First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆.

BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Gonadotropin-releasing hormone agonist induces downregulation of tensin 1 in women with endometriosis.

INTRODUCTION: Many cell migration-related molecules are associated with endometriosis. Tensin 1 (TNS1), which has been implicated in cell migration, may play a role in endometriosis. The study goal was to evaluate the TNS1 expression in endometrial tissue and serum from women with endometriosis treated with gonadotropin-releasing hormone agonist (GnRHa). MATERIAL AND METHODS: Tissue and serum samples were collected from women with endometriosis who were treated (n = 29) with GnRHa or untreated (n = 30). TNS1 mRNA was examined using quantitative PCR. TNS1 protein levels in tissue and serum samples were investigated using Western blot, immunohistochemistry and ELISA. Eleven women with endometriosis participated in a follow-up investigation of serum TNS1 before and after GnRHa treatment. RESULTS: TNS1 mRNA (P = 0.006) and protein (P = 0.001) were significantly downregulated in endometriotic tissue from women with endometriosis who received GnRHa. Immunolocalization of TNS1 showed strong expression in the epithelial and stromal cells of endometriotic tissue from women untreated with GnRHa, whereas endometriotic tissue from GnRHa-treated women showed low TNS1 expression. Follow-up monitoring of serum TNS1 concentration in 11 women showed an average decrease in concentration of 53%, from 294.9 ± 66.69 to 140.3 ± 55.21 pg/mL, following GnRHa treatment (P = 0.003). CONCLUSIONS: GnRHa induces downregulation of TNS1 in tissue and serum in women with endometriosis. These results emphasize the importance TNS1 as a potential therapeutic molecular target for the treatment of endometriosis with GnRHa.

Discovery and preliminary structure-activity relationship of the marine natural product manzamines as herpes simplex virus type-1 inhibitors.

Herpes simplex virus type-1 (HSV-1) is a member of alpha-herpesviridae family and is known to cause contagious human infections. The marine habitat is a rich source of structurally unique bioactive secondary metabolites. A small library of marine natural product classes 1-10 has been screened to discover a new hit entity active against HSV-1. Manzamine A showed potent activity against HSV-1 via targeting the viral gene ICP0. Manzamine A is a ß-carboline alkaloid isolated from the Indo-Pacific sponge Acanthostrongylophora species. Currently, acyclovir is the drug of choice for HSV-1 infections. Compared with 50 µM acyclovir, manzamine A at 1 µM concentration produced potent repressive effects on viral replication and release of infectious viruses in SIRC cells in recent studies. The potent anti-HSV-1 activity of manzamine A prompted a preliminary structure-activity relationship study by testing targeted manzamines. These included 8-hydroxymanzamine A (11), to test the effect of the C-8 hydroxy substitution at the ß-carboline moiety; manzamine E (12), to assess the importance of substitution at the azacyclooctane ring; and ircinal A (13), to determine whether the ß-carboline ring is required for the activity. Manzamine A was chemically transformed to its salt forms, manzamine A monohydrochloride (14) and manzamine A monotartrate (15), to test whether improving water solubility and hydrophilicity will positively affect the activity. Compounds were tested for activity against HSV-1 using fluorescent microscopy and plaque assay. The results showed the reduced anti-HSV-1 activity of 11, suggesting that C-8 hydroxy substitution might adversely affect the activity. Similarly, manzamines 12 and 13 showed no activity against HSV-1, indicating the preference of the unsubstituted azacylcooctane and ß-carboline rings to the activity. Anti-HSV-1 activity was significantly improved for the manzamine A salts 14 and 15, suggesting that improving the overall water solubility as salt forms can significantly enhance the activity. Manzamines have significant potential for future development as anti-HSV-1 entity.

Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors.

BACKGROUND: Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours. METHODS: Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m(-2) and CP 60-75 mg m(-2). Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m(-2), CP 60 mg m(-2)) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days. RESULTS: On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m(-2), 60 mg m(-2)); G 3 anorexia/fatigue/hypokalemia (1.2 mg m(-2), 60 mg m(-2)); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m(-2), 60 mg m(-2)). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m(-2), 60 mg m(-2)); G 4 mucositis (1.4 mg m(-2), 60 mg m(-2)); and G 3 hypokalemia (1.2 mg m(-2), 75 mg m(-2)). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m(-2) (days 1, 8) and CP 75 mg m(-2) (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers). CONCLUSIONS: On the 21-day cycle, eribulin mesylate 1.2 mg m(-2), administered on days 1 and 8, in combination with CP 75 mg m(-2), administered on day 1 is well tolerated and showed preliminary anticancer activity.

