Dietary Zinc Ameliorates TNBS-Induced Colitis in Mice Associated with Regulation of Th1/Th2/Th17 Balance and NF-κB/NLRP3 Signaling Pathway.

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are chronic relapsing inflammatory gastrointestinal tract diseases of uncertain origin, which are frequently associated with zinc deficiency. Animal models have a considerable value in elucidating the process of IBD. In this study, 50 male C57BL/6 J mice were randomly assigned to five groups: control group (Con), 2,4,6-trinitrobenzenesulfonic acid (TNBS) group, and three zinc supplementation groups, namely 160 ppm group, 400 ppm group, and 1000 ppm group. The results showed that supplementation of dietary zinc with zinc oxide could effectively relieve the severity of ulcerative colitis induced by TNBS in mice. We demonstrate that the protective mechanism involves the immunomodulation of dietary zinc by increasing CD3+, CD3+CD8+, and Th2 cells, suppressing Th1 and Th17 cells, and decreasing the production of serum IL-1ß and IL-18. The dietary zinc oxide seems to be able to suppress the NF-κB/NLRP3 signaling pathway by downregulating the mRNA and protein expression of NIK, IKK, NF-κB, and NLRP3. The results suggest that dietary supplementation of zinc oxide may protect against colitis, and proper daily zinc supplementation may reduce the risk of IBD.

Severe copper deficiency anemia caused by zinc supplement use.

Copper deficiency is an uncommon condition primarily affecting the hematologic and neurologic systems. We report a unique case of severe anemia in a patient with copper deficiency caused by zinc supplement use.

Clinical study on the efficacy and tolerability of an oral supplement based on arginine, l-cystine, zinc and B6 vitamin (Cystiphane®) in patients with telogen effluvium.

BACKGROUND: Telogen effluvium (TE) is a common cause of non-cicatricial hair loss with no treatment-standardized protocol. The aim of our study was to evaluate the efficacy, tolerability, and patient compliance of a treatment with an oral supplement based on arginine, l-cystine, zinc and B6 vitamin (Cystiphane®, Laboratoires Bailleul, Geneva, Switzerland) with hair-growth properties, administered 4 times daily, in patients affected by TE. METHODS: We recruited 20 patients, aged between 18 and 70 years old, affected by TE. Patients were asked to take the oral supplement as a monotherapy, four tablets daily, in one or two administrations during meals. The study lasted 3 months. We evaluated the efficacy and tolerability of the treatment both qualitatively by collecting the clinician's opinion through a clinical evaluation and clinical-anamnestic form filled in by the researcher, and quantitatively through global photography and trichoscopy. We collected the patient's opinion through a self-assessment test, at the beginning of the recruitment and after 3 months of treatment. RESULTS: Eighteen patients were evaluated. After 3 months of taking the supplement, the researcher rated an average improvement of 2.89 at the clinical evaluation. For what concerns hair quantity, at the control trichoscopy, the mean trichoscopic value had risen to +2.055, whereas for hair diameter the mean trichoscopic diameter value had increased to +1.83. After 3 months of treatment, patients gave an average efficacy opinion of 3.61. CONCLUSIONS: The oral supplement has proved effective as an adjuvant in the treatment of TE in our cohort of patients.

Severe leukocytopenia due to copper deficiency induced by zinc supplementation in a patient on peritoneal dialysis: a case report.

Zinc deficiency is one cause of anemia. However, it has been reported that some patients who were treated with zinc supplementation to resolve this anemia subsequently experienced copper deficiency, which lead to continued anemia, as well as leukocytopenia and other symptoms. However, only two patients with copper deficiency induced by zinc supplementation undergoing peritoneal dialysis have been reported. Here, we report the case of a 59 year-old man with copper deficiency after zinc supplementation undergoing peritoneal dialysis (PD). He took meals only once a day and drank about 750 mL/day of wine every day. He had been receiving zinc supplementation for 4 months. He was diagnosed with severe leukocytopenia and worsening anemia at a planned outpatient visit; in addition, his copper levels had markedly decreased. Thus, zinc supplementation was discontinued, and the patient was instructed to take cocoa for copper supplementation. Because of severe leukocytopenia, he was admitted to our hospital, and granulocyte colony-stimulating factor was administered. Red blood cell transfusions were performed for anemia. After discontinuing zinc supplementation, his white blood cell count and hemoglobin levels improved.To avoid Cu deficiency, patients' dietary history should be checked in detail and Cu should be monitored carefully when Zn is supplemented in patients undergoing PD.

