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Background: Older adults are prone to vitamin D3 (VD3) deficiency, which may impair their health. A high dose of VD3 (HDVD3 = 100,000 IU) could improve their 25-hydroxyvitamin D3 [25(OH)D] level and health outcomes. However, evidence for such a beneficial effect of HDVD3 in older adults coming from clinical trials is mixed., Objective: To review the literature on the efficacy of a single dose of 100,000 IU of VD3 in older people., Methods: We searched PubMed/Medline, Science Direct, and NIH's clinical trials registry for clinical studies on the effect of a single high dose of VD3 on various health outcomes in older people. We also performed a meta-analysis using the standardized mean difference to assess the effect of VD3 on its blood level. Due to expected high heterogeneity, its amount (i.e., tau 2 ) was estimated using the DerSimonian-Laird estimator. To estimate tau 2 , the Q-test for heterogeneity and the I 2 statistic were calculated., Results: Search results identify 13 studies that reported diverse health outcomes, such as lung and cardiovascular function, skin cancer progression, intensive care unit mortality, immune system response, and bone density. The meta-analysis showed a significant increase in 25(OH)D blood levels after treatment in 10 studies, with an average standardized mean difference of 2.60 ng/mL (95% CI: 2.07 to 3.13). Their results suggested that a single high dose of VD3 may benefit intensive care unit patients and skin cancer patients in remission. However, evidence for other beneficial health effects of HDVD3 was mixed due to high heterogeneity among studies., Conclusions: A single high dose of VD3 may positively affect some health outcomes in older people, possibly due to its pleiotropic and immunomodulatory effects. However, the evidence needs to be more extensive and consistent, and more rigorous studies are required to confirm the benefits and safety of VD3 high doses in older patients.

The adverse events related to sodium colistimethate have had variability regarding the prevalence of nephrotoxicity, neurotoxicity, and less frequent respiratory depression. In recent years, its use has been relevant due to the increase of multidrug-resistant bacteria since it is considered the last-line drug, being its main adverse event and reason for discrepancies between authors' nephrotoxicity. The indiscriminate use of antibiotic therapy has generated multiple mechanisms of resistance, the most common being related to Colistin, the bactericidal escape effect. Based on the search criteria, no randomized clinical trials were identified showing safety and efficacy with the use of Colistin, inferring that the application of the appropriate dose is governed by expert opinion and retrospective and prospective observational studies, which confounding factors such as the severity of the patient and the predisposition to develop acute renal failure are constant. In this review, we focus on identifying the mechanism of nephrotoxicity and bacterial resistance, where much remains to be known., Competing Interests: Victor Hugo Ahumada Topete and Kevin Jesus de Dios Sanchez are co-first authors for this study. The authors declare that they have no conflict of interest in this work., (© 2023 Ahumada Topete et al.)

•Improvement of therapeutic ratio by novel unconventional radiotherapy approaches.•Immunomodulation using high-dose spatially fractionated radiotherapy.•Boosting radiation anti-tumor effects by adding an immune-mediated cell killing., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.Chandan Guha reported the following COI: Advisor/Consultant with Focused Ultrasound Foundation, Janssen and Siemens. Slavisa Tubin reported the following COI: pending patent(s)/international patent application PCT/EP2019/052164 published as WO 2019/162050. Xiaodong Wu is the primary inventor of US Patent No. 8,395,131: Method of 3D Lattice Radiotherapy. Yolanda Prezado holds a patent on the implementation of MBRT at a small animal irradiator USBR16CNRRAD/sl (USA) and PCT/EP2017/078096 (international). Robert Timmerman is PI of grants – Varian Medical Systems, Elekta Oncology, and Accuray, Inc., (© 2023 The Author(s).)

To assess the impact of the route of administration and doses of second-generation antipsychotics (SGAs) on treatment adherence, hospital admissions, and suicidal behaviour in patients with severe schizophrenia (Clinical Global Impression−Severity−CGI-S ≥ 5), we implemented an observational 5-year follow-up study. A total of 37.5% of the patients on oral antipsychotics (Aps) and 11.5% of those on long-acting injectables (LAIs) abandoned the treatment (p < 0.001). There were no differences in treatment discontinuation between the LAI-AP standard and high-dose groups. A total of 28.1% of the patients on oral Aps had at least one hospitalisation, as well as 13.1% of patients on LAIs (p < 0.001). There were fewer hospitalisations of patients on LAIs in the high-dose group (p < 0.05). Suicide attempts were recorded for 18% of patients on oral Aps but only for 4.6% of patients on LAIs (p < 0.001). No differences were found between the dosage groups on LAIs. Tolerability was good for all Aps and somewhat better for LAIs than oral Aps in terms of side effects (p < 0.05). There were no differences between the standard and high-dose groups. More patients discontinued treatment due to side effects in the oral AP group (p < 0.01). LAI SGA treatment was more effective than oral AP in terms of adherence and treatment outcomes for managing people with severe schizophrenia. Moreover, significant improvements were found that favour high-dose LAI SGA treatment for some of these patients. This study highlights the need to consider LAI antipsychotics and high-dose strategies for patients with severe schizophrenia.

