Home-Nebulized Inhaled Glucocorticoid Therapy in Pediatric Respiratory Diseases

Objective:To evaluate the therapeutic effect of home-nebulized inhaled glucocorticoid therapy in pediatric respiratory diseases.Methods:60 cases of children with respiratory diseases admitted between October 2022 and October 2023 were selected as study subjects and randomly divided into the control group and the observation group,30 cases each.The control group was provided with conventional treatment only,while the observation group was provided with home-nebulized inhalation glucocorticosteroid treatment,and the treatment effects,clinical symptom relief time,disease recurrence rate,and treatment satisfaction of the children’s families were recorded and compared between the two groups.Results:A comparison of the two groups in terms of gender and age showed that the differences were not statistically significant(P>0.05).In terms of clinical efficacy,the total effective rate of the observation group was 90.00%,which was significantly higher than that of the control group of 66.67%(P<0.05).Compared with the control group,the disappearance time of the clinical symptoms of the observed group was significantly shortened(P<0.05).In addition,the satisfaction scores of the families of the children in the observation group were significantly higher than those of the control group(P<0.05).Conclusion:Home-nebulized inhalation glucocorticoid therapy shows significant clinical efficacy in pediatric respiratory diseases,significantly reduces the time of disappearance of clinical symptoms,and improves the satisfaction of patients’families,which provides an effective treatment option for children.

Effectiveness of one-to-one feedback methods of teaching with proper metered-dose inhaler technique and correcting errors in chronic obstructive lung disease patients

Objective:To determine the most common mistakes made during the use of a metered-dose inhaler(MDI),and the effect of the repeated trainings performed with demonstration method by providing one-to-one feedback on these mistakes.Methods:This is a quasi-experimental study with a control group.A total of 100 chronic obstructive pulmonary disease(COPD)patients(50 in the control group and 50 in the experimental group)were included in the research.“Patient Information Form(PIF)”(to determine the descriptive characteristics of patients)through the face-to-face interview method,using“MDI Skill Assessment Form”(MDISAF)(it is composed of 10 skill steps about the use of MDI)through observation method was used.Patients in both the groups were asked to use MDI and their abilities regarding use of MDI were assessed.Then in the intervention group,usage of MDI was explained by a nurse via demonstration and placebo MDI.Trainings were repeated on days 1,3,and 5 as from hospitalization of the patient.In the intervention group,three methods were used in this study:“face-to-face training,”“one-to-one,”and“with feedbacks and repeated.”Routine training regarding use of MDI was given by the nurses in the clinic to patients in the control group.The use of an MDI was assessed using MDISAF before training and after the training on the first,third and fifth days of hospitalization.On the seventh day,the last measurement was performed.Percentage,chi square,and mean were used to assess the data.Results:After repetitive training with one-to-one feedback,several differences between the groups in favor of the experimental group were found in 7 of the 10 skill levels of the MDI.There was a significant difference after“training”between the groups in the third,fourth,fifth,sixth,seventh,eighth and ninth MDI steps in posttest measurement(P<0.05).Evaluating the skills of the groups to use MDI from pretest to posttest,it was determined that while the intervention group made less mistakes in steps in which mistakes were made mostly,the control group continued to make mistakes.Conclusions:Inhaler technique intervention with repeated,face to face,and one-to-one feedback trainings can significantly enhance the MDI techniques in COPD patients.The patients in the intervention group made less mistakes during MDI application and their application skills improved.It may be asser ted that the training provided to the intervention group was effective for using the device correctly,while the training provided in the clinic for the control group was inadequate.

