Nanomechanical and Microstructural Characterization of Biocompatible Ti3Au Thin Films Grown on Glass and Ti6Al4V Substrates.

Ti-Au intermetallic-based material systems are being extensively studied as next-generation thin film coatings to extend the lifetime of implant devices. These coatings are being developed for application to the articulating surfaces of total joint implants and, therefore, must have excellent biocompatibility combined with superior mechanical hardness and wear resistance. However, these key characteristics of Ti-Au coatings are heavily dependent upon factors such as the surface properties and temperature of the underlying substrate during thin film deposition. In this work, Ti3Au thin films were deposited by magnetron sputtering on both glass and Ti6Al4V substrates at an ambient and elevated substrate temperature of 275 °C. These films were studied for their mechanical properties by the nanoindentation technique in both variable load and fixed load mode using a Berkovich tip. XRD patterns and cross-sectional SEM images detail the microstructure, while AFM images present the surface morphologies of these Ti3Au thin films. The biocompatibility potential of the films is assessed by cytotoxicity tests in L929 mouse fibroblast cells using Alamar blue assay, while leached ion concentrations in the film extracts are quantified using ICPOEMS. The standard deviation for hardness of films deposited on glass substrates is ∼4 times lower than that on Ti6Al4V substrates and is correlated with a corresponding increase in surface roughness from 2 nm for glass to 40 nm for Ti6Al4V substrates. Elevating substrate temperature leads to an increase in film hardness from 5.1 to 8.9 GPa and is related to the development of a superhard ß phase of the Ti3Au intermetallic. The standard deviation of this peak mechanical hardness value is reduced by ∼3 times when measured in fixed load mode compared to the variable load mode due to the effect of nanoindentation tip penetration depth. All tested Ti-Au thin films also exhibit excellent biocompatibility against L929 fibroblast cells, as viability levels are above 95% and leached Ti, Al, V, and Au ion concentrations are below 0.1 ppm. Overall, this work demonstrates a novel Ti3Au thin film system with a unique combination of high hardness and excellent biocompatibility with potential to be developed into a new wear-resistant coating to extend the lifetime of articulating total joint implants.

Biocompatible Ti3Au-Ag/Cu thin film coatings with enhanced mechanical and antimicrobial functionality.

BACKGROUND: Biofilm formation on medical device surfaces is a persistent problem that shelters bacteria and encourages infections and implant rejection. One promising approach to tackle this problem is to coat the medical device with an antimicrobial material. In this work, for the first time, we impart antimicrobial functionality to Ti3Au intermetallic alloy thin film coatings, while maintaining their superior mechanical hardness and biocompatibility. METHODS: A mosaic Ti sputtering target is developed to dope controlled amounts of antimicrobial elements of Ag and Cu into a Ti3Au coating matrix by precise control of individual target power levels. The resulting Ti3Au-Ag/Cu thin film coatings are then systematically characterised for their structural, chemical, morphological, mechanical, corrosion, biocompatibility-cytotoxicity and antimicrobial properties. RESULTS: X-ray diffraction patterns reveal the formation of a super hard ß-Ti3Au phase, but the thin films undergo a transition in crystal orientation from (200) to (211) with increasing Ag concentration, whereas introduction of Cu brings no observable changes in crystal orientation. Scanning and transmission electron microscopy analysis show the polyhedral shape of the Ti3Au crystal but agglomeration of Ag particles between crystal grains begins at 1.2 at% Ag and develops into large granules with increasing Ag concentration up to 4.1 at%. The smallest doping concentration of 0.2 at% Ag raises the hardness of the thin film to 14.7 GPa, a 360% improvement compared to the ∼4 GPa hardness of the standard Ti6Al4V base alloy. On the other hand, addition of Cu brings a 315-330% improvement in mechanical hardness of films throughout the entire concentration range of 0.5-7.1 at%. The thin films also show good electrochemical corrosion resistance and a > tenfold reduction in wear rate compared to Ti6Al4V alloy. All thin film samples exhibit very safe cytotoxic profiles towards L929 mouse fibroblast cells when analysed with Alamar blue assay, with ion leaching concentrations lower than 0.2 ppm for Ag and 0.08 ppm for Cu and conductivity tests reveal the positive effect of increased conductivity on myogenic differentiation. Antimicrobial tests show a drastic reduction in microbial survival over a short test period of < 20 min for Ti3Au films doped with Ag or Cu concentrations as low as 0.2-0.5 at%. CONCLUSION: Therefore, according to these results, this work presents a new antimicrobial Ti3Au-Ag/Cu coating material with excellent mechanical performance with the potential to develop wear resistant medical implant devices with resistance to biofilm formation and bacterial infection.

Multi-functional bioactive silver- and copper-doped diamond-like carbon coatings for medical implants.

Diamond-like carbon (DLC) coatings doped with bioactive elements of silver (Ag) and copper (Cu) have been receiving increasing attention in the last decade, particularly in the last 5 years, due to their potential to offer a combination of enhanced antimicrobial and mechanical performance. These multi-functional bioactive DLC coatings offer great potential to impart the next generation of load-bearing medical implants with improved wear resistance and strong potency against microbial infections. This review begins with an overview of the status and issues with current total joint implant materials and the state-of-the art in DLC coatings and their application to medical implants. A detailed discussion of recent advances in wear resistant bioactive DLC coatings is then presented with a focus on doping the DLC matrix with controlled quantities of Ag and Cu elements. It is shown that both Ag and Cu doping can impart strong antimicrobial potency against a range of Gram-positive and Gram-negative bacteria, but this is always accompanied so far by a reduction in mechanical performance of the DLC coating matrix. The article concludes with discussion of potential synthesis methods to accurately control bioactive element doping without jeopardising mechanical properties and gives an outlook to the potential long-term impact of developing a superior multifunctional bioactive DLC coating on implant device performance and patient health and wellbeing. STATEMENT OF SIGNIFICANCE: Multi-functional diamond-like carbon (DLC) coatings doped with bioactive elements of silver (Ag) and copper (Cu) offer great potential to impart the next generation of load-bearing medical implants with improved wear resistance and strong potency against microbial infections. This article provides a critical review of the state-of-the-art in Ag and Cu doped DLC coatings, beginning with an overview of the current applications of DLC coatings in implant technology followed by a detailed discussion of Ag/Cu doped DLC coatings with particular focus on the relationship between their mechanical and antimicrobial performance. Finally, it ends with a discussion on the potential long-term impact of developing a truly multifunctional ultra-hard wearing bioactive DLC coating to extend the lifetime of total joint implants.

Advances in nanomaterial-based immunosensors for prostate cancer screening.

Prostate cancer is one of the most common health hazards for men worldwide, specifically in Western countries. Rapid prostate cancer screening by analyzing the prostate-specific antigen present in male serum has brought about a sharp decline in the mortality index of this disease. Immunoassay technology quantifies the target analyte in the sample using the antigen-antibody reaction. Immunoassays are now pivotal in disease diagnostics, drug monitoring, and pharmacokinetics. Recently, immunosensors have gained momentum in delivering better results with high specificity and lower limit of detection (LOD). Nanomaterials like gold, silver, and copper exhibit numerous exceptional features and their use in developing immunosensors have garnered excellent results in the diagnostic field. This review highlights the recent and different immunoassay techniques used to detect prostate-specific antigens and discusses the advances in nanomaterial-based immunosensors to detect prostate cancer efficiently. The review also explores the importance of specific biomarkers and nanomaterials-based biosensors with good selectivity and sensitivity to prostate cancer.

2D materials, synthesis, characterization and toxicity: A critical review.

Nanotechnology is an arena of exploration and innovation concerned with building things generally, advancing resources and devices based on highly specific and superior nanomaterials with unmatched properties dependent on their morphology and diameter. 2D materials such as graphene have unique properties and applications varying from imaging, delivery of drugs, and theranostics of diseases. Each 2D material, ranging from the graphene family, MXenes, chalcogenides, and 2D oxides, have a unique potential based on their shape and morphology. In addition, 2D materials have intriguing physiochemical characteristics, increased aspect ratio and associated increased reactivity that make them an ideal contender in multiple applications. This review aims to answer the existing knowledge gaps in various 2D materials having interdisciplinary roles. We have presented a brief overview of the 2D materials, followed by their synthesis methods and techniques. We have also highlighted the different characterization methods used to characterise various 2D materials. Next, we performed an in-depth analysis of the potential toxicities of 2D materials to assess their risks in multiple applications. Lastly, we conclude our review by presenting the challenges and future perspectives of 2D materials as promising forerunners of science and technology.

Frontiers in Antimicrobial Materials.

The aim of this Special Edition is to highlight the exponential work performed in the field of antimicrobial material research from the beginning of the current COVID-19 pandemic [...].

Thermal activation of Ti(1-x)Au(x) thin films with enhanced hardness and biocompatibility.

The lifetime of orthopaedic implants can be extended by coating the softer Ti6Al4V alloy with harder biocompatible thin films. In this work, thin films of Ti(1-x)Au(x) are grown on Ti6Al4V and glass substrates by magnetron sputtering in the entire x = 0-1 range, before their key biomechanical properties are performance tuned by thermal activation. For the first time, we explore the effect of in-situ substrate heating versus ex-situ post-deposition heat-treatment, on development of mechanical and biocompatibility performance in Ti-Au films. A ∼250% increase in hardness is achieved for Ti-Au films compared to bulk Ti6Al4V and a ∼40% improvement from 8.8 GPa as-grown to 11.9 and 12.3 GPa with in-situ and ex-situ heat-treatment respectively, is corelated to changes in structural, morphological and chemical properties, providing insights into the origins of super-hardness in the Ti rich regions of these materials. X-ray diffraction reveals that as-grown films are in nanocrystalline states of Ti-Au intermetallic phases and thermal activation leads to emergence of mechanically hard Ti-Au intermetallics, with films prepared by in-situ substrate heating having enhanced crystalline quality. Surface morphology images show clear changes in grain size, shape and surface roughness following thermal activation, while elemental analysis reveals that in-situ substrate heating is better for development of oxide free Ti3Au ß-phases. All tested Ti-Au films are non-cytotoxic against L929 mouse fibroblast cells, while extremely low leached ion concentrations confirm their biocompatibility. With peak hardness performance tuned to >12 GPa and excellent biocompatibility, Ti-Au films have potential as a future coating technology for load bearing medical implants.

Recent Advances in Metal-Based Antimicrobial Coatings for High-Touch Surfaces.

International interest in metal-based antimicrobial coatings to control the spread of bacteria, fungi, and viruses via high contact human touch surfaces are growing at an exponential rate. This interest recently reached an all-time high with the outbreak of the deadly COVID-19 disease, which has already claimed the lives of more than 5 million people worldwide. This global pandemic has highlighted the major role that antimicrobial coatings can play in controlling the spread of deadly viruses such as SARS-CoV-2 and scientists and engineers are now working harder than ever to develop the next generation of antimicrobial materials. This article begins with a review of three discrete microorganism-killing phenomena of contact-killing surfaces, nanoprotrusions, and superhydrophobic surfaces. The antimicrobial properties of metals such as copper (Cu), silver (Ag), and zinc (Zn) are reviewed along with the effects of combining them with titanium dioxide (TiO2) to create a binary or ternary contact-killing surface coatings. The self-cleaning and bacterial resistance of purely structural superhydrophobic surfaces and the potential of physical surface nanoprotrusions to damage microbial cells are then considered. The article then gives a detailed discussion on recent advances in attempting to combine these individual phenomena to create super-antimicrobial metal-based coatings with binary or ternary killing potential against a broad range of microorganisms, including SARS-CoV-2, for high-touch surface applications such as hand rails, door plates, and water fittings on public transport and in healthcare, care home and leisure settings as well as personal protective equipment commonly used in hospitals and in the current COVID-19 pandemic.

Fourth-generation glucose sensors composed of copper nanostructures for diabetes management: A critical review.

More than five decades have been invested in understanding glucose biosensors. Yet, this immensely versatile field has continued to gain attention from the scientific world to better understand and diagnose diabetes. However, such extensive work done to improve glucose sensing devices has still not yielded desirable results. Drawbacks like the necessity of the invasive finger-pricking step and the lack of optimization of diagnostic interventions still need to be considered to improve the testing process of diabetic patients. To upgrade the glucose-sensing devices and reduce the number of intermediary steps during glucose measurement, fourth-generation glucose sensors (FGGS) have been introduced. These sensors, made using robust electrocatalytic copper nanostructures, improve diagnostic efficiency and cost-effectiveness. This review aims to present the essential scientific progress in copper nanostructure-based FGGS in the past 10 years (2010 to present). After a short introduction, we presented the working principles of these sensors. We then highlighted the importance of copper nanostructures as advanced electrode materials to develop reliable real-time FGGS. Finally, we cover the advantages, shortcomings, and prospects for developing highly sensitive, stable, and specific FGGS.

Electro- and photon-induced cooling in BNT-BT-SBET relaxors with in situ optical temperature sensing.

A novel lead-free luminescent ferroelectric (FE) ceramic, ${{\rm Bi}_{0.5}}{{\rm Na}_{0.5}}{{\rm TiO}_3} {-} {0.{06\; \rm BaTiO}_3} {-} {0.{055\;\rm Sr}_{0.7}}{{\rm Bi}_{0.18}}{{\rm Er}_{0.02 \,\square\, 0.1}}$Bi0.5Na0.5TiO3-0.06BaTiO3-0.055Sr0.7Bi0.18Er0.02◻0.1${{\rm TiO}_3}$TiO3 (BNT-BT-SBET), is developed with an adiabatic temperature change ($\Delta T$ΔT) of 0.7 K under an electric field ($E$E) of 60 kV/cm at room temperature, an anti-Stokes fluorescence cooling, and a maximum optical $T$T sensitivity of ${0.0055}\;{{\rm K}^{ - 1}}$0.0055K-1 at 522 K. Interestingly, the electrocaloric response reaches a saturation at permittivity shoulder $T$T of 100°C; meanwhile, the maximized emission intensity of $^2{{\rm H}_{11/2}}{ \to ^4}{{\rm I}_{15/2}}$2H11/2→4I15/2 occurs. $T$T- and $E$E-tunable enhancement of $^2{{\rm H}_{11/2}}{ \to ^4}{{\rm I}_{15/2}}$2H11/2→4I15/2 emission intensity is due to the population inversion from the $^4{{\rm S}_{3/2}}$4S3/2 to $^2{{\rm H}_{11/2}}$2H11/2 states caused by an incoherent regime consisting of FE phase and polar nanoregions in a relaxor matrix.

A Numerical and Experimental Study of Adhesively-Bonded Polyethylene Pipelines.

Adhesive bonding of polyethylene gas pipelines is receiving increasing attention as a replacement for traditional electrofusion welding due to its potential to produce rapid and low-cost joints with structural integrity and pressure tight sealing. In this paper a mode-dependent cohesive zone model for the simulation of adhesively bonded medium density polyethylene (MDPE) pipeline joints is directly determined by following three consecutive steps. Firstly, the bulk stress-strain response of the MDPE adherend was obtained via tensile testing to provide a multi-linear numerical approximation to simulate the plastic deformation of the material. Secondly, the mechanical responses of double cantilever beam and end-notched flexure test specimens were utilised for the direct extraction of the energy release rate and cohesive strength of the adhesive in failure mode I and II. Finally, these material properties were used as inputs to develop a finite element model using a cohesive zone model with triangular shape traction separation law. The developed model was successfully validated against experimental tensile lap-shear test results and was able to accurately predict the strength of adhesively-bonded MPDE pipeline joints with a maximum variation of <3%.

Effect of Abrasive Machining on the Electrical Properties Cu86Mn12Ni2 Alloy Shunts.

This paper studies the effect of abrasive trimming on the electrical properties of Cu86Mn12Ni2 Manganin alloy shunt resistors. A precision abrasive trimming system for fine tuning the resistance tolerance of high current Manganin shunt resistors is proposed. The system is shown to be capable of reducing the resistance tolerance of 100 µΩ shunts from their standard value of ±5% to <±1% by removing controlled amounts of Manganin material using a square cut trim geometry. The temperature coefficient of resistance (TCR), high current, and high temperature performance of the trimmed shunts was compared to that of untrimmed parts to determine if trimming had any detrimental effect on these key electrical performance parameters of the device. It was shown that the TCR value was reduced following trimming with typical results of +106 ppm/°C and +93 ppm/°C for untrimmed and trimmed parts respectively. When subjected to a high current of 200 A the trimmed parts showed a slight increase in temperature rise to 203 °C, as compared to 194 °C for the untrimmed parts, but both had significant temporary increases in resistance of up to 1.3 µΩ. The results for resistance change following high temperature storage at 200 °C for 168 h were also significant for both untrimmed and trimmed parts with shifts of 1.85% and 2.29% respectively and these results were related to surface oxidation of the Manganin alloy which was accelerated for the freshly exposed surfaces of the trimmed part.

A comparison of the efficacy and safety of olanzapine versus haloperidol during transition from intramuscular to oral therapy.

BACKGROUND: Acutely agitated patients with schizophrenia who receive intramuscular (IM) medications typically are switched to oral (PO) antipsychotic maintenance therapy. OBJECTIVE: The goal of this study was to assess the efficacy and safety of olanzapine versus those of haloperidol during transition from IM to PO therapy. We used additional data from a previously reported trial to test the hypothesis that the reduction in agitation achieved by IM olanzapine 10 mg or IM haloperidol 7.5 mg would be maintained following transition to 4 days of PO olanzapine or PO haloperidol (5-20 mg/d for both). We also hypothesized that olanzapine would maintain its more favorable extrapyramidal symptom (EPS) safety profile. METHODS: This was a multinational (hospitals in 13 countries), double-blind, randomized, controlled trial. Acutely agitated inpatients with schizophrenia were treated with 1 to 3 IM injections to olanzapine 10 mg or haloperidol 7.5 mg over 24 hours and were entered into a 4-day PO treatment period with the same medication (5-20 mg/d for both). The primary efficacy measurement was reduction in agitation, as measured by the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score. Adverse events and scores on EPS rating scales were assessed. RESULTS: A total of 311 patients (204 men, 107 women; mean [SD] age, 38.2 [11.6] years) were enrolled (131, 126, and 54 patients in the olanzapine, haloperidol, and placebo groups, respectively). In all, 93.1% (122/131) of olanzapine-treated patients and 92.1% (116/126) of haloperidol-treated patients completed the IM period and entered the PO period; 85.5% (112/131) of olanzapine-treated patients and 84.1% (106/126) of haloperidol-treated patients completed the PO period. IM olanzapine and IM haloperidol effectively reduced agitation over 24 hours (mean [SD] PANSS-EC change, -7.1 [4.81 vs -6.7 [4.3], respectively). Reductions in agitation were sustained throughout the PO period with both study drugs (mean [SD] change from PO period baseline, -0.6 [4.8] vs -1.3 [4.4], respectively). During PO treatment, haloperidol-treated patients spontaneously reported significantly more acute dystonia than olanzapine-treated patients (4.3%[5/116] vs 0% [0/122], respectively; P = 0.026) and akathisia (5.2% [6/116] vs 0% [0/122], respectively; P = 0.013). Significantly more haloperidol-treated patients than olanzapine-treated patients met categorical criteria for treatment-emergent akathisia (18.5% [17/92] vs 6.5% [7/107], respectively; P = 0.015). CONCLUSIONS: In the acutely agitated patients with schizophrenia in this study, both IM olanzapine 10 mg and IM haloperidol 7.5 mg effectively reduced agitation over 24 hours. This alleviation of agitation was sustained following transition from IM therapy to 4 days of PO treatment (5-20 mg/d for both). During the 4 days of PO treatment, olanzapine-treated patients did not spontaneously report any incidences of acute dystonia, and olanzapine had a superior EPS safety profile to that of haloperidol. The combination of IM and PO olanzapine may help improve the treatment of acutely agitated patients with schizophrenia.

Intramuscular olanzapine and intramuscular haloperidol in acute schizophrenia: antipsychotic efficacy and extrapyramidal safety during the first 24 hours of treatment.

OBJECTIVE: To determine the antipsychotic efficacy and extrapyramidal safety of intramuscular (i.m.) olanzapine and i.m. haloperidol during the first 24 hours of treatment of acute schizophrenia. METHOD: Patients (n = 311) with acute schizophrenia were randomly allocated (2:2:1) to receive i.m. olanzapine (10.0 mg, n = 131), i.m. haloperidol (7.5 mg, n = 126), or i.m. placebo (n = 54). RESULTS: After the first injection, i.m. olanzapine was comparable to i.m. haloperidol and superior to i.m. placebo for reducing mean change scores from baseline on the Brief Psychiatric Rating Scale (BRPS) Positive at 2 hours (-2.9 olanzapine, -2.7 haloperidol, and -1.5 placebo) and 24 hours (-2.8 olanzapine, -3.2 haloperidol, and -1.3 placebo); the BPRS Total at 2 hours (-14.2 olanzapine,-13.1 haloperidol, and -7.1 placebo) and 24 hours (-12.8 olanzapine, -12.9 haloperidol, and -6.2 placebo); and the Clinical Global Impressions (CGI) scale at 24 hours (-0.5 olanzapine, -0.5 haloperidol, and -0.1 placebo). Patients treated with i.m. olanzapine had significantly fewer incidences of treatment-emergent parkinsonism (4.3% olanzapine vs 13.3% haloperidol, P = 0.036), but not akathisia (1.1% olanzapine vs 6.5% haloperidol, P = 0.065), than did patients treated with i.m. haloperidol; they also required significantly less anticholinergic treatment (4.6% olanzapine vs 20.6% haloperidol, P < 0.001). Mean extrapyramidal symptoms (EPS) safety scores improved significantly from baseline during i.m. olanzapine treatment, compared with a general worsening during i.m. haloperidol treatment (Simpson-Angus Scale total score mean change: -0.61 olanzapine vs 0.70 haloperidol; P < 0.001; Barnes Akathisia Scale global score mean change: -0.27 olanzapine vs 0.01 haloperidol; P < 0.05). CONCLUSION: I.m. olanzapine was comparable to i.m. haloperidol for reducing the symptoms of acute schizophrenia during the first 24 hours of treatment, the efficacy of both being evident within 2 hours after the first injection. In general, more EPS were observed during treatment with i.m. haloperidol than with i.m. olanzapine.

A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia.

BACKGROUND: An intramuscular (IM) formulation of olanzapine has been developed because there are no rapid-acting IM atypical antipsychotic drugs currently available in the United States for treating acute agitation in patients with schizophrenia. METHODS: Recently hospitalized acutely agitated patients with schizophrenia (N = 270) were randomized to receive 1 to 3 IM injections of olanzapine (2.5, 5.0, 7.5, or 10.0 mg), haloperidol (7.5 mg), or placebo within 24 hours. A dose-response relationship for IM olanzapine in the reduction of agitation was assessed by measuring the reduction in Positive and Negative Syndrome Scale Excited Component (PANSS-EC) scores 2 hours after the first injection. Safety was assessed by recording adverse events and with extrapyramidal symptom scales and electrocardiograms at 24 hours after the first injection. RESULTS: Olanzapine exhibited a dose-response relationship for reduction in agitation (F(1,179)= 14.4; P<.001). Mean PANSS-EC reductions 2 hours after the first injection of olanzapine (2.5 mg = -5.5; 5.0 mg = -8.1; 7.5 mg = -8.7; 10.0 mg = -9.4) were superior to those with placebo (-2.9; P =.01 vs olanzapine at 2.5 mg; P<.001 for each other olanzapine dose) but not with haloperidol (-7.5). A dose of 5.0, 7.5, or 10.0 mg of olanzapine caused a greater reduction in agitation than placebo 30 minutes after the first injection. There were no differences between treatment groups for hypotension, the most frequently reported adverse event, or for clinically relevant changes in the QTc interval. There was a greater incidence of treatment-emergent parkinsonism during treatment with IM haloperidol (16.7%) than with 2.5 (P =.03), 5.0 (P =.03), or 7.5 mg (P =.01) of IM olanzapine (0%) or with placebo (0%) (P =.01). CONCLUSIONS: Intramuscular olanzapine at a dose of 2.5 to 10.0 mg per injection exhibits a dose-response relationship in the rapid treatment of acute agitation in patients with schizophrenia and demonstrates a favorable safety profile.

Short-term safety and efficacy of human GH replacement therapy in 595 adults with GH deficiency: a comparison of two dosage algorithms.

The aim of GH replacement therapy in GH-deficient adults is to optimize response with minimum incidence of adverse reactions, but optimal therapy regimens are still to be established. This two-arm parallel study examined effects of two GH dose algorithms in adults with GH deficiency of adult or childhood onset. Patients on low dose (LD; n = 302) received GH at 3 microg/kg per day for 3 months increasing to 6 microg/kg per day for 3 months, and those on conventional dose (CD; n = 293) started on 6 microg/kg per day for 3 months increasing to 12 microg/kg per day for 3 months. The proportion of patients completing therapy was greater for the LD group than the CD group for the first 3 months (93.0% vs. 88.1%; P = 0.037) and overall for the 6 months (90.7% vs. 84.0%; P = 0.013). Both dose groups showed significant increases in lean body mass and decreases in fat mass for all time points. Percent increase in lean body mass was less with LD than CD over the first 3 months (2.43 +/- 4.33 vs. 3.58 +/- 4.69%; P = 0.006) but not overall for the 6-month period (4.38% +/- 5.34% vs. 5.21% +/- 5.99%; P = 0.141). Percent decrease in fat mass was less with LD than CD for the first 3 months (-2.81% +/- 7.81% vs. -5.53% +/- 8.64%; P < 0.001) and overall for the 6-month period (-6.35% +/- 9.42% vs. -9.45% +/- 12.07%; P = 0.006). IGF-I SD score increased less with LD than CD for 0 to 3 and 0 to 6 months, although for IGF-binding protein-3 SD score, there was no significant difference between doses at any time. Arthralgia was the only adverse event that occurred significantly less frequently with LD than with CD. Calculated changes based on gender and onset indicated greater changes in males than females for body composition, but there was little difference in GH-related adverse events between males and females. The lower starting dose with dose titration appeared more favorable, but differences in response between genders and onset of GH deficiency need to be taken into account when setting an individual dose regimen.