It is established that moderate-to-high doses of ionising radiation increase the risk of subsequent cancer in the exposed individual, but the question arises as to the risk of cancer from higher doses, such as those delivered during radiotherapy, accidents, or deliberate acts of malice. In general, the cumulative dose received during a course of radiation treatment is sufficiently high that it would kill a person if delivered as a single dose to the whole body, but therapeutic doses are carefully fractionated and high/very high doses are generally limited to a small tissue volume under controlled conditions. The very high cumulative doses delivered as fractions during radiation treatment are designed to inactivate diseased cells, but inevitably some healthy cells will also receive high/very high doses. How the doses (ranging from <1 Gy to tens of Gy) received by healthy tissues during radiotherapy affect the risk of second primary cancer is an increasingly important issue to address as more cancer patients survive the disease. Studies show that, except for a turndown for thyroid cancer, a linear dose-response for second primary solid cancers seems to exist over a cumulative gamma radiation dose range of tens of gray, but with a gradient of excess relative risk per Gy that varies with the type of second cancer, and which is notably shallower than that found in the Japanese atomic bomb survivors receiving a single moderate-to-high acute dose. The risk of second primary cancer consequent to high/very high doses of radiation is likely to be due to repopulation of heavily irradiated tissues by surviving stem cells, some of which will have been malignantly transformed by radiation exposure, although the exact mechanism is not known, and various models have been proposed. It is important to understand the mechanisms that lead to the raised risk of second primary cancers consequent to the receipt of high/very high doses, in particular so that the risks associated with novel radiation treatment regimens-for example, intensity modulated radiotherapy and volumetric modulated arc therapy that deliver high doses to the target volume while exposing relatively large volumes of healthy tissue to low/moderate doses, and treatments using protons or heavy ions rather than photons-may be properly assessed., (Creative Commons Attribution license.)

Introduction: The Republic of Korea (ROK) military has a high incidence of respiratory diseases at training centres. Vitamin C has been reported to reduce the incidence of colds. For the purpose of preventing soldiers' respiratory diseases, this study aimed to investigate whether vitamin C intake can prevent common colds in the ROK Army soldiers., Methods: This was a randomised, placebo-controlled, and double-blind trial of soldiers who enlisted in the Korea Army Training Centre for 30 days from 12 February to 13 March 2018. The study participants were divided into groups (vitamin C vs placebo). The military medical records were searched to determine whether the participants had a common cold. Multiple logistic regression analysis was performed to identify the association between vitamin C intake and diagnosis of common colds. In addition, subgroup analysis on the relationship between vitamin C intake and common cold according to smoking status, training camp and physical rank was conducted., Results: A total of 1444 participants were included in our study. Of these participants, 695 received vitamin C (6000 mg/day, vitamin C group), while 749 participants received placebo (0 mg/day, placebo group). The vitamin C group had a 0.80-fold lower risk of getting a common cold than did the placebo group. Subgroup analyses showed that this effect was stronger among subjects in camp A, among never smokers and among those in physical rank 3., Conclusion: Vitamin C intake provides evidence to suggest that reducing the common colds in Korean Army soldiers. Our results may serve as a basis for introducing military healthcare policies that can provide vitamin C supplementation for military personnel in basic military training., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Iron deficiency anemia is among the most frequent causes of disability. Intravenous iron is the quickest way to correct iron deficiency, bypassing the bottleneck of iron intestinal absorption, the only true mechanism of iron balance regulation in human body. Intravenous iron administration is suggested in patients who are refractory/intolerant to oral iron sulfate. However, the intravenous way of iron administration requires several precautions; as the in-hospital administration requires a resuscitation service, as imposed in Europe by the European Medicine Agency, it is very expensive and negatively affects patient's perceived quality of life. A new oral iron formulation, Sucrosomial iron, bypassing the normal way of absorption, seems to be cost-effective in correcting iron deficiency anemia at doses higher than those usually effective with other oral iron formulations. In this multicentric randomized study, we analyze the cost-effectiveness of intravenous sodium ferrigluconate vs oral Sucrosomial iron in patients with iron deficiency anemia refractory/intolerant to oral iron sulfate without other interfering factors on iron absorption., (© 2020. The Author(s).)