Inhaler use in chronic obstructive pulmonary disease patients: a meta-analysis

Objective: To evaluate errors in the use of inhalation techniques in patients with chronic obstructive pulmonary disease(COPD), and to provide evidence for improving the effectiveness of drugs.Methods: A meta-analysis was performed after searching for literature at Pub Med, Embase, Web of Science, Cochrane Library, CINAHL, China National Knowledge Infrastructure(CNKI), Wan Fang, VIP, and Sion Med databases which were published from January 2011 to October 2020, addressing errors in the use of inhalation technologies for the treatment of COPD. After reviewing the literature, extracting per tinent information, and evaluating the risk of bias for the included studies, statistical analysis was performed using Stata 15.1.Results: Thir teen papers(12 in English and 1 in Chinese), representing 2527 patients, met the search criteria and were included in the meta-analysis. The results showed that the combined effect size of COPD patients making at least one operational error was 76%(95% CI: 0.69–0.83). The error rate varied with inhaler type;the combined effect size error for powered inhalers was 66%(95% CI: 0.57, 0.74), 67%(95% CI. 0.57, 0.77) for metered-dose inhalers(MDI), and 51%(95% CI: 0.38, 0.64) for soft mist inhalers(SMI).Conclusions: More than 75% of patients with COPD were unable to consistently use inhalers correctly, with the highest error rate for MDI. Therefore, health care providers must continue to educate patients on proper use of inhaler, ensuring their correct use and reducing the risk of acute COPD exacerbations.

EFFECT OF INHALED NANO-TiO_2 ON LUNG AND SERUM BIOCHEMICAL INDEXES OF MICE

The effect of inhaled nano-TiO2 on lung histology and serum biochemical indexes is evaluated in healthy and adult Kunming mice（eight in each group）after exposure to TiO2 aerosols（1 500 mg/m3）in a sealed chamber.Another eight mice are exposed to indoor air to be served as a control group.Lung tissue and blood are collected after euthanizing the animals.The results show that lactate dehydrogenase（LDH）activity increases in all experimental groups.Alanine aminotransferase（ALT）activity and blood urea nitrogen（BUN）levels are increased in the group exposed to TiO2 aerosols for 28 d,and creatinine（Cr）levels are increased in 14 d and 28 d samples（P0.05）.No obvious changes are observed in other serum indexes.Lungs of mice exposed to 28 d exposure show significant but moderate increase in pulmonary inflammation,and many TiO2 particles are found in the interstitium of pulmonary alveoli.

Agglomeration rate and action forces between atomized particles of agglomerator and inhaled-particles from coal combustion

In order to remove efficiently haled-particles emissions from coal combustions, a new way was used to put forward the process of agglomeration and the atomization was produced by the nozzle and then sprayed into the flue before precipitation devices of power station boiler in order to make inhaled-particles agglomerate into bigger particles, which can be easily removed but not change existing running conditions of boiler. According to this idea, a model is set up to study agglomeration rate and effect forces between fly ash inhaled-particles and atomized agglomerator particles. The developed agglomeration rate was expressed by relative particle number decreasing speed per unit volume. The result showed that viscosity force and flow resistance force give main influences on agglomeration effect of inhaled-particles, while springiness force and gravity have little effect on agglomeration effect of theirs. Factors influencing the agglomeration rate and effect forces are studied, including agglomerator concentration, agglomerator flux and agglomerator density, atomized-particles diameters and inhaled-particles diameter and so on.

Pulmonary delivery of liposomal dry powder inhaler formulation for effective treatment of idiopathic pulmonary fibrosis

Dry powder inhaler Liposomes were prepared to investigate the effectiveness of pulmonary delivery of Colchicine and Budesonide for Idiopathic Pulmonary fibrosis. Budesonide(BUD) and Colchicine(COL) liposomes were prepared by thin layer film hydration method(TFH) using 1,2-Dipalmitoyl-sn-glycero-3-phosphoglycerol sodium(DPPG), Hydrogenated Soyaphosphotidylcholine(HSPC), Soyaphosphatidylcholine(SPC), cholesterol(CHOL) and drug in different weight ratios. The optimum lipid composition for BUD(74.22 ± 0.97%) was DPPG:HSPC: CHOL(4:5:1) and for COL(50.94 ± 2.04%) was DPPG: SPC: CHOL(3:6:1). These compositions retained drug for a longer period of time so selected for further study. Liposomes were found to be spherical in shape with mean size below 100 nm. Liposomes lyophilized using Mannitol as carrier and cryoprotectant showed high entrapment efficiency(97.89-98.6%). The powder was dispersed through an Andersen cascade impactor to evaluate the performance of the aerosolized powder. It was found that prepared liposomal dry powder inhaler(DPIs) sustained the drug release up to 24 hours. Optimized Budesonide DPI Formulation B2(86.53 ± 1.9%), Colchicine DPI Formulation C2(90.54 ± 2.3 %) and BUD and COL DPI Combination M2(89.91 ± 1.8%, 91.23 ± 1.9%). Histopathological results, measurements of lung hydroxyproline content, Myeloperoxidase activity indicated that liposomal drypowder inhaler administration attenuates lung fibrosis induced by bleomycin. Long term stability studies indicated that lyophilised BUD and COL liposomes were stable for 6 months at(25 °C± 2 °C, 60% ± 5% RH) and refrigerated conditions(2-8 °C). These results supported that combination of budesonide and colchicine liposomal dry powder inhaler pulmonary drug delivery for treatment of idiopathic Pulmonary Fibrosis exhibits prolonged drug retention at targeted site and reduces the systemic exposure.