Assessment of the Antitumor Activity of Green Biosynthesized Zinc Nanoparticles as Therapeutic Agent Against Renal Cancer in Rats.

Zinc nanoparticles (Zn-NPs) have garnered a great deal of attention as potential cancer therapy. The use of microorganisms in the synthesis of nanoparticles emerges as an eco-friendly and exciting approach. This study was designed to assess biosynthesized Zn-NPs as therapeutic agent against kidney cancer induced by ferric-nitrilotriacetate (Fe-NTA) in rats.Zn-NPs were synthesized from edible mushroom then characterized by transmission electron microscopy analysis, dynamic light scattering, and Fourier transform infrared spectroscopy. Rats were divided into 4 different groups: group I (control), group II (Fe-NTA group), group III (Zn-NPs group), and group IV (Fe-NTA + Zn-NPs group). Animals were sacrificed then kidney and liver function tests, MDA level, glutathione, glutathione peroxidase, and superoxide dismutase activities were measured by using colorimetric methods. Caspase-3 level and carcinoembryonic antigen concentration were measured by using ELISA. Finally, DNA fragmentation was visualized by using agarose gel electrophoresis.Treatment with Zn-NPs significantly suppressed renal oxidative stress by restoring glutathione level, glutathione peroxidase, and superoxide dismutase activities and ameliorated oxidative damage parameters of lipid peroxidation as well as renal toxicity markers. Molecular and tumor markers showed significant improvement with respect to induction group, and this was well appreciated with the histopathological alteration findings in the treated groups.Microbial synthesized Zn-NPs possess antitumor-promoting activity against Fe-NTA-induced toxicity and carcinogenesis, which should be evaluated in a clinical study.

Zinc supplement use and risk of aggressive prostate cancer: a 30-year follow-up study.

BACKGROUND: Zinc supplementation was hypothesized to have therapeutic potential against prostate cancer, but its influence on prostate cancer incidence especially at high doses is controversial. METHODS: A total of 47,240 men from the Health Professionals Follow-up Study were followed from 1986 to 2016. Men reported their zinc supplement use at baseline and biennially thereafter. Clinical features of prostate cancer included stage, grade, lethal and aggressive (T4 or N1 or M1 or Gleason 8-10) outcome. Multivariable Cox proportional hazards models were used to evaluate the association between zinc supplement use and incidence of prostate cancer. RESULTS: During a median follow-up of 28.3 years, we documented 6,980 incident prostate cancer cases including 1,053 lethal and 1,143 aggressive. Zinc supplement use was not associated with overall, localized, low- and intermediate-grade prostate cancer. However, compared to never-users, men who used supplement zinc more than 75 mg/day were at higher risk for lethal (HR: 1.76, 95% CI: 1.16-2.66, Ptrend = 0.001) and aggressive prostate cancer (HR: 1.80, 95% CI: 1.19-2.73, Ptrend = 0.006). Similarly, men who took supplemental zinc for 15 or more years had a higher risk for lethal (HR: 1.91, 95% CI: 1.28-2.85, Ptrend <0.001) and aggressive prostate cancer (HR: 1.55, 95% CI: 1.03-2.33, Ptrend = 0.004). CONCLUSION: Zinc supplementation of more than 75 mg per day or over 15 years may substantially increase risk of lethal and aggressive prostate cancer. Caution is warranted regarding excessive usage of zinc supplements among adult men.

Adverse Effects of Excessive Zinc Intake in Infants and Children Aged 0-3 Years: A Systematic Review and Meta-Analysis.

