliff aversion, negative geotaxis, and free-fall righting. Intervention with 10 and 100 mg/kg of riboflavin anticipated the reflex maturation of vibrissae placement. Eye-opening, upper incisor eruption, and lower incisor eruption reached maturational age more quickly for animals treated with 100 mg/kg, while caudal growth and body weight gain were reduced from the second week of treatment, for groups R2 and R3. Pearson's correlation analysis indicated a positive association between the administration of high doses of riboflavin and murine growth in the first week of treatment. There was, however, a negative association between treatment with a high dose of riboflavin and growth in the second week of administration, coinciding with a reduction in body weight gain in the R3 group. Treatment with 100 mg/kg of riboflavin also reduced energy expenditure parameters in the open field and catwalk. Although high-dose treatment stimulates the physiological plasticity of the CNS and reduces weight gain, hepatic parameters were preserved, highlighting the participation of the liver in the supply of fatty acids for neural maturation. Furthermore, hypothalamic NRF-1 expression was increased in the R3 group inversely to the reduction in weight gain. Our results suggest that high-dose riboflavin stimulates sensorimotor and somatic development and reduces the energy invested in growth, body weight gain, and locomotor activity, possibly involving NRF-1 gene modulation in the hypothalamus.

A comprehensive and longitudinal evaluation of the different populations of lymphoid and myeloid cells in the peripheral blood of patients treated with chemoradiotherapy for head and neck cancer

BackgroundImmunotherapy provided significant survival benefits for recurrent and metastatic patients with head and neck cancer. These improvements could not be reproduced in patients treated with curative-intent chemoradiotherapy (CRT) and the optimal radio-immunotherapy (RIT) concepts have yet to be designed. Exploration and analysis of the pre-therapeutic immune status of these patients and the changes occurring during the treatment course could be crucial in rationally designing future combined treatments.MethodsBlood samples were collected from a cohort of 25 head and neck cancer patients treated with curative-intended (C)-RT prior to therapy, after the first week of treatment, and three months after treatment completion. Peripheral blood mononuclear cells (PBMCs) or all nucleated blood cells were isolated and analyzed via flow cytometry.ResultsAt baseline, patients showed reduced monocyte and lymphocyte counts compared to healthy individuals. Although overall CD8+ T-cell frequencies were reduced, the proportion of memory subsets were increased in patients. Radiotherapy (RT) treatment led to a further increase in CD8+ effector memory T-cells. Among myeloid populations, tumor-promoting subsets became less abundant after RT, in favor of pro-inflammatory cells.ConclusionThe present study prospectively demonstrated a complex interplay and distinct longitudinal changes in the composition of lymphocytic and myeloid populations during curative (C)-RT of head and neck cancer. Further validation of this method in a larger cohort could allow for better treatment guidance and tailored incorporation of immunotherapies (IT) in the future.

Use of Traditional Japanese Herbal Medicine Daikenchuto for the Treatment of Abdominal Distention in Very-Low-Birth-Weight Infants.

Background: Very-low-birth-weight (VLBW) infants often experience feeding intolerance owing to organ immaturity, and the most frequent sign is the presence of abdominal distention. Daikenchuto (DKT), a traditional Japanese herbal medicine, is used to improve gastrointestinal function, particularly in adults. The aim of this study was to investigate the effectiveness of DKT in reducing abdominal distention and intestinal gas in VLBW infants. Methods: This study involved a retrospective chart review of 24 VLBW infants treated with DKT at Hamamatsu University Hospital between April 2016 and March 2021. The effects of DKT treatment at a dose of 0.3 g/kg/day were evaluated through clinical parameters and abdominal radiography. Results: Before treatment, marked abdominal distention was observed in 46% of the infants, which reduced to 4% within a week of DKT administration. The gas volume score (GVS) decreased in 92% of the patients within the first week of treatment and markedly decreased by ≥20% in 46% of the patients. The effects of improving abdominal distention and decreasing the GVS on radiography persisted for 1-2 weeks after treatment initiation. No clinical parameters affecting a GVS reduction of ≥20% and no notable adverse effects were observed. Conclusions: While the preliminary findings suggest that DKT may help manage abdominal distention in VLBW infants, further studies with placebo-controlled trials, larger sample sizes, use of advanced image processing software, and consideration of additional influencing factors are required to substantiate these results and identify predictors of treatment response.

Assessment of the Short-Term Efficacy of a Wet-Cupping Therapy Session in Alleviating Symptoms of Fibromyalgia Syndrome: A Single-Arm Clinical Trial

Fibromyalgia holds significant importance in both primary care and physical treatment settings due to its high prevalence and the challenges associated with its diagnosis and management. This study aims to assess the short-term efficacy of a wet-cupping therapy session in alleviating symptoms of Fibromyalgia Syndrome (FMS). This study employed a prospective, single-arm intervention design. Baseline and post-treatment evaluations encompassed a comprehensive battery of assessment tools: Socio-Demographic Questionary, Visual Analog Scale (VAS) for Pain, Fatigue Severity Scale (FSS), Beck Depression Scale (BDS), Fibromyalgia Impact Questionnaire (FIQ). A total of 20 eligible individuals were enrolled in the study. Significant alterations in pain perception, as measured by the VAS, were evident both prior to treatment and at the end of the first week of treatment (p < 0.001). Additionally, significant favorable effects of the treatment were observed on FSS and BDS levels during the initial week of therapy (p = 0.001, p = 0.01; respectively). Moreover, a marked improvement was identified in FIQ scores after treatment compared to baseline (p < 0.001). Across all evaluated clinical indicators, cupping therapy exhibited a significant positive influence on FMS. In conclusion, wet cupping therapy yields favorable outcomes in terms of pain perception, fatigue reduction, mood enhancement, and the overall impact of fibromyalgia syndrome. Thus, it offers a promising avenue for therapeutic intervention among individuals afflicted by this condition.

A Comparative Analysis of Camellia sinensis Extract and Salicylic Acid in the Management of Acne Vulgaris in Students

Purpose: This study aims to compare the efficacy of Camellia sinensis extract serum with salicylic acid gel in treating acne vulgaris. Method: The bioactive compounds from the Camellia sinensis leaf extract were extracted using distilled water and formulated into a serum for topical application. Salicylic acid was also formulated into a gel-based cream for topical application, and the effect on acne was investigated over the course of two weeks. This entails a longitudinal, open-label, and random treatment of six selected subjects with Camellia sinensis bioactive compound serum and others with salicylic acid gel for 14 days under close observation. Results: The Camellia sinensis gel-based cream was found to be effective in the treatment of certain types of acne vulgaris. The salicylic acid gel (standard) effectively treated all types of acne. The effect of salicylic acid on various forms of acne as presented on test subjects in Group A didn’t peak until the second week, with a visible reduction in blackheads (open comedones). While Camellia sinensis peaked in the first week of treatment, there was little to no reduction in blackheads, but there was a visible reduction in pore size, indicating that it may have preventive properties against acne formation. Subjects treated with Camellia sinensis experienced no adverse effects, while others experienced slight tingling, dryness, and irritation while using salicylic acid. Conclusion: Based on this study, the treatment that showed faster results within the short period allocated to the study shows promising use as a standard form of treatment for acne vulgaris as compared to salicylic acid because no adverse effect was experienced with Camellia sinensis.

Psoriasis with Leg Involvement as the New Difficult-To-Treat Area: A Cohort Study of Patients Treated With Risankizumab.

Historically, difficult-to-treat areas in psoriasis included face, scalp, folds, genitalia, nails, and palmoplantar region. Recent studies have found that lower limbs behave like a "new" difficult-to-treat area as they can be the only site of residual disease even in patients undergoing biologic therapies. We aimed to evaluate whether legs had different response rates and response times to treatment with a new biologic drug, risankizumab, compared to other body sites. We conducted a real-life, observational, retrospective, multicenter study including patients affected by moderate-to-severe psoriasis with leg involvement and undergoing biological therapy with risankizumab for more than 16 weeks. The Psoriasis Area Severity Index (PASI) and Leg-PASI were collected at T0 and at weeks 16, 28, 40, 52, 64, and 76. Statistical analysis using Student's t test and linear regression analysis were performed. A total of 124 patients were included. The difference between the improvement percentage compared to baseline was statistically significant at weeks 16 and 28, demonstrating that Leg-PASI improved less than PASI. From the linear regression it was deduced that the slope is statistically less steep for Leg-PASI than for overall PASI, confirming that this site responds more slowly to the therapy. Leg response to risankizumab appears to differ significantly from other body sites in the first weeks of treatment, even if after 28 weeks, statistical significance is lost. Our preliminary finding suggests that risankizumab can be considered an effective treatment for leg psoriasis but with longer response times than other areas, demonstrating the relative nature of resistance to treatment of this district.

Safety of high-dose amikacin in the first week of all-oral rifampicin-resistant tuberculosis treatment for the prevention of acquired resistance (STAKE): protocol for a single-arm clinical trial

IntroductionAn effective rifampicin-resistant tuberculosis (RR-TB) treatment regimen should include prevention of resistance amplification. While bedaquiline (BDQ) has been recommended in all-oral RR-TB treatment regimen since 2019, resistance is rising at...

An international survey on canine urinary incontinence: case frequency, diagnosis, treatment and follow-up.

Urinary incontinence (UI) consists of involuntary leakage of urine during the storage phase of urination. An anonymous survey was given to Spanish and Italian veterinarians about canine UI treated cases, diagnosis, treatment, follow-up, and professional interest. Most veterinarians treated ≤3 cases/quarter, resulting in the percentage of incontinence males being lower than that of females (1-4% vs 0-24%). The percentage of spayed incontinent females was lower in Spain (0-24%) than in Italy (75-100%). Most diagnoses were based on a diagnostic algorithm (Spain: 88.7%; Italy: 65.3%); patient report and history, blood work, urinalysis and abdominal ultrasound. Urethral/bladder pressure measurement was unusual (Spain: 0.2%; Italy: 2.4%). In Spain, radiology with contrast medium and CT urography (26.3% and 34.4%, respectively) were more frequent than in Italy (11.6% and 22.7%, respectively). When suspecting urethral sphincter mechanism incompetence pharmacological trial (Spain: 93.2%; Italy: 78.9%). The first-choice medical treatment was Phenylpropanolamine, followed by Ephedrine and Deslorelin. When pharmacotherapy failed, the most frequent option was drug change, followed by increased drug dosage/frequency of administration, surgical therapy and colposuspension. A review was completed after the first week of treatment followed by periodic reviews. Most of the respondents participated in continuing education only if UI occurred in their everyday practice (Spain: 63.0%; Italy: 55.4%) and about 30% responders did it regardless of the number of UI cases treated (Spain: 30.5%; Italy: 37.4%). Some recommendations in clinical practice were made. UI can be underestimated by owners; therefore, a complete history should be obtained by veterinarians. Veterinarians should carefully evaluate if spaying is advisable considering it could increase UI risk. A step-by-step approach is recommended and a specific diagnostic-therapeutic algorithm for UI in dogs is provided. Conservative approaches (regular exercise, weight loss in overweight dogs and observing an "incontinence diary" to identify abnormal patterns of urination) are advisable.

Redisplacement of reduced distal radius fractures in adults: does the type of casting play a role? The CAST study, a multicentre cluster randomized controlled trial.

It is not clear which type of casting provides the best initial treatment in adults with a distal radial fracture. Given that between 32% and 64% of adequately reduced fractures redisplace during immobilization in a cast, preventing redisplacement and a disabling malunion or secondary surgery is an aim of treatment. In this study, we investigated whether circumferential casting leads to fewer the redisplacement of fewer fractures and better one-year outcomes compared with plaster splinting. In a pragmatic, open-label, multicentre, two-period cluster-randomized superiority trial, we compared these two types of casting. Recruitment took place in ten hospitals. Eligible patients aged ≥ 18 years with a displaced distal radial fracture, which was acceptably aligned after closed reduction, were included. The primary outcome measure was the rate of redisplacement within five weeks of immobilization. Secondary outcomes were the rate of complaints relating to the cast, clinical outcomes at three months, patient-reported outcome measures (PROMs) (using the numerical rating scale (NRS), the abbreviated version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH), and Patient-Rated Wrist/Hand Evaluation (PRWHE) scores), and adverse events such as the development of compartment syndrome during one year of follow-up. We used multivariable mixed-effects logistic regression for the analysis of the primary outcome measure. The study included 420 patients. There was no significant difference between the rate of redisplacement of the fracture between the groups: 47% (n = 88) for those treated with a plaster splint and 49% (n = 90) for those treated with a circumferential cast (odds ratio 1.05 (95% confidence interval (CI) 0.65 to 1.70); p = 0.854). Patients treated in a plaster splint reported significantly more pain than those treated with a circumferential cast, during the first week of treatment (estimated mean NRS 4.7 (95% CI 4.3 to 5.1) vs 4.1 (95% CI 3.7 to 4.4); p = 0.014). The rate of complaints relating to the cast, clinical outcomes and PROMs did not differ significantly between the groups (p > 0.05). Compartment syndrome did not occur. Circumferential casting did not result in a significantly different rate of redisplacement of the fracture compared with the use of a plaster splint. There were comparable outcomes in both groups.

Assessment of the Dietary Intake Changes in Patients with Head and Neck Cancer Treated with Radical Radiotherapy.

Patients during radiotherapy due to head and neck cancers experience a lot of side effects which may have a considerable impact on the patients' ability to meet individual daily energy demands by means of oral diet. The study included 104 head and neck cancer patients who qualified for radical radiotherapy. Radical treatment takes 6 weeks and every week the patients were assessed for dietary intake. The subjects were covered with the constant care of a dietician, received FSMP (food for special medical purposes), and, if necessary, enteral nutrition. In the first week of treatment, the patients, from the kitchen diet alone, met 91.5% of the energy demand, while in the last week of treatment, only 40.9%. After introducing the FSMP or enteral nutrition, the patients met 120% of the demand in the first week of therapy and 95% in the last week, respectively. The patients who followed the dietary recommendations were characterized by significantly lower weight loss (3.07 kg) compared to non-adherent patients (5.56 kg). The used therapy significantly contributed to decreasing nutritional intake in the subsequent weeks of treatment. On the other hand, incorporating FSMP in the diet and enteral nutrition with industrial diets significantly increased the fulfilled energy demand of patients.

Intestinal Dialysis Research Progress and the Early Treatment of a NonDiabetic Patient with Symptomatic Uremia and Fatty Liver with Intestinal Dialysis: The Practice of Evidence-Based Medicine

Background: Chronic renal failure results from a variety of pathophysiological mechanisms and etiologies, and is associated with progressive and irreversible damage and loss of the kidneys’ tissue leading to failure of the kidneys to excrete waste products, and also failure to perform some other functions. Many patients with chronic renal failure in a country like Iraq has been reported to be reluctant to accept dialysis therapies because of the wide spread notion of its association with high mortality. The lack of effective, convenient, and affordable therapy for chronic renal failure in many regions of the world should not mean should that the patients with advanced chronic renal failure are left without other suitable, convenient and acceptable care. The aim of this paper is to describe the early treatment of a patient with symptomatic uremia with intestinal dialysis. Patients and Methods: A 60-year non-diabetic male patient was experiencing progressive symptomatic uremia. On the 18th of November, 2023, blood urea was elevated at 217 mg/dL, serum creatine was 5.2 mg/dL, and he had symptomatic uremia with nausea, vomiting, fatigue, pruritus and anemia. The patient was treated with intestinal dialysis (Acacia gum supplementation plus conservative dietary and pharmacological management of chronic renal failure) which was prescribed according to the latest published guidelines. It was necessary during the first week of treatment to eliminate almost all dietary protein, and his diet was consisting mainly of high calorie juices, grapes, and water melon. Results: When the patient was seen on the 2nd of December, 2023, treatment was associated with marked symptomatic and laboratory improvements. Blood urea was 115 mg /dL, serum creatine was 3.6 mg /dL However, and serum calcium was 5.3 mg/dL (Normal ranges: 8-10.5 mg/dL). Therefore, oral alphacalcidol was added in a dose of 1 microgram daily. Conclusion: Intestinal dialysis will continue to be used to improve the management of chronic renal failure and symptomatic uremia as long as there is no convenient and affordable therapy for chronic renal failure in many regions of the world.

Low-intensity pulsed ultrasound stimulation (LIPUS) modulates microglial activation following intracortical microelectrode implantation

Microglia are important players in surveillance and repair of the brain. Implanting an electrode into the cortex activates microglia, produces an inflammatory cascade, triggers the foreign body response, and opens the blood-brain barrier. These changes can impede intracortical brain-computer interfaces performance. Using two-photon imaging of implanted microelectrodes, we test the hypothesis that low-intensity pulsed ultrasound stimulation can reduce microglia-mediated neuroinflammation following the implantation of microelectrodes. In the first week of treatment, we found that low-intensity pulsed ultrasound stimulation increased microglia migration speed by 128%, enhanced microglia expansion area by 109%, and a reduction in microglial activation by 17%, indicating improved tissue healing and surveillance. Microglial coverage of the microelectrode was reduced by 50% and astrocytic scarring by 36% resulting in an increase in recording performance at chronic time. The data indicate that low-intensity pulsed ultrasound stimulation helps reduce the foreign body response around chronic intracortical microelectrodes.

Robustness of intensity modulated proton treatment of esophageal cancer for anatomical changes and breathing motion

Background and purposeIn this study, we assessed the robustness of intensity modulated proton therapy (IMPT) in esophageal cancer for anatomical variations during treatment. MethodsThe first sixty esophageal cancer patients, treated clinically with chemoradiotherapy were included. The treatment planning strategy was based on an internal target volume (ITV) approach, where the ITV was created from the clinical target volumes (CTVs) delineated on all phases of a 4DCT. For optimization, a 3 mm isotropic margin was added to the ITV, combined with robust optimization using 5 mm setup and 3 % range uncertainty. Each patient received weekly repeat CTs (reCTs). Robust plan re-evaluation on all reCTs, and a robust dose summation was performed. To assess the factors influencing ITV coverage, a multivariate linear regression analysis was performed. Additionally, clinical adaptations were evaluated. ResultsThe target coverage was adequate (ITV V94%>98 % on the robust voxel-wise minimum dose) on most reCTs (91 %), and on the summed dose in 92 % of patients. Significant predictors for ITV coverage in the multivariate analysis were diaphragm baseline shift and water equivalent depth (WED) of the ITV in the beam direction. Underdosage of the ITV mainly occurred in week 1 and 4, leading to treatment adaptation of eight patients, all on the first reCT. ConclusionOur IMPT treatment of esophageal cancer is robust for anatomical variations. Adaptation appears to be most effective in the first week of treatment. Diaphragm baseline shifts and WED are predictive factors for ITV underdosage, and should be incorporated in an adaptation protocol.

A real-world longitudinal assessment of the treatment-related symptoms and associated burden among patients receiving chemotherapy.

e23158 Background: For patients (pts) with cancer, treatment with cytotoxic chemotherapy is associated with a variety of treatment-related symptoms including nausea, vomiting, diarrhea and constipation. Often the ability to manage these symptoms when they occur is the difference between completion of chemotherapy and early discontinuation. The first weeks of treatment are critical for understanding the pts’ acute experience with chemotherapy. The objective of this study is to longitudinally evaluate treatment-related symptoms and associated treatment burden among chemotherapy pts through a real-world electronic remote symptom monitoring system. Methods: Pts treated with chemotherapy in U.S. academic cancer centers were enrolled in Carevive’s Patient Reported Outcomes Mobile Platform (Carevive PROmpt®) between September 2020 and Dec 2023, with 3 month median follow-up. A total of 476 pts were enrolled, across early (81%) and late (19%) stage disease. Weekly PRO-CTCAE-derived surveys assessed severity, frequency, and interference for 16 symptoms often associated with cancer treatment: anxiety, constipation, cough, decreased appetite, diarrhea, fatigue, general pain, insomnia, mouth/throat sores, muscle pain, nausea, numbness and tingling, rash, sadness, shortness of breath, and vomiting. The GP5 assessed weekly overall bother with the side effects of treatment. Questionnaires were administered weekly starting at treatment initiation. Results: The mean age of chemotherapy pts was 67.3 (SD = 13.2) years, with 75% female, and 20% African American. At treatment initiation, 302 pts reported symptoms by PRO-CTCAE, and 100 completed the GP5. At week 1, constipation, general pain (GP), nausea, numbness/tingling (N/T), and shortness of breath were experienced by 20-25% of pts. Over the first 4 weeks of treatment, pts reported an increase in constipation, decreased appetite, diarrhea, and nausea at week 2, with a return to week 1 frequency over the remaining weeks. Diarrhea, however, remained elevated. While week 1 capture rates were lower, patterns for treatment bother were similar. At week 1, 34% of pts reported being bothered at least “Somewhat” by the side effects of treatment. This increased to 48% at week 2, but returned to near the week 1 frequency over the remaining weeks. Conclusions: For remote-monitored pts in this real-world data set treated with chemotherapy both alone and in combination, the most frequent symptoms at the start of treatment were nausea, GP, and N/T. The frequency of pts with GP and N/T did not change over the course of treatment suggesting their possible presence prior to the observed regimen. Increases in chemotherapy-related symptoms show the importance of ongoing assessment over the first 4 weeks of treatment, ideally with feedback to treating physicians and concomitant symptom management to optimize successful chemotherapy completion.

Efficacy of Lemborexant in Adults ≥ 65 Years of Age with Insomnia Disorder.

Pharmacologic treatments are available to treat insomnia, a common and burdensome sleep disorder, but may be contraindicated in older adults who are prone to side effects from sleep-promoting drugs. These analyses of sleep diary data from Study E2006-G000-303 (Study 303) investigated the benefits of lemborexant 5mg (LEM5) and 10mg (LEM10) in the subgroup age ≥ 65years with insomnia. Study 303, a 12-month, double-blind study of LEM5 and LEM10 in adults (age ≥ 18years) with insomnia disorder (sleep onset and/or maintenance difficulties) assessed subject-reported (subjective) sleep-onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), and total sleep time (sTST). Morning sleepiness/alertness, insomnia severity (Insomnia Severity Index [ISI]), fatigue (Fatigue Severity Scale [FSS]), perceptions of sleep-related medication effects (Patient Global Impression-Insomnia [PGI-I] questionnaire), and safety were also evaluated. In this subgroup of older adults (≥ 65years; n = 262), there were significantly larger changes from baseline for sSOL, sSE, sTST, and sWASO with LEM5 and LEM10 versus placebo through month 6 (except sWASO month 1), indicating improvement; these improvements were sustained through month 12. Subject-reported increases in morning alertness were significantly greater with one or both LEM doses versus placebo through month 6 and sustained through month 12. There were significantly larger ISI total and daytime functioning score decreases (improvement) from baseline with LEM versus placebo at months 1, 3, and 6 (total score: both doses; daytime functioning: LEM5 month 1 and both doses months 3 and 6) and decreases from baseline FSS at months 1 and 3 (LEM5) and month 6 (both doses), sustained to month 12. Compared with placebo, more subjects reported that LEM (both doses) positively impacted ability to sleep, time to fall asleep, and TST through month 6, sustained to month 12, with no rebound after drug withdrawal. LEM was well tolerated to month 12; mild somnolence was the most common treatment-emergent adverse event. Improvements in subject-reported efficacy in LEM-treated adults age ≥ 65years with insomnia were observed as early as the first week of treatment and sustained through end of month 12. LEM was well tolerated. ClinicalTrials.gov identifier NCT02952820: E2006-G000-303; Study 303; SUNRISE-2 (First posted: October 2016); EudraCT 2015-001463-39 (First posted: November 2016).