Manzamine A as a novel inhibitor of herpes simplex virus type-1 replication in cultured corneal cells.

This study investigated the putative inhibitory effect of manzamine A on HSV-1 infection. Our results indicated that manzamine A effectively inhibited viral replication and infection in the cell line SIRC, a corneal cell line, at 1 µM. The existing anti-HSV-1 drug acyclovir was analyzed and showed a comparable activity at 50 µM. Plaque assays demonstrated that manzamine A reduced the release of infectious virus by 10 (11)-fold. RTPCR assays indicated that HSV-1 virion host shutoff (vhs) activity and ICP0 transcription were decreased by manzamine A treatment. These results bode well for the development of manzamines as potential leads to reduce viral infection in corneal cells and to prevent HSV-1-induced eye infections such as keratitis.

Regulation of herpes simplex virus type 1 thymidine kinase gene expression by thyroid hormone receptor in cultured neuronal cells.

Herpes simplex virus type 1 (HSV-1) undergoes acute infection in epithelial cells followed by establishment of latency in the neurons of trigeminal ganglia. The latent virus maintains a dormant state and can recurs spontaneously, suggesting transcriptional silencing and reactivation occur in neurons. Computer data mining identified a nuclear hormone response element (NRE), the binding site for the thyroid hormone receptor (TR) or other nuclear hormone receptor, in the promoter of HSV-1 thymidine kinase (TK). TRs are transcription factors whose activity is dependent on their ligand thyroid hormone (T(3); triiodothyronine). We hypothesize that TR and T(3) exert regulation on HSV-1 gene expression in neurons. A neuroblastoma cell line expressing the TR isoform beta (N2aTRbeta) was utilized for in vitro investigation. Results showed that liganded TR repressed TK promoter activity but unliganded TR relieved the inhibition. The mutagenesis study demonstrated that one nucleotide mutation at the NRE abolished the T(3)/TR-mediated regulation. N2aTRbeta cells treated with T(3) were suppressive to TK expression and virus release but the removal of T(3) de-repressed TK expression and increased virus release, confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and plaque assays, respectively. Chromatin immunoprecipitation (ChIP) assays showed that TRs were enriched at TK NRE in the presence of T(3). Additional results demonstrated that hyper acetylated histone H4 and monomethylated H3 modified at lysine 9 (H3K9me1) were enriched at transcriptionally active TK promoters but were dissociated from the NRE by T(3)/TR. These results suggest that T(3) could regulate HSV-1 gene expression through its receptor via histone modification in cultured neuronal cells.

Low-level laser therapy for carpal tunnel syndrome: systematic review and network meta-analysis.

BACKGROUND: Splinting is recommended by various organisations as a non-surgical first-line treatment for carpal tunnel syndrome (CTS), despite the limited evidence supporting its effectiveness. Previous studies on the effectiveness of low-level laser therapy (LLLT) have reported mixed results, and this systematic review aimed to resolve this controversy. OBJECTIVE: To perform a network meta-analysis (NMA) for evaluating the effectiveness of LLLT compared with other conservative treatments for CTS. METHODS: Eighteen electronic databases were searched for potential randomised controlled trials (RCTs). RCTs evaluating LLLT or other non-surgical treatments as an add-on to splinting were included. Included RCTs measured at least one of the following three outcomes with validated instruments: pain, symptom severity and functional status. RESULTS: Six RCTs (418 patients) were included. NMA suggested that LLLT plus splinting has the highest probability (75%) of pain reduction, compared with sham laser plus splinting (61%), ultrasound plus splinting (57%) and splinting alone (8%). However, while LLLT plus splinting is significantly more effective than sham laser plus splinting for pain reduction, the magnitude is not clinically significant (Visual Analogue Scale mean difference -0.53cm, 95% confidence interval -1.01 to -0.05cm; P=0.03, I2=25%). The effect of LLLT plus splinting on symptom severity and functional status was not superior to splinting alone. CONCLUSION: The use of LLLT in addition to splinting for the management of CTS is not recommended, as LLLT offers limited additional benefits over splining alone in terms of pain reduction, reduction of symptom severity or improved functional status. PROSPERO for systematic reviews and meta-analyses registration number CRD42017082650.