Zinc supplementation reduces morbidity, but evidence suggests that excessive intakes can have negative health consequences. Current guidelines of upper limits (ULs) of zinc intake for young children are extrapolated from adult data. This systematic review (PROSPERO; registration no. CRD42020215187) aimed to determine the levels of zinc intake at which adverse effects are observed in young children. Studies reporting potential adverse effects of zinc intake in children aged 0-3 y were identified (from inception to August 2020) in MEDLINE, Embase, and the Cochrane Library, with no limits on study design. Adverse clinical and physical effects of zinc intake were synthesized narratively, and meta-analyses of biochemical outcomes were conducted. Random effects models were used to generate forest plots to examine the evidence by age category, dose, dose duration, chemical formula of zinc, and zinc compared with placebo. The Joanna Briggs Institute Critical Appraisal Checklist, Cochrane Risk of Bias 2, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guideline were employed to assess risk of bias and to appraise the certainty of evidence. Fifty-eight studies assessed possible adverse effects of zinc doses ranging from 3 to 70 mg/d. Data from 39 studies contributed to meta-analyses. Zinc supplementation had an adverse effect on serum ferritin, plasma/serum copper concentration, serum transferrin receptor, hemoglobin, hematocrit, and the odds of anemia in ≥1 of the subgroups investigated. Lactulose:mannitol ratio was improved with zinc supplementation, and no significant effect was observed on C-reactive protein, erythrocyte superoxide dismutase, zinc protoporphyrin, blood cholesterol, and iron deficiency anemia. The certainty of the evidence, as assessed using GRADE, was very low to moderate. Although possible adverse effects of zinc supplementation were observed in some subgroups, it is unclear whether these findings are clinically important. The synthesized data can be used to undertake a dose-response analysis to update current guidelines of ULs of zinc intake for young children.

Heavy Metals in Breast Implant Capsules and Breast Tissue: Findings from the Systemic Symptoms in Women-Biospecimen Analysis Study: Part 2.

BACKGROUND: Breast Implant Illness (BII), as described in recent medical literature and by social media, describes a range of symptoms in patients with breast implants for which there are no physical findings or laboratory results that explain their symptoms. OBJECTIVES: Part 2 of this study aims to determine whether heavy metals are present in the capsules around saline and silicone implants and if there are statistical differences in the type or level of these metals between women with or without symptoms. Demographic data was collected to investigate potential alternate sources of metals: inhaled, absorbed, or ingested. METHODS: A prospective, blinded study enrolled 150 consecutive subjects divided equally into in three cohorts: (A) women with systemic symptoms they attribute to their implants who requested implant removal, (B) women with breast implants requesting removal or exchange who do not have symptoms they attribute to their implants, and (C) women undergoing cosmetic mastopexy who have never had any implanted medical device. Capsule tissue was removed from Cohort A and B for analysis of 22 heavy metals. Additionally, breast tissue was obtained from a control group with no previous exposure to any implanted medical device. RESULTS: The study was performed between 2019-2021. Heavy metal content was compared between the capsule tissue from Cohort A and B. The only statistically significant differences identified in Cohort A were higher levels of arsenic and zinc, and lower levels of cobalt, manganese, silver, and tin. There were no elevated levels or statistically significant differences in the other metals tested between Cohorts A and B. CONCLUSIONS: This study analyzes the metal content in capsules surrounding both saline and silicone breast implants. Heavy metals were also detected in the non-implant control group breast tissue, with some metals at numerically higher levels than either breast implant cohort. Smoking, gluten free diets, dietary supplements, and the presence of tattoos were all identified as statistically significant sources of arsenic and zinc in Cohort A. The risk of heavy metal toxicity should not be used as an indication for total capsulectomy if patients elect to remove their breast implants.

Zinc Exposure Promotes Commensal-to-Pathogen Transition in Pseudomonas aeruginosa Leading to Mucosal Inflammation and Illness in Mice.

The opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa) is associated gastrointestinal (GI) inflammation and illness; however, factors motivating commensal-to-pathogen transition are unclear. Excessive zinc intake from supplements is common in humans. Due to the fact that zinc exposure enhances P. aeruginosa colonization in vitro, we hypothesized zinc exposure broadly activates virulence mechanisms, leading to inflammation and illness. P. aeruginosa was treated with excess zinc and growth, expression and secretion of key virulence factors, and biofilm production were determined. Effects on invasion, barrier function, and cytotoxicity were evaluated in Caco-2 cells co-cultured with P. aeruginosa pre-treated with zinc. Effects on colonization, mucosal pathology, inflammation, and illness were evaluated in mice infected with P. aeruginosa pre-treated with zinc. We found the expression and secretion of key virulence factors involved in quorum sensing (QS), motility (type IV pili, flagella), biosurfactants (rhamnolipids), toxins (exotoxin A), zinc homeostasis (CzcR), and biofilm production, were all significantly increased. Zinc exposure significantly increased P. aeruginosa invasion, permeability and cytotoxicity in Caco-2 cells, and enhanced colonization, inflammation, mucosal damage, and illness in mice. Excess zinc exposure has broad effects on key virulence mechanisms promoting commensal-to-pathogen transition of P. aeruginosa and illness in mice, suggesting excess zinc intake may have adverse effects on GI health in humans.

Anti-COVID property of subcutaneous ivermectin in synergy with zinc among midlife moderately symptomatic patients: a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The study objective is to quantify the effectiveness of ivermectin (subcutaneous/oral IVM) in the presence or absence of zinc (Zn) for clinical and radiological improvement in coronavirus disease 2019 (COVID-19) patients with moderate severity. TRIAL DESIGN: This quadruple-blinded, placebo-controlled randomized clinical trial will be a multiarmed multi-centered study with superiority framework. PARTICIPANTS: Quinquagenarian and sexagenarian patients with moderate COVID-19 symptoms and positive severe respiratory syndrome coronavirus -2 (SARS-CoV-2) PCR will be included. Participants with co-morbidities and pregnant women will be excluded. Patient recruitment will be done in Shaikh Zayed Medical Complex, Doctors Lounge and Ali Clinic in Lahore (Pakistan). INTERVENTION AND COMPARATOR: The registered patients will be allocated in 6 groups (30 participants each). Patients will be taking subcutaneous IVM at 200 µg/kg/48 h (Arm A) or subcutaneous IVM at 200 µg/kg/48 h and oral Zn 20mg/8 h (Arm B) or oral IVM at 0.2 mg/kg/day (Arm C) or oral IVM at 0.2 mg/kg/day and oral Zn 20mg/8 h (Arm D) or alone oral Zn 20mg/8 h (Arm E) or placebo alone (Arm X). Patients in all arms will receive standard care and respective placebo (empty capsule 8 hourly and/or subcutaneous normal saline 2ml/48 h). MAIN OUTCOMES: Primary endpoints will be duration of symptomatic phase and SARS-CoV-2 clearance along with high resolution CT (HRCT) chest score and clinical grade scale (CGS) on day 6. 30-day mortality will be documented as a secondary endpoint. SARS-CoV-2 clearance will be calculated by second PCR on day 7. HRCT chest score will be measured by the percentage and lung lobes involvement on day 6 with a maximum score of 25. CGS will be recorded on a seven-point scale; grade 1 (not hospitalized, no evidence of infection and resumption of normal activities), grade 2 (not hospitalized, but unable to resume normal activities), grade 3 (hospitalized, not requiring supplemental oxygen), grade 4 (hospitalized, requiring supplemental oxygen), grade 5 (hospitalized, requiring nasal high-flow oxygen therapy and/or noninvasive mechanical ventilation), grade 6 (hospitalized, requiring ECMO and/or invasive mechanical ventilation) and grade 7 (death). RANDOMISATION: A simple lottery method will be used to randomly allocate scrutinized patients in 1:1:1:1:1:1 ratio in 6 groups. BLINDING (MASKING): Patients, primary care physicians, outcome assessors and the data collection team will be blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 180 participants will be randomized into six arms with five investigational and one placebo group. TRIAL STATUS: Institutional Review Board Shaikh Zayed Post-Graduate Medical Complex, Lahore, Pakistan has approved the protocol (version 2.3) with ID SZMC/IRB/Internal0056/2020. The trial was approved on July 14, 2020, and enrolment started on July 30, 2020. The estimated completion date is October 30, 2021. TRIAL REGISTRATION: Clinical Trial has been retrospectively registered on www.clinicaltrials.gov with registration ID NCT04472585 dated July 16, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). With the intention of expediting dissemination of this trial, the conventional formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.

Hypocupraemia-induced anaemia, sensory ataxia and cognitive impairment secondary to zinc-containing dental adhesive.

A 67-year-old man presented with 5 months of worsening memory impairment and sensory gait ataxia on the background of symptomatic anaemia. He experienced falls, agitation and became socially withdrawn over 3 weeks, resulting in hospital admission. On examination, he had sensory gait ataxia consistent with a dorsal column syndrome. He scored 13/30 on the Montreal Cognitive Assessment. Serum analysis showed normocytic anaemia and leucopenia, severe hypocupraemia, reduced caeruloplasmin and normal zinc levels. Overuse of zinc-containing denture cream was the cause of excess zinc ingestion and resultant copper deficiency, leading to blood dyscrasia and myelopathy. The cream was withdrawn and intravenous and then oral copper supplementation was implemented. Direct questions with regard to excess zinc in the diet and serological testing of copper and zinc should be considered in any patient with a dorsal column syndrome, particularly with concurrent anaemia. Copper deficiency may also have a role in exacerbating pre-existing cognitive impairment.

Per-protocol analysis of the ZINC trial for HIV disease among alcohol users.

BACKGROUND: The Zinc for INflammation and Chronic disease in HIV (ZINC) trial randomized person who live with HIV (PLWH) who engage in heavy drinking to either daily zinc supplementation or placebo. The primary outcome was change in the Veterans Aging Cohort Study (VACS) index, a predictor of mortality, between baseline and 18 months. Because adherence and follow-up were suboptimal, the intention-to-treat analysis, which was not statistically significant, may have underestimated the effect of the zinc supplementation. OBJECTIVE: We estimated the per-protocol effect of zinc versus placebo in the ZINC trial (i.e., the effect that would have been observed if all participants had had high adherence and none was lost to follow-up). METHODS: Adherence was measured as the self-reported percentage of pills taken in the previous 6 weeks and assessed at all post-baseline visits. We used inverse probability weighting to estimate and compare the change in the VACS index at 18 months in the zinc and placebo groups, had all the trial participants had high adherence (i.e., cumulative adherence ≥80% at 18 months). To examine trends by level of adherence, we rerun the analyses using thresholds for high adherence of 70% and 90% of average self-reported pill coverage. RESULTS: The estimated (95% confidence interval) change in the VACS index was - 2.16 (- 8.07, 3.59) and 5.84 (0.73, 11.80) under high adherence and no loss to follow-up in the zinc and placebo groups, respectively. The per-protocol effect estimate of the mean difference in the change between the zinc and placebo groups was - 8.01 (- 16.42, 0.01), somewhat larger than the intention-to-treat effect difference in change (- 4.68 (- 9.62, 0.25)), but it was still not statistically significant. The mean difference in the change between individuals in the zinc and placebo groups was - 4.07 (- 11.5, 2.75) and -12.34 (- 20.14, -4.14) for high adherence defined as 70% and 90% of pill coverage, respectively. CONCLUSIONS: Overall, high adherence to zinc was associated with a lower VACS score, but confidence intervals were wide and crossed 0. Further studies with a larger sample size are needed to quantify the benefits of zinc supplementation in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT01934803 . Registered on August 30, 2013.

Nutritive Manganese and Zinc Overdosing in Aging C. elegans Result in a Metallothionein-Mediated Alteration in Metal Homeostasis.

SCOPE: Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn-Zn-interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age-dependent neurodegeneration. METHODS AND RESULTS: Chronic co-exposure of C. elegans to Mn and Zn increases metal uptake, exceeding levels of single metal exposures. Supplementation with Mn and/or Zn also leads to an age-dependent increase in metal content, a decline in overall mRNA expression, and metal co-supplementation induced expression of target genes involved in Mn and Zn homeostasis, in particular metallothionein 1 (mtl-1). Studies in transgenic worms reveal that mtl-1 played a prominent role in mediating age- and diet-dependent alterations in metal homeostasis. Metal dyshomeostasis is further induced in parkin-deficient nematodes (Parkinson's disease (PD) model), but this did not accelerate the age-dependent dopaminergic neurodegeneration. CONCLUSIONS: A nutritive overdose of Mn and Zn can alter interactions between essential metals in an aging organism, and metallothionein 1 acts as a potential protective modulator in regulating homeostasis.

Zinc as a complementary treatment for cancer patients: a systematic review.

Zinc is a trace element that plays an important role in the immune system and cell growth. The role of zinc in cancer treatment has been discussed for some time, however without reaching an evidenced-based consensus. Therefore, we aim to critically examine and review existing evidence on the role of zinc during cancer treatment. In January 2019, a systematic search was conducted searching five electronic databases (Embase, Cochrane, PsychINFO, CINAHL and PubMed) to find studies concerning the use, effectiveness and potential harm of zinc therapy on cancer patients. Out of initial 5244 search results, 19 publications concerning 23 studies with 1230 patients were included in this systematic review. The patients treated with zinc were mainly diagnosed with head and neck cancer and underwent chemo-, radio- or concurrent radio-chemotherapy. Interventions included the intake of different amounts of zinc supplements and oral zinc rinses. Outcomes (primary endpoints) investigated were mucositis, xerostomia, dysgeusia, pain, weight, dermatitis and oral intake of nutrients. Secondary endpoints were survival data, quality of life assessments and aspects of fatigue, immune responses and toxicities of zinc. The studies were of moderate quality reporting heterogeneous results. Studies have shown a positive impact on the mucositis after radiotherapy. No protection was seen against mucositis after chemotherapy. There was a trend to reduced loss of taste, less dry mouth and oral pain after zinc substitution. No impact was seen on weight, QoL measurements, fatigue, and survival. The risk of side effects from zinc appears to be relatively small. Zinc could be useful in the prevention of oral toxicities during irradiation. It does not help in chemotherapy-induced side effects.

Dietary supplements in dermatology: A review of the evidence for zinc, biotin, vitamin D, nicotinamide, and Polypodium.

Dietary supplements are commonly recommended by dermatologists in the treatment of skin, hair, and nail disorders. This review of oral over-the-counter supplement use in dermatology summarizes current evidence for the use of zinc, biotin, vitamin D, nicotinamide, and Polypodium in the management of common dermatologic disorders. Evidence for the safety and efficacy of these supplements is limited. Very few large-scale randomized controlled trials exist for these over-the-counter supplements, particularly biotin and Polypodium. The lack of standardized dosing and standardized outcome measures makes comparison across existing studies challenging, and the lack of adverse events reporting in the majority of studies limits analysis of supplement safety. The most promising evidence exists for the use of nicotinamide in preventing nonmelanoma skin cancers. There is some evidence for the role of vitamin D in decreasing melanoma risk and progression in some individuals and for the photoprotective role of Polypodium, although additional high-quality studies are needed to determine appropriate dosing. Current evidence is insufficient to recommend the use of biotin or zinc supplements in dermatology. Large-scale randomized controlled trials investigating safety and efficacy are needed before widespread incorporation of these oral supplements into the general practice of dermatology.

Randomised controlled trial for high-dose intravenous zinc as adjunctive therapy in SARS-CoV-2 (COVID-19) positive critically ill patients: trial protocol.

INTRODUCTION: SARS-CoV-2 (COVID-19) has caused an international pandemic of respiratory illness, resulting in significant healthcare and economic turmoil. To date, no robust vaccine or treatment has been identified. Elemental zinc has previously been demonstrated to have beneficial effects on coronaviruses and other viral respiratory infections due to its effect on RNA polymerase. Additionally, zinc has well-demonstrated protective effects against hypoxic injury-a clear mechanism of end-organ injury in respiratory distress syndrome. We aimed to assess the effect of high-dose intravenous zinc (HDIVZn) on SARS-CoV-2 infection. The end of study analyses will evaluate the reduction of impact of oxygen saturations or requirement of oxygen supplementation. METHODS AND ANALYSIS: We designed a double-blind randomised controlled trial of daily HDIVZn (0.5 mg/kg) versus placebo. Primary outcome measures are lowest oxygen saturation (or greatest level of supplemental oxygenation) for non-ventilated patients and worst PaO2/FiO2 for ventilated patients. Following power calculations, 60 hospitalised patients and 100 ventilated patients will be recruited to demonstrate a 20% difference. The duration of follow-up is up to the point of discharge. ETHICS AND DISSEMINATION: Ethical approval was obtained through the independent Human Research Ethics Committee. Participant recruitment will commence in May 2020. Results will be published in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: ACTRN126200000454976.

The efficacy of Siddha Medicine, Kabasura Kudineer (KSK) compared to Vitamin C & Zinc (CZ) supplementation in the management of asymptomatic COVID-19 cases: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The primary objectives of this study are to determine efficacy of Siddha medicine, Kabasura kudineer in reduction of SARS-CoV-2 viral load and reducing the onset of symptoms in asymptomatic COVID-19 when compared to Vitamin C and Zinc (CZ) supplementation. In addition, the trial will examine the changes in the immunological markers of the Siddha medicine against control. The secondary objectives of the trial are to evaluate the safety of the Siddha medicine and to document clinical profile of asymptomatic COVID-19 as per principles of Siddha system of Medicine. TRIAL DESIGN: A single centre, open-label, parallel group (1:1 allocation ratio), exploratory randomized controlled trial. PARTICIPANTS: Cases admitted at non-hospital settings designated as COVID Care Centre and managed by the State Government Stanley Medical College, Chennai, Tamil Nadu, India will be recruited. Eligible participants will be those tested positive for COVID-19 by Reverse Transcriptase Polymerase Chain reaction (RT-PCR) aged 18 to 55 years without any symptoms and co-morbidities like diabetes mellitus, hypertension and bronchial asthma. Those pregnant or lactating, with severe respiratory disease, already participating in COVID trials and with severe illness like malignancy will be excluded. INTERVENTION AND COMPARATOR: Adopting traditional methods, decoction of Kabasura kudineer will be prepared by boiling 5g of KSK powder in 240 ml water and reduced to one-fourth (60ml) and filtered. The KSK group will receive a dose of 60ml decoction, orally in the morning and evening after food for 14 days. The control group will receive Vitamin C (60000 IU) and Zinc tablets (100mg) orally in the morning and evening respectively for 14 days. MAIN OUTCOMES: The primary outcomes are the reduction in the SARS-CoV-2 load [as measured by cyclic threshold (CT) value of RT-PCR] from the baseline to that of seventh day of the treatment, prevention of progression of asymptomatic to symptomatic state (clinical symptoms like fever, cough and breathlessness) and changes in the immunity markers [Interleukins (IL) 6, IL10, IL2, Interferon gamma (IFNγ) and Tumor Necrosis Factor (TNF) alpha]. Clinical assessment of COVID-19 as per standard Siddha system of medicine principles and the occurrence of adverse effects will be documented as secondary outcomes. RANDOMISATION: The assignment to the study or control group will be allocated in equal numbers through randomization using random number generation in Microsoft Excel by a statistician who is not involved in the trial. The allocation scheme will be made by an independent statistician using a sealed envelope. The participants will be allocated immediately after the eligibility assessment and informed consent procedures. BLINDING (MASKING): This study is unblinded. The investigators will be blinded to data analysis, which will be carried out by a statistician who is not involved in the trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Sample size could not be calculated, as there is no prior trial on KSK. This trial will be a pilot trial. Hence, we intend to recruit 60 participants in total using a 1:1 allocation ratio, with 30 participants randomised into each arm. TRIAL STATUS: Protocol version 2.0 dated 16th May 2020. Recruitment is completed. The trial started recruitment on the 25th May 2020. We anticipate study including data analysis will finish on November 2020. We also stated that protocol was submitted before the end of data collection TRIAL REGISTRATION: The study protocol was registered with clinical trial registry of India (CTRI) with CTRI/2020/05/025215 on 16 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Impact of Different Strategies for Delivering Supplemental Zinc on Selected Fecal Markers of Environmental Enteric Dysfunction among Young Laotian Children: A Randomized Controlled Trial.

The objective of this study was to assess the impact of different strategies for delivering supplemental zinc on fecal myeloperoxidase (MPO), neopterin (NEO), and calprotectin (CAL) among young Laotian children. In a double-blind controlled trial, children aged 6-23 months were randomized to receive either daily preventive zinc (PZ) tablets (7 mg/day), daily micronutrient powder (MNP; containing 10 mg zinc and 14 other micronutrients), therapeutic zinc (TZ) supplements for diarrhea treatment (20 mg/day for 10 days), or daily placebo powder and followed for ∼36 weeks. Stool samples were collected at baseline and endline. Fecal MPO, NEO, and CAL concentrations were determined in a randomly selected subsample of 720 children using commercially available ELISA kits. At baseline, the mean age was 14.1 ± 4.9 months and prevalence of stunting was 39%. The endline prevalence of stunting was 43%; there was no overall treatment effect on physical growth in the parent trial. At endline, the mean (95% CI) MPO in the PZ group was 1,590 [1,396; 1,811] ng/mL and did not differ from that in the MNP (1,633 [1,434; 1,859] ng/mL), TZ (1,749 [1,535; 1,992] ng/mL), and control (1,612 [1,415; 1,836] ng/mL) groups (P = 0.749). Similarly, there was no overall treatment effect on NEO and CAL concentrations (P = 0.226 and 0.229, respectively). In this population, the provision of PZ or TZ supplements or MNP had no impact on growth or environmental enteric dysfunction (EED) as assessed by fecal MPO, NEO, and CAL. Additional research is needed to better understand the etiology and proposed mechanisms of EED pathogenesis.