Do inhaled corticosteroids increase the risk of Pneumocystis pneumonia in people with lung cancer?

Pneumocystis pneumonia(PCP) is a life-threatening infection in immunocompromised patients. It is relatively uncommon in patients with lung cancer. We report a case of PCP in a 59-year-old man with a past medical history of chronic obstructive pulmonary disease treated with formoterol and a moderate daily dose of inhaled budesonide. He had also advanced stage non-small lung cancer treated with concurrent chemo-radiation with a cisplatin-etoposide containing regimen. The diagnosis of PCP was suspected based on the context of rapidly increasing dyspnea, lymphopenia and the imaging findings. Polymerase chain reaction testing on an induced sputum specimen was positive for Pneumocystis jirovecii. The patient was treated with oral trimethoprim-sulfamethoxazole and systemic corticotherapy and had showed clinical and radiological improvement. Six months after the PCP diagnosis, he developed a malignant pleural effusion and expired on hospice care. Through this case, we remind the importance of screening for PCP in lung cancer patients under chemotherapeutic regimens and with increasing dyspnea. In addition, we alert to the fact that long-term inhaled corticosteroids may be a risk factor for PCP in patients with lung cancer. Despite intensive treatment, the mortality of PCP remains high, hence the importance of chemoprophylaxis should be considered.

Salvianolic acid B dry powder inhaler for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis(IPF)is a serious and fatal pulmonary inflammatory disease with an increasing incidenceworldwide.The drugs nintedanib and pirfenidone,are listed as conditionally recommended drugs in the“Evidence-Based Guidelines for the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis”.However,these two drugs have many adverse reactions in clinical application.Salvianolic acid B(Sal B),a water-soluble component of Salvia miltiorrhiza,could alleviate bleomycin-induced peroxidative stress damage,and prevent or delay the onset of IPF by regulating inflammatory factors and fibrotic cytokines during the disease’s progression.However,Sal B is poorly absorbed orally,and patient compliance is poor when administered intravenously.Therefore,there is an urgent need to find a new non-injection route of drug delivery.In this study,Sal B was used as model drug and l-leucine(LL)as excipient to prepare Sal B dry powder inhaler(Sal B-DPI)by spray drying method.Modern preparation evaluation methods were used to assess the quality of Sal B-DPI.Sal B-DPI is promising for the treatment of IPF,according to studies on pulmonary irritation evaluation,in vivo and in vitro pharmacodynamics,metabolomics,pharmacokinetics,and lung tissue distribution.

Insight into the interaction of inhaled corticosteroids with human serum albumin: A spectroscopic-based study

It is well known that the safety and efficacy profile of an inhaled cortocosteroid(ICS) is influenced by the pharmacokinetic properties and associated pharmacodynamic effects of the drug. Freely circulating,protein unbound, and active ICS can cause systemic adverse effects. Therefore, a detailed investigation of drug-protein interaction could be of great interest to understand the pharmacokinetic behaviour of corticosteroids and for the design of new analogues with effective pharmacological properties. In the present work, the interaction between some corticosteroids and human serum albumin(HSA) has been studied by spectroscopic approaches. UV–Vis spectroscopy confirmed that all the investigated corticosteroids can bind to HSA forming a protein-drug complex. The intrinsic fluorescence of HSA was quenched by all the investigated drugs, which was rationalized in terms of a static quenching mechanism. The thermodynamic parameters determined by the Van't Hoff analysis of the binding constants(negative ΔH and ΔS values) clearly indicate thathydrogen bonds and van der Waals forces play a major role in the binding process between albumin and betamethasone, flunisolide and prednisolone, while hydrophobic forces may play a major role in stabilizing albumin-triamcinolone complexes.

Preparation of slab-shaped lactose carrier particles for dry powder inhalers by air jet milling

Dry powder inhalers are often formulated by attaching micronized drug particles onto carrier particles, which are generally lactose. In this study, commercially available lactose was air jet milled to produce unique slab-like coarse carrier particles, which have larger and rougher surfaces compared to other commercially available lactose. Two key processing factors, i.e.,classifier speed and jet milling pressure, were systematically investigated. The largest fraction of slab-like particles in the resulting powder was obtained at a classifier speed of 3000 rpm.The slab-like coarse carrier particles are expected to exhibit superior performance than commercial lactose due to their unique surface properties.

Effects of Direct Switching Dual Bronchodilators between Dry Powder and Soft Mist Inhalers in COPD Patients

Objective: Dual bronchodilation with long-acting muscarinic antagonist and long-acting β2-agonist combinations are available worldwide in COPD patients. However, the choice of agents remains under debate. We hypothesized that switching devices between dry powder and soft mist inhalers without a wash-out period to mimic clinical practice would improve clinical symptoms and lung function. The aim of this study was to examine the effects of switching between once-daily glycopyrronium/indacaterol (GLY/IND) or umeclidinium/vilanterol (UMEC/VI), dry powder inhalers, and tiotropium/olodaterol (TIO/OLO), a soft mist inhaler, in COPD patients. Methods: This was a prospective, open-label, 8-week, observational study with follow-up. Subjects included 57 COPD patients, who attended outpatient clinics at Shizuoka General Hospital for routine check-ups between February and December 2015, receiving GLY/IND (50/110 μg) or UMEC/VI (62.5/25 μg). After an 8-week run-in period, medications were switched to TIO/OLO (5/5 μg). Study outcomes included patient’s global rating (PGR), modified MRC (mMRC), COPD assessment test (CAT), and spirometric and forced oscillatory parameters after 8 weeks. PGR used in this study was a 7-point scale ranging from 1 to 7, with 4 in the middle. Patients who consented to switch from TIO/OLO to GLY/IND or UMEC/VI were followed-up thereafter. Results: In total, 53 patients completed the study (mean age, 75 years;48 males and 5 females;GOLD 1/2/3/4 = 19/27/6/1;mMRC 0/1/2/3/4 = 14/22/12/4/1;UMEC/VI 26, GLY/IND 27). PGR, mMRC, and CAT improved in 20 (38%), 9 (17%), and 15 patients (28%), respectively. Respiratory system resistance at 5 Hz (R5), 20 Hz (R20), and the difference between R5 and R20 (R5 - R20) significantly improved. In a follow-up of 16 patients after switching from TIO/OLO to UMEC/VI (9) or GLY/IND (7), PGR, mMRC, and CAT improved in 5 (31%), 3 (12%), and 4 patients (25%), respectively, and R20 significantly improved (p = 0.011). Conclusions: Switching dual bronchodilators between dry powder and soft mist inhalers improves symptoms and airway narrowing in some COPD patients.

Comparison of inhaled milrinone, nitric oxide and prostacyclin in acute respiratory distress syndrome

AIM To evaluate the safety and efficacy of inhaled milrinone in acute respiratory distress syndrome(ARDS).METHODS Open-label prospective cross-over pilot study where fifteen adult patients with hypoxemic failure meeting standard ARDS criteria and monitored with a pulmonary artery catheter were recruited in an academic 24-bed medico-surgical intensive care unit. Random sequential administration of i NO(20 ppm) or nebulized epoprostenol(10 μg/mL) was done in all patients. Thereafter, inhaled milrinone(1 mg/mL) alone followed by inhaled milrinone in association with inhaled nitric oxide(iN O) was administered. A jet nebulization device synchronized with the mechanical ventilation was use to administrate the epoprostenol and the milrinone. Hemodynamic measurements and partial pressure of arterial oxygen(PaO_2) were recorded before and after each inhaled therapyadministration.RESULTS The majority of ARDS were of pulmonary cause(n = 13) and pneumonia(n = 7) was the leading underlying initial disease. Other pulmonary causes of ARDS were: Post cardiopulmonary bypass(n = 2), smoke inhalation injury(n = 1), thoracic trauma and pulmonary contusions(n = 2) and aspiration(n = 1). Two patients had an extra pulmonary cause of ARDS: A polytrauma patient and an intra-abdominal abscess Inhaled nitric oxide, epoprostenol, inhaled milrinone and the combination of inhaled milrinone and i NO had no impact on systemic hemodynamics. No significant adverse events related to study medications were observed. The median increase of PaO 2 from baseline was 8.8 mmH g [interquartile range(IQR) = 16.3], 6.0 mm Hg(IQR = 18.4), 6 mm Hg(IQR = 15.8) and 9.2 mm Hg(IQR = 20.2) respectively with i NO, epoprostenol, inhaled milrinone, and i NO added to milrinone. Only i NO and the combination of inhaled milrinone and i NO had a statistically significant effect on PaO 2. CONCLUSION When comparing the effects of inhaled NO, milrinone and epoprostenol, only NO significantly improved oxygenation. Inhaled milrinone appeared safe but failed to improve oxygenation in ARDS.

Inhaled nicotine replacement therapy

There are a large number of smokers who want to quit smoking but have failed in their attempts to do so,with many having been unsuccessful at quitting multiple times over their lifetime.The existing marketed nicotine replacement therapies(NRT)have only marginal effectiveness and none provide a comparable physiological response to that derived from cigarette smoking;that is,rapid absorption of nicotine from the lung leading to peak levels of nicotine in the bloodstream to target the receptors in the brain.Instead,existing NRTs produce a slower and delayed rise in nicotine blood levels which is less effective at reducing the craving sensations.Published data for electronic cigarettes show that they typically deliver nicotine with a profile closer to that for nicotine patches,with a slow rise that can take 30–60 min,or longer,to reach the same peak nicotine concentration that is produced in less than 3 min from a single cigarette.A number of attempts have been made to develop an inhaled product which would deliver the nicotine through the lung and mimic the physiological response from smoking,but many of them produced intolerable aversive reactions or delivered an ineffective dose.This paper discusses examples of the potential for the recent inhaled nicotine products in development to be effective as NRTs,but is not meant to be a comprehensive review.

The Role of Inhaled Insulin in the Management of Type 2 Diabetes

Type 2 diabetes continues to place a major burden on the health care system of the United States and worldwide. Type 2 diabetes involves two major defects: decreased insulin production from the pancreas and increased insulin resistance. Many patients with type 2 diabetes have decreased insulin production which requires exogenous insulin therapy in order to manage their disease. Despite this need, there is often a reluctance to initiate insulin therapy from both providers and patients. One reason for this reluctance may be a fear of needles or of administering injections. Delivering insulin through the lungs has been studied for decades, with the first inhaled insulin product coming to market in 2006. This product’s launch was considered unsuccessful, and the product was discontinued by the manufacturer the following year. A new inhaled insulin, Technosphere? insulin, was approved for use in type 1 and type 2 diabetes in 2014. This product was shown superior to placebo and non-inferior to a premixed bi-phasic subcutaneous insulin in patients with type 2 diabetes, and may offer an alternative to patients who are averse to giving subcutaneous injections.

Extracorporeal membrane oxygenation and inhaled sedation in coronavirus disease 2019-related acute respiratory distress syndrome

Coronavirus disease 2019(COVID-19)related acute respiratory distress syndrome(ARDS)is a severe complication of infection with severe acute respiratory syndrome coronavirus 2,and the primary cause of death in the current pandemic.Critically ill patients often undergo extracorporeal membrane oxygenation(ECMO)therapy as the last resort over an extended period.ECMO therapy requires sedation of the patient,which is usually achieved by intravenous administration of sedatives.The shortage of intravenous sedative drugs due to the ongoing pandemic,and attempts to improve treatment outcome for COVID-19 patients,drove the application of inhaled sedation as a promising alternative for sedation during ECMO therapy.Administration of volatile anesthetics requires an appropriate delivery.Commercially available ones are the anesthetic gas reflection systems AnaConDa®and MIRUSTM,and each should be combined with a gas scavenging system.In this review,we describe respiratory management in COVID-19 patients and the procedures for inhaled sedation during ECMO therapy of COVID-19 related ARDS.We focus particularly on the technical details of administration of volatile anesthetics.Furthermore,we describe the advantages of inhaled sedation and volatile anesthetics,and we discuss the limitations as well as the requirements for safe application in the clinical setting.

Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery

The therapeutic potential of small nucleic acids such as small interfering RNA(siRNA) to treat lung diseases has been successfully demonstrated in many in vivo studies. A major barrier to their clinical application is the lack of a safe and efficient inhaled formulation.In this study, spray freeze drying was employed to prepare dry powder of small nucleic acids.Mannitol and herring sperm DNA were used as bulking agent and model of small nucleic acid therapeutics, respectively. Formulations containing different solute concentration and DNA concentration were produced. The scanning electron microscope(SEM) images showed that the porosity of the particles increased as the solute concentration decreased. Powders prepared with solute concentration of 5% w/v were found to maintain a balance between porosity and robustness. Increasing concentration of DNA improved the aerosol performance of the formulation. The dry powder formulation containing 2% w/w DNA had a median diameter of 12.5 μm, and the aerosol performance study using next generation impactor(NGI) showed an emitted fraction(EF) and fine particle fraction(FPF) of 91% and 28% respectively. This formulation(5% w/v solute concentration and 2% w/w nucleic acid) was adopted subsequently to produce siRNA powder. The gel retardation and liquid chromatography assays showed that the siRNA remained intact after spray freeze drying even in the absence of delivery vector. The siRNA powder formulation exhibited a high EF of 92.4%and a modest FPF of around 20%. Further exploration of this technology to optimise inhaled siRNA powder formulation is warranted.

Rethinking bioequivalence and equivalence requirements of orally inhaled drug products

Orally inhaled drug products(OIPs),such as corticosteroids and bronchodilators,are at the forefront of asthma and chronic obstructive pulmonary disease treatments,two diseases that afflict worldwide populations.Introducing generics of these products is essential,as the pricing of these medications remain a barrier to adequate patient care.Currently,there is no consensus between regulatory bodies as to the bioequivalence and equivalence requirements of OIPs that are intended for local action in the lungs.This manuscript critically reviews these requirements and presents future directions for clinicians,scientists,and regulators to consider to optimize the development and approval of OIPs.

EFFECTS OF INHALED TiO_2 NANOTUBES ON LUNG TISSUE AND SERUM BIOCHEMICAL INDEXES OF MICE

To evaluate the acute lung toxicity and the effect on serum biochemical indexes of inhaled TiO2 nanotubes , healthy and adult Kunming mice are exposed to aerosols of TiO2nanotubes in a sealed chamber , the concentration of which is 250mg / m 3 while another group of mice are exposed to room air only served as control.The blood , alveolar lavaged fluid and lungs of the mice are collected and examined after exposed for 7 , 14and 28d , respectively.The serum analysis shows that glucose ( Glu ) values with 7dexposure , alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) activities with 28dinhalation , and total bile acid ( TBA ) values with 7 , 28d as well as the creatine kinase ( CK ) levels with 28dexposure are significantly different from those of controls ( P< 0.05 ) .The pathological findings exhibit that more TiO 2 nanotubes are found in the interstitium of pulmonary alveoli with the experimental time prolonged.The results suggest that TiO 2 nanotubes do produce adverse responses to the lung and serum biochemical indexes of mice.Moreover , the responses become severer with the exposed-time prolonged.

Drug/polymer nanoparticles prepared using unique spray nozzles and recent progress of inhaled formulation

Inhaled formulations are promising for pulmonary and systemic non-pulmonary diseases.Functional engineered particles including drugs and drug-loaded nanocarriers have been anticipated because they can improve drug delivery efficacy against target sites in the lungs or blood.In this review,unique spray nozzles(e.g.,four-fluid spray nozzle and twosolution mixing type nozzle)for the preparation of nanocomposite particles which mean microparticles containing drug nanoparticles are described.These nozzles can produce nanocomposite particles in one-step and their spray drying system is suitable for scalingup.Nanocomposite particles are useful in improving drug absorption and delivery efficacy against alveolar macrophages.In addition,recent studies on several pulmonary diseases(tuberculosis,lung cancer,cystic fibrosis,pneumonia,vaccine and others)and related inhaled formulations were also reviewed.