Technique and preliminary findings for in vivo quantification of brain motion during injurious head impacts.

Computational models of the human brain are widely used in the evaluation and development of helmets and other protective equipment. These models are often attempted to be validated using cadaver tissue displacements despite studies showing neural tissue degrades quickly after death. Addressing this limitation, this study aimed to develop a technique for quantifying living brain motion in vivo using a closed head impact animal model of traumatic brain injury (TBI) called CHIMERA. We implanted radiopaque markers within the brain of three adult ferrets and resealed the skull while the animals were anesthetized. We affixed additional markers to the skull to track skull kinematics. The CHIMERA device delivered controlled, repeatable head impacts to the head of the animals while the impacts were fluoroscopically stereo-visualized. We observed that 1.5 mm stainless steel fiducials (∼8 times the density of the brain) migrated from their implanted positions while neutral density targets remained in their implanted position post-impact. Brain motion relative to the skull was quantified in neutral density target tests and showed increasing relative motion at higher head impact severities. We observed the motion of the brain lagged behind that of the skull, similar to previous studies. This technique can be used to obtain a comprehensive dataset of in vivo brain motion to validate computational models reflecting the mechanical properties of the living brain. The technique would also allow the mechanical response of in vivo brain tissue to be compared to cadaveric preparations for investigating the fidelity of current human computational brain models.

Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.

BACKGROUND: Vaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors. PATIENTS AND METHODS: Eleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression. RESULTS: We observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8+ T cells and elevation of expression of multiple immune response genes. Borderline or undetectable p53-specific T cell responses in 7/11 patients were related to no immediate clinical benefit. The first study patient had a grade 5 fatal myocarditis. After the study was amended for enhanced cardiac monitoring, no additional cardiac toxicities were noted. CONCLUSION: We have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.

Methodological quality of systematic reviews on treatments for depression: a cross-sectional study.

AIMS: Depression is one of the most common mental disorders and identifying effective treatment strategies is crucial for the control of depression. Well-conducted systematic reviews (SRs) and meta-analyses can provide the best evidence for supporting treatment decision-making. Nevertheless, the trustworthiness of conclusions can be limited by lack of methodological rigour. This study aims to assess the methodological quality of a representative sample of SRs on depression treatments. METHODS: A cross-sectional study on the bibliographical and methodological characteristics of SRs published on depression treatments trials was conducted. Two electronic databases (the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects) were searched for potential SRs. SRs with at least one meta-analysis on the effects of depression treatments were considered eligible. The methodological quality of included SRs was assessed using the validated AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool. The associations between bibliographical characteristics and scoring on AMSTAR items were analysed using logistic regression analysis. RESULTS: A total of 358 SRs were included and appraised. Over half of included SRs (n = 195) focused on non-pharmacological treatments and harms were reported in 45.5% (n = 163) of all studies. Studies varied in methods and reporting practices: only 112 (31.3%) took the risk of bias among primary studies into account when formulating conclusions; 245 (68.4%) did not fully declare conflict of interests; 93 (26.0%) reported an 'a priori' design and 104 (29.1%) provided lists of both included and excluded studies. Results from regression analyses showed: more recent publications were more likely to report 'a priori' designs [adjusted odds ratio (AOR) 1.31, 95% confidence interval (CI) 1.09-1.57], to describe study characteristics fully (AOR 1.16, 95% CI 1.06-1.28), and to assess presence of publication bias (AOR 1.13, 95% CI 1.06-1.19), but were less likely to list both included and excluded studies (AOR 0.86, 95% CI 0.81-0.92). SRs published in journals with higher impact factor (AOR 1.14, 95% CI 1.04-1.25), completed by more review authors (AOR 1.12, 95% CI 1.01-1.24) and SRs on non-pharmacological treatments (AOR 1.62, 95% CI 1.01-2.59) were associated with better performance in publication bias assessment. CONCLUSION: The methodological quality of included SRs is disappointing. Future SRs should strive to improve rigour by considering of risk of bias when formulating conclusions, reporting conflict of interests and authors should explicitly describe harms. SR authors should also use appropriate methods to combine the results, prevent language and publication biases, and ensure timely updates.

Effectiveness of smartphone technologies on glycaemic control in patients with type 2 diabetes: systematic review with meta-analysis of 17 trials.

Patient education and behavioural interventions for self-management of type 2 diabetes mellitus (T2DM) are effective but place demands on manpower resources. This systematic review aimed to investigate the effectiveness of smartphone technologies (STs) for improving glycaemic control among T2DM patients. CENTRAL, MEDLINE, Embase, CINAHL and ScienceDirect were searched through December 2016. Randomized controlled trials comparing STs with usual diabetes care among T2DM patients and reporting change in glycated haemoglobin (HbA1c) level were included. Seventeen trials (2,225 participants) were included. There was a significant reduction in HbA1c (pooled weighted mean difference: -0.51%; 95% confidence interval: -0.71% to -0.30%; p < 0.001), favouring ST intervention. The pooled weighted mean difference was -0.83% in patients with T2DM <8.5 years and -0.22% in patients with T2DM ≥8.5 years, with significant subgroup difference (p = 0.007). No subgroup differences were found among different follow-up durations, trial locations, patients' age, healthcare provider contract time, baseline body mass index and baseline HbA1c. Compared with usual diabetes care, STs improved glycaemic control among T2DM patients, especially for patients at earlier disease stages (duration of diagnosis <8.5 years). STs could be a complement or alternative to labour-intensive patient education and behavioural interventions, but more studies on up-to-date technologies are needed.

Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification.

BACKGROUND: During primary infection of its human host, Herpes Simplex Virus Type-1 (HSV-1) establishes latency in neurons where the viral genome is maintained in a circular form associated with nucleosomes in a chromatin configration. During latency, most viral genes are silenced, although the molecular mechanisms responsible for this are unclear. We hypothesized that neuronal factors repress HSV-1 gene expression during latency. A search of the HSV-1 DNA sequence for potential regulatory elements identified a Repressor Element-1/Neuronal Restrictive Silencer Element (RE-1/NRSE) located between HSV-1 genes ICP22 and ICP4. We predicted that the Repressor Element Silencing Transcription Factor/Neuronal Restrictive Silencer Factor (REST/NRSF) regulates expression of ICP22 and ICP4. RESULTS: Transient cotransfection indicated that REST/NRSF inhibited the activity of both promoters. In contrast, cotransfection of a mutant form of REST/NRSF encoding only the DNA-binding domain of the protein resulted in less inhibition. Stably transformed cell lines containing episomal reporter plasmids with a chromatin structure showed that REST/NRSF specifically inhibited the ICP4 promoter, but not the ICP22 promoter. REST/NRSF inhibition of the ICP4 promoter was reversed by histone deacetylase (HDAC) inhibitor Trichostatin A (TSA). Additionally, chromatin immuno-precipitation (ChIP) assays indicated that the corepressor CoREST was recruited to the proximity of ICP4 promoter and that acetylation of histone H4 was reduced in the presence of REST/NRSF. CONCLUSION: Since the ICP4 protein is a key transactivator of HSV-1 lytic cycle genes, these results suggest that REST/NRSF may have an important role in the establishment and/or maintenance of HSV-1 gene silencing during latency by targeting ICP4 expression.

Receipt of thyroid hormone deficiency treatment and risk of herpes zoster.

OBJECTIVE: Thyroid hormone (TH) has been suggested to control herpes virus gene expression and replication in neurons via epigenetics through its nuclear receptors. It has previously been shown that patients with hypothyroidism are predisposed to herpes zoster (HZ), suggesting that the TH deficiency may be a risk factor for varicella zoster virus (VZV) reactivation. The aim of this study was to test the hypothesis that TH treatment will ameliorate the complication of HZ. METHODS: This study investigated the hypothesis by enquiring into a comprehensive medical database at Kaiser Permanente Southern California (KPSC) to verify whether patients taking TH medication experience a reduction in HZ occurrence. RESULTS: It was shown by Kaplan-Meier analysis that hypothyroidism patients taking TH medicines had a lower risk of HZ. The fully adjusted analysis indicated that patients receiving medication for the treatment of TH deficiency exhibited a reduced risk of HZ (hazard ratio 0.60, 95% confidence interval 0.51-0.71). This lower risk of HZ was significant in all age groups except the 18-39 years cohort. In addition, female patients taking TH treatment exhibited a lower risk than their male counterparts. CONCLUSIONS: Together these findings support the hypothesis that a constant level of TH will provide a degree of protection from contracting HZ. More studies are underway to evaluate the laboratory data for an analysis of hormonal effects on individuals.

Interplay of hot electrons from localized and propagating plasmons.

Plasmon-induced hot-electron generation has recently received considerable interest and has been studied to develop novel applications in optoelectronics, photovoltaics and green chemistry. Such hot electrons are typically generated from either localized plasmons in metal nanoparticles or propagating plasmons in patterned metal nanostructures. Here we simultaneously generate these heterogeneous plasmon-induced hot electrons and exploit their cooperative interplay in a single metal-semiconductor device to demonstrate, as an example, wavelength-controlled polarity-switchable photoconductivity. Specifically, the dual-plasmon device produces a net photocurrent whose polarity is determined by the balance in population and directionality between the hot electrons from localized and propagating plasmons. The current responsivity and polarity-switching wavelength of the device can be varied over the entire visible spectrum by tailoring the hot-electron interplay in various ways. This phenomenon may provide flexibility to manipulate the electrical output from light-matter interaction and offer opportunities for biosensors, long-distance communications, and photoconversion applications.Plasmon-induced hot electrons have potential applications spanning photodetection and photocatalysis. Here, Hoang et al. study the interplay between hot electrons generated by localized and propagating plasmons, and demonstrate wavelength-controlled polarity-switchable photoconductivity.

Massage intervention for promoting mental and physical health in infants aged under six months.

BACKGROUND: Infant massage is increasingly being used in the community for low-risk babies and their primary care givers. Anecdotal claims suggest benefits for sleep, respiration, elimination and the reduction of colic and wind. Infant massage is also thought to reduce infant stress and promote positive parent-infant interaction. OBJECTIVES: The aim of this review was to assess the effectiveness of infant massage in promoting infant physical and mental health in population samples. SEARCH STRATEGY: Searches were undertaken of CENTRAL 2005 (Issue 3), MEDLINE (1970 to 2005), PsycINFO (1970 to 2005), CINAHL (1982 to 2005), EMBASE (1980 to 2005), and a number of other Western and Chinese databases. SELECTION CRITERIA: Studies in which babies under the age of six months were randomised to an infant massage or a no-treatment control group, and utilising a standardised outcome measuring infant mental or physical development. DATA COLLECTION AND ANALYSIS: Weighted and standardised mean differences and 95% confidence intervals are presented. Where appropriate the results have been combined in a meta-analysis using a random effects model. MAIN RESULTS: Twenty-three studies were included in the review. One was a follow-up study and thirteen were included in a separate analysis due to concerns about the uniformly significant results and the lack of dropout. The results of nine studies providing primary data suggest that infant massage has no effect on growth, but provides some evidence suggestive of improved mother-infant interaction, sleep and relaxation, reduced crying and a beneficial impact on a number of hormones controlling stress. Results showing a significant impact on number of illnesses and clinic visits were limited to a study of Korean orphanage infants. There was no evidence of effects on cognitive and behavioural outcomes, infant attachment or temperament. The data from the 13 studies regarded to be at high risk of bias show uniformly significant benefits on growth, sleep, crying and bilirubin levels. AUTHORS' CONCLUSIONS: The only evidence of a significant impact of massage on growth was obtained from a group of studies regarded to be at high risk of bias. There was, however, some evidence of benefits on mother-infant interaction, sleeping and crying, and on hormones influencing stress levels. In the absence of evidence of harm, these findings may be sufficient to support the use of infant massage in the community, particularly in contexts where infant stimulation is poor. Further research is needed, however, before it will be possible to recommend universal provision.