In radiation physics, the study of new alternative dosimeters is of interest to the growing branch of dosimetric characterization for radiotherapy applications. The goal of this work was to expose bone samples to high doses and evaluate their linearity response to gamma rays. The Fourier Transform Infrared (FTIR) spectrophotometry technique was employed as the evaluation technique, and based on the spectrophotometry absorbance profiles the linearity was assessed based on the following methods: Area Under the Curve (AUC), Wavenumber Method (WM), Partial Component Regression (PCR) and Partial Least-Square Regression (PLSR) methods. The bone samples were irradiated with absorbed doses of 10 Gy up to 500 Gy using a 60 Co Gamma Cell-220 system. The results showed, for the calibration curves of the system, adequate linearity on all methods. In conclusion, the results indicate a good linear response and therefore an interesting potential radiation detector., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

This study systematically investigates how a single high-dose therapeutic proton beam versus X-rays influences cell-cycle phase distribution and DNA damage in human peripheral blood lymphocytes (HPBLs). Blood samples from ten volunteers (both male and female) were irradiated with doses of 8.00, 13.64, 15.00, and 20.00 Gy of 250 kV X-rays or 60 MeV protons. The dose-effect relations were calculated and distributed by plotting the frequencies of DNA damage of excess Premature Chromosome Condensation (PCC) fragments and rings in the G2/M phase, obtained via chemical induction with calyculin A. The Papworth's u test was used to evaluate the distribution of DNA damage. The study shows that high doses of protons induce HPBL DNA damage in the G2/M phase differently than X-rays do. The results indicate a different distribution of DNA damage following high doses of irradiation with protons versus photons between donors, types of radiation, and doses. The proliferation index confirms the impact of high doses of mitosis and the influence of radiotherapy type on the different HPBL response. The results illuminate the cellular and molecular mechanisms that underlie differences in the distribution of DNA damage and cell-cycle phases; these findings may yield an improvement in the efficacy of the radiotherapies used.

Spasticity is a common disabling disorder in adult subjects suffering from stroke, brain injury, multiple sclerosis (MS) and spinal cord injury (SCI). Spasticity may be a disabling symptom in people during rehabilitation and botulinum toxin type A (BTX-A) has become the first-line therapy for the local form. High BTX-A doses are often used in clinical practice. Advantages and limitations are debated and the evidence is unclear. Therefore, we analysed the efficacy, safety and evidence for BTX-A high doses. Studies published from January 1989 to February 2020 were retrieved from MEDLINE/PubMed, Embase, Cochrane Central Register. Only obabotulinumtoxinA (obaBTX-A), onabotulinumtoxinA (onaBTX-A), and incobotulinumtoxinA (incoBTX-A) were considered. The term "high dosage" indicated ≥ 600 U. Thirteen studies met the inclusion criteria. Studies had variable method designs, sample sizes and aims, with only two randomised controlled trials. IncoBTX-A and onaBTX-A were injected in three and eight studies, respectively. BTX-A high doses were used predominantly in treating post-stroke spasticity. No studies were retrieved regarding treating spasticity in MS and SCI. Dosage of BTX-A up to 840 U resulted efficacious and safety without no serious adverse events (AEs). Evidence is insufficient to recommend high BTX-A use in clinical practice, but in selected patients, the benefits of high dose BTX-A may be clinically acceptable., Competing Interests: The authors declare no conflict of interest.

For many years, administration of drugs by inhalation has been the mainstay treatment for obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease. Antibiotics and other drugs have been administered for decades as aerosols to treat other pulmonary disease in a clinical setting, but it was until the early 1980's that colistin was formally marketed as a solution for nebulization in Europe (Colomycin, Pharmax, Bexley). The solubility of other drugs and the size of the dose required to achieve therapeutic concentrations at the site of action, made treatment times long and difficult to be performed at home. High dose dry powder delivery is a potentially effective way to deliver low potency drugs such as antibiotics. There are three major barriers to achieving the desired pharmacodynamic effect with these compounds: aerosol delivery, lung deposition and clearance. The powder formulation and device technology influence aerosol generation and may influence the size of the dose that can be achieved by inhalation in one puff. The site of deposition in the lungs is dictated by mechanisms of deposition which are influenced by the aerosol properties, particularly aerodynamic particle size distribution and the anatomy and physiology of the lungs. Finally, mechanisms of clearance dictate the local and systemic disposition of the drug, which in turn affects its pharmacokinetics and ultimately the pharmacodynamic effect and efficacy of treatment. Each of these factors will be considered and the implications for antimicrobial agent delivery as a high dose delivery example will be given., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The purpose of this work was to study a new dry powder inhaler (DPI) of tobramycin capable to simplify the dose administration maneuvers to maximize the cystic fibrosis (CF) patient care in antibiotic inhalation therapy. For the purpose, tobramycin/sodium stearate powder (TobraPS) having a high drug content, was produced by spray drying, characterized and the aerodynamic behavior was investigated in vitro using different RS01 DPI inhalers. The aerosols produced with 28, 56 or 112 mg of tobramycin in TobraPS powder using capsules size #3, #2 or #0 showed that there was quasi linear relationship between the amount loaded in the device and the FPD. An in vivo study in healthy human volunteers showed that 3-6 inhalation acts were requested by the volunteers to inhale 120 mg of TobraPS powder loaded in a size #0 capsule aerosolized with a prototype RS01 device, according to their capability to inhale. The amount of powder emitted at 4 kPa pressure drop at constant air flow well correlated with the in vivo emission at dynamic flow, when the same volume of air passed through the device. The novel approach for the administration of 112 mg of tobramycin in one capsule could improve the convenience and adherence of the CF patient to the antibiotic therapy., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Strong acid inhibition increases cure rates with triple therapy and 14-day are more effective than 7-day treatments. The combination of amoxicillin plus metronidazole at full doses has been shown to overcome metronidazole resistance and to achieve good eradication rates even in patients harboring resistant strains. No previous studies have been reported in Latin-America with this optimized triple-therapy scheme., Aims: The aim of the present study was to assess the eradication rate and tolerance of a new first-line treatment regimen associating strong acid inhibition, amoxicillin and metronidazole., Methods: Patients from the Clínica de Gastroenterología of the Hospital de Clínicas (Montevideo, Uruguay) were included. Hp status was mainly assessed by at least one of the following: histologyor urea breath test (UBT). A 14-day treatment was prescribed comprising esomeprazole 40mg twice a day plus amoxicillin 1g and metronidazole 500mg, both three times a day. H. pylori cure was assessed by UBT., Results: Forty-one patients were enrolled. Mean age was 53.3±13 years and 17.1% of patients were male. Main indications for treatment were: functional dyspepsia (27.5%), gastritis (45%), gastric or duodenal erosions (20%), gastric ulcer (5%) and intestinal metaplasia (2.5%). H. pylori eradication was achieved in 33 of the 37 patients who returned for follow-up. Eradication rates were 80.5% (95% CI: 68.4-92.6) by intention-to-treat (ITT) analysis and 89.2% (95% CI; 79.2-99.2) per protocol (PP). No major side effects were reported; 26 patients (65.8%) complained of mild side effects (nausea, diarrhea and headache)., Conclusions: Cure rates of this triple therapy including esomeprazole, amoxicillin and metronidazole were 81% per ITT and the treatment was well tolerated. These optimal results with a simple clarithromycin-free triple therapy are better than described for standard triple therapy but there is still room for improvement to reach the desired target of 90% per ITT., (Copyright © 2017 Elsevier España, S.L.U., AEEH y AEG. All rights reserved.)

Current guidelines suggested a dosage up to 600units (U) of botulinum toxin type A (BoNT-A) (onabotulinumtoxinA or incobotulinumtoxinA) in reducing spastic hypertonia with low prevalence of complications, although a growing body of evidence showed efficacy with the use of high doses (>800U). The available evidence mainly referred to a single set of injections evaluating the efficacy and safety of the neurotoxin 30days after the treatment. In a prospective, non-randomized, open-label study, we studied the safety of repeated higher doses of incobotulinumtoxinA in post-stroke upper and lower limb spasticity. Two years after the first set of injections, we evaluated in 20 stroke survivors with upper and lower limb spasticity the long-term safety of repeated high doses of incobotulinumtoxinA (up to 840U) for a total of eight sets of injections. Patients reported an improvement of their clinical picture concerning a reduction of spasticity measured with the Asworth Scale (AS) for elbow, wrist, fingers and ankle flexor muscles and disability measured with the Disability Assessment Scale (DAS) 30days after the last set of injections (eighth set) compared to the baseline (p<0.0001). No difference in AS and DAS scores has been found between t 1 (30days after the first injection set) and t 2 (30days after the eighth set of injections), with also similar safety. In a two-year follow-up, repeated high doses of incobotulinumtoxinA, administered for eight sets of injections, appeared to be safe in patients with upper and lower limb spasticity after stroke without general adverse effects., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Biofilms typically exist as complex communities comprising multiple species with the ability to adapt to a variety of harsh conditions. In clinical settings, antibiotic treatments based on planktonic susceptibility tests are often ineffective against biofilm infections. Using a CO2 evolution measurement system we delineated the real-time metabolic response in continuous flow biofilms to streptomycin doses much greater than their planktonic susceptibilities. Stable biofilms from a multispecies culture (containing mainly Pseudomonas aeruginosa and Stenotrophomonas maltophilia), Gram-negative environmental isolates, and biofilms formed by pure culture P. aeruginosa strains PAO1 and PAO1 ΔMexXY (minimum planktonic inhibitory concentrations between 1.5 and 3.5 mg/l), were exposed in separate experiments to 4000 mg/l streptomycin for 4 h after which growth medium resumed. In complex medium, early steady state multispecies biofilms were susceptible to streptomycin exposure, inferred by a cessation of CO2 production. However, multispecies biofilms survived high dose exposures when there was extra carbon in the antibiotic medium, or when they were grown in defined citrate medium. The environmental isolates and PAO1 biofilms showed similar metabolic profiles in response to streptomycin; ceasing CO2 production after initial exposure, with CO2 levels dropping toward baseline levels prior to recovery back to steady state levels, while subsequent antibiotic exposure elicited increased CO2 output. Monitoring biofilm metabolic response in real-time allowed exploration of conditions resulting in vulnerability after antibiotic exposure compared to the resistance displayed following subsequent exposures.

Assessment of radiation doses through measurement of dicentric chromosomes may be difficult due to the inability of damaged cells to reach mitosis. After high-dose exposures, premature chromosome condensation (PCC) has become an important method in biodosimetry. PCC can be induced upon fusion with mitotic cells, or by treatment with chemicals such as calyculin A or okadaic acid. Several different cytogenetic endpoints have been measured with chemically induced PCC, e.g., via scoring of extra chromosome pieces or ring chromosomes. The dose-effect curves published with chemically induced PCC show differences in their coefficients and in the distribution of rings among cells. Here we present a study with calyculin A to induce PCC in peripheral blood lymphocytes irradiated at nine different doses of γ-rays up to 20Gy. Colcemid was also added in order to observe metaphase cells. During microscopical analysis the chromosome aberrations observed in the different cell-cycle phases (G2/M-PCC, M/A-PCC and M cells) were recorded. The proportion of G2/M-PCC cells was predominant from 3 to 20Gy, M cells decreased above 1Gy and M/A-PCC cells remained constant at all doses and showed the highest frequencies of PCC rings. Depending on the cell-cycle phase there was a difference in the linear coefficients in the dose-effect curves of extra fragments and rings. Poisson distribution among PCC rings was observed after calyculin A+colcemid treatment, facilitating the use of this methodology also for partial body exposures to high doses. This has been tested with two simulated partial exposures to 6 and 12Gy. The estimated doses in the irradiated fraction were very close to the real dose, indicating the usefulness of this methodology., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The balance between oxidation and antioxidation is believed to be critical in maintaining healthy biological systems. Under physiological conditions, the human antioxidative defense system including e.g., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) and others, allows the elimination of excess reactive oxygen species (ROS) including, among others superoxide anions (O2(·-)), hydroxyl radicals (OH·), alkoxyl radicals (RO·) and peroxyradicals (ROO·). However, our endogenous antioxidant defense systems are incomplete without exogenous originating reducing compounds such as vitamin C, vitamin E, carotenoids and polyphenols, playing an essential role in many antioxidant mechanisms in living organisms. Therefore, there is continuous demand for exogenous antioxidants in order to prevent oxidative stress, representing a disequilibrium redox state in favor of oxidation. However, high doses of isolated compounds may be toxic, owing to prooxidative effects at high concentrations or their potential to react with beneficial concentrations of ROS normally present at physiological conditions that are required for optimal cellular functioning. This review aims to examine the double-edged effects of dietary originating antioxidants with a focus on the most abundant compounds, especially polyphenols, vitamin C, vitamin E and carotenoids. Different approaches to enrich our body with exogenous antioxidants such as via synthetic antioxidants, diets rich in fruits and vegetables and taking supplements will be reviewed and experimental and epidemiological evidences discussed, highlighting that antioxidants at physiological doses are generally safe, exhibiting interesting health beneficial effects.

Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.