Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer.

Small cell lung cancers (SCLC) are comprised of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLC, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes, including non-canonical BAF (ncBAF) complexes, as top dependencies specific to POU2F3-positive SCLC. Notably, clinical-grade pharmacologic mSWI/SNF inhibition attenuates proliferation of all POU2F3-positive SCLCs, while disruption of ncBAF via BRD9 degradation is uniquely effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, chemical targeting of SMARCA4/2 mSWI/SNF ATPases and BRD9 decrease POU2F3-SCLC tumor growth and increase survival in vivo . Taken together, these results characterize mSWI/SNF-mediated global governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for SCLC.

Corrigendum: Systematic review and meta-analysis of screening tools for language disorder.

[This corrects the article DOI: 10.3389/fped.2022.801220.].

Evaluating the Patient Boarding during Omicron Surge in Hong Kong: Time Series Analysis.

The fifth wave of COVID-19 outbreaks in Hong Kong (HK) from January to March 2022 has the highest confirmed cases and deaths compared with previous waves. Severe hospital boarding (to inpatient wards) was noted in various Emergency Departments (EDs). Our objective is to identify factors associated with hospital boarding during Omicron surge in HK. We conducted a retrospective cohort study including all ED visits and inpatient (IP) ward admissions from January 1st to March 31st, 2022. Vector Autoregression model evaluated the effects of a single variable on the targeted hospital boarding variables. Admissions from elderly homes with 6 lag days held the highest positive value of statistical significance (t-stat = 2.827, P < .05) caused prolonged admission waiting time, while medical patients with 4 lag days had the highest statistical significance (t-stat = 2.530, P < .05) caused an increased number of boarding patients. Within one week after impulses, medical occupancy's influence on the waiting time varied from 0.289 on the 1st day to -0.315 on the 7th day. While occupancy of medical wards always positively affected blocked number of patients, and its response was maximized at 0.309 on the 2nd day. Number of confirmed COVID-19 cases was not the sole significant contributor, while occupancy of medical wards was still a critical factor associated with patient boarding. Increasing ward capacity and controlling occupancy were suggested during the outbreak. Moreover, streamlining elderly patients in ED could be an approach to relieve pressure on the healthcare system.

Association of Molnupiravir and Nirmatrelvir-Ritonavir with reduced mortality and sepsis in hospitalized omicron patients: a territory-wide study.

This study evaluates the association between antivirals (Molnupiravir and Nirmatrelvir-Ritonavir) and all-cause and respiratory mortality and organ dysfunction among high-risk COVID-19 patients during an Omicron outbreak. Two cohorts, Nirmatrelvir-Ritonavir versus control and Molnupiravir versus control, were constructed with inverse probability treatment weighting to balance baseline characteristics. Cox proportional hazards models evaluated the association of their use with all-cause mortality, respiratory mortality, and all-cause sepsis (a composite of circulatory shock, respiratory failure, acute liver injury, coagulopathy, and acute liver impairment). Patients recruited were hospitalized and diagnosed with the COVID-19 Omicron variant between February 22, 2022 and April 15, 2022, and followed up until May 15, 2022. The study included 17,704 patients. There were 4.67 and 22.7 total mortalities per 1000 person-days in the Nirmatrelvir-Ritonavir and control groups respectively before adjustment (weighted incidence rate ratio, - 18.1 [95% CI - 23.0 to - 13.2]; hazard ratio, 0.18 [95% CI, 0.11-0.29]). There were 6.64 and 25.9 total mortalities per 1000 person-days in the Molnupiravir and control groups respectively before adjustment (weighted incidence rate ratio per 1000 person-days, - 19.3 [95% CI - 22.6 to - 15.9]; hazard ratio, 0.23 [95% CI 0.18-0.30]). In all-cause sepsis, there were 13.7 and 35.4 organ dysfunction events per 1000 person-days in the Nirmatrelvir-Ritonavir and control groups respectively before adjustment (weighted incidence rate ratio per 1000 person-days, - 21.7 [95% CI - 26.3 to - 17.1]; hazard ratio, 0.44 [95% CI 0.38-0.52]). There were 23.7 and 40.8 organ dysfunction events in the Molnupiravir and control groups respectively before adjustment (weighted incidence ratio per 1000 person-days, - 17.1 [95% CI, - 20.6 to - 13.6]; hazard ratio, 0.63 [95% CI 0.58-0.69]). Among COVID-19 hospitalized patients, use of either Nirmatrelvir-Ritonavir or Molnupiravir compared with no antiviral use was associated with a significantly lower incidence of 28-days all-cause and respiratory mortality and sepsis.

Enhancing Consumer Confidence and Response Efficacy in Tourism: Typology and Effectiveness of the Hotel Industry's Responses to COVID-19.

Although the tourism industry, including hotels, has been ravaged by the COVID-19 pandemic, few empirical studies have systematically examined the typology and effectiveness of their responses. To capture common response strategies within the hotel industry and assess their effectiveness, two studies were conducted. Study 1 adopted a hybrid approach involving deductive and inductive thematic analyses to evaluate 4,211 news articles. Five broad themes emerged: (1) revenue management, (2) crisis communication, (3) alternative approaches to service delivery, (4) human resource management, and (5) corporate social responsibility. Drawing upon protection motivation theory, Study 2 included a pre-test, pilot study, and main experimental study to examine the effectiveness of several common response strategies. Results showed that reassuring crisis communication and contactless services can foster consumer confidence and response efficacy, leading to positive consumers' attitudes and booking intentions. Crisis communication and price discount were found to influence consumers' attitudes and booking intentions directly.

Systematic Review and Meta-Analysis of Screening Tools for Language Disorder.

Language disorder is one of the most prevalent developmental disorders and is associated with long-term sequelae. However, routine screening is still controversial and is not universally part of early childhood health surveillance. Evidence concerning the detection accuracy, benefits, and harms of screening for language disorders remains inadequate, as shown in a previous review. In October 2020, a systematic review was conducted to investigate the accuracy of available screening tools and the potential sources of variability. A literature search was conducted using CINAHL Plus, ComDisCome, PsycInfo, PsycArticles, ERIC, PubMed, Web of Science, and Scopus. Studies describing, developing, or validating screening tools for language disorder under the age of 6 were included. QUADAS-2 was used to evaluate risk of bias in individual studies. Meta-analyses were performed on the reported accuracy of the screening tools examined. The performance of the screening tools was explored by plotting hierarchical summary receiver operating characteristic (HSROC) curves. The effects of the proxy used in defining language disorders, the test administrators, the screening-diagnosis interval and age of screening on screening accuracy were investigated by meta-regression. Of the 2,366 articles located, 47 studies involving 67 screening tools were included. About one-third of the tests (35.4%) achieved at least fair accuracy, while only a small proportion (13.8%) achieved good accuracy. HSROC curves revealed a remarkable variation in sensitivity and specificity for the three major types of screening, which used the child's actual language ability, clinical markers, and both as the proxy, respectively. None of these three types of screening tools achieved good accuracy. Meta-regression showed that tools using the child's actual language as the proxy demonstrated better sensitivity than that of clinical markers. Tools using long screening-diagnosis intervals had a lower sensitivity than those using short screening-diagnosis intervals. Parent report showed a level of accuracy comparable to that of those administered by trained examiners. Screening tools used under and above 4yo appeared to have similar sensitivity and specificity. In conclusion, there are still gaps between the available screening tools for language disorders and the adoption of these tools in population screening. Future tool development can focus on maximizing accuracy and identifying metrics that are sensitive to the dynamic nature of language development. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=210505, PROSPERO: CRD42020210505.

Brahma safeguards canalization of cardiac mesoderm differentiation.

Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1,2. Canalization is essential for stabilizing cell fate, but the mechanisms that underlie robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin-remodelling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite the establishment of a well-differentiated precardiac mesoderm, Brm-/- cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed a sudden acquisition of a non-mesodermal identity in Brm-/- cells. Mechanistically, the loss of Brm prevented de novo accessibility of primed cardiac enhancers while increasing the expression of neurogenic factor POU3F1, preventing the binding of the neural suppressor REST and shifting the composition of BRG1 complexes. The identity switch caused by the Brm mutation was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modelling supports these observations and demonstrates that Brm deletion affects cell fate trajectory by modifying saddle-node bifurcations2. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1-mutant phenotypes, severely compromising cardiogenesis, and reveals an in vivo role for Brm. Our results show that Brm is a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.

68Ga-PSMA-PET screening and transponder-guided salvage radiotherapy to the prostate bed alone for biochemical recurrence following prostatectomy: interim outcomes of a phase II trial.

PURPOSE: To evaluate outcomes for men with biochemically recurrent prostate cancer who were selected for transponder-guided salvage radiotherapy (SRT) to the prostate bed alone by 68Ga-labelled prostate-specific membrane antigen positron emission tomography (68Ga-PSMA-PET). METHODS: This is a single-arm, prospective study of men with a prostate-specific antigen (PSA) level rising to 0.1-2.5 ng/mL following radical prostatectomy. Patients were staged with 68Ga-PSMA-PET and those with a negative finding, or a positive finding localised to the prostate bed, continued to SRT only to the prostate bed alone with real-time target-tracking using electromagnetic transponders. The primary endpoint was freedom from biochemical relapse (FFBR, PSA > 0.2 ng/mL from the post-radiotherapy nadir). Secondary endpoints were time to biochemical relapse, toxicity and patient-reported quality of life (QoL). RESULTS: Ninety-two patients (median PSA of 0.18 ng/ml, IQR 0.12-0.36), were screened with 68Ga-PSMA-PET and metastatic disease was found in 20 (21.7%) patients. Sixty-nine of 72 non-metastatic patients elected to proceed with SRT. At the interim (3-year) analysis, 32 (46.4%) patients (95% CI 34.3-58.8%) were FFBR. The median time to biochemical relapse was 16.1 months. The rate of FFBR was 82.4% for ISUP grade-group 2 patients. Rates of grade 2 or higher gastrointestinal and genitourinary toxicity were 0% and 15.2%, respectively. General health and disease-specific QoL remained stable. CONCLUSION: Pre-SRT 68Ga-PSMA-PET scans detect metastatic disease in a proportion of patients at low PSA levels but fail to improve FFBR. Transponder-guided SRT to the prostate bed alone is associated with a favourable toxicity profile and preserved QoL. TRIAL REGISTRATION NUMBER: ACTRN12615001183572, 03/11/2015, retrospectively registered.

Molecular basis of CTCF binding polarity in genome folding.

Current models propose that boundaries of mammalian topologically associating domains (TADs) arise from the ability of the CTCF protein to stop extrusion of chromatin loops by cohesin. While the orientation of CTCF motifs determines which pairs of CTCF sites preferentially stabilize loops, the molecular basis of this polarity remains unclear. By combining ChIP-seq and single molecule live imaging we report that CTCF positions cohesin, but does not control its overall binding dynamics on chromatin. Using an inducible complementation system, we find that CTCF mutants lacking the N-terminus cannot insulate TADs properly. Cohesin remains at CTCF sites in this mutant, albeit with reduced enrichment. Given the orientation of CTCF motifs presents the N-terminus towards cohesin as it translocates from the interior of TADs, these observations explain how the orientation of CTCF binding sites translates into genome folding patterns.

Elimination of Calm1 long 3'-UTR mRNA isoform by CRISPR-Cas9 gene editing impairs dorsal root ganglion development and hippocampal neuron activation in mice.

The majority of mouse and human genes are subject to alternative cleavage and polyadenylation (APA), which most often leads to the expression of two or more alternative length 3' untranslated region (3'-UTR) mRNA isoforms. In neural tissues, there is enhanced expression of APA isoforms with longer 3'-UTRs on a global scale, but the physiological relevance of these alternative 3'-UTR isoforms is poorly understood. Calmodulin 1 (Calm1) is a key integrator of calcium signaling that generates short (Calm1-S) and long (Calm1-L) 3'-UTR mRNA isoforms via APA. We found Calm1-L expression to be largely restricted to neural tissues in mice including the dorsal root ganglion (DRG) and hippocampus, whereas Calm1-S was more broadly expressed. smFISH revealed that both Calm1-S and Calm1-L were subcellularly localized to neural processes of primary hippocampal neurons. In contrast, cultured DRG showed restriction of Calm1-L to soma. To investigate the in vivo functions of Calm1-L, we implemented a CRISPR-Cas9 gene editing strategy to delete a small region encompassing the Calm1 distal poly(A) site. This eliminated Calm1-L expression while maintaining expression of Calm1-S Mice lacking Calm1-L (Calm1ΔL/ΔL ) exhibited disorganized DRG migration in embryos, and reduced experience-induced neuronal activation in the adult hippocampus. These data indicate that Calm1-L plays functional roles in the central and peripheral nervous systems.

Fractionated stereotactic body radiotherapy for up to five prostate cancer oligometastases: Interim outcomes of a prospective clinical trial.

Stereotactic body radiotherapy (SBRT) can delay escalation to systemic treatment in men with oligometastatic prostate cancer (PCa). However, large, prospective studies are still required to evaluate the efficacy of this approach in different patient groups. This is the interim analysis of a prospective, single institution study of men relapsing with up to five synchronous lesions following definitive local treatment for primary PCa. Our aim was to determine the proportion of patients not requiring treatment escalation following SBRT. In total, 199 patients were enrolled to receive fractionated SBRT (50 Gray in 10 fractions) to each visible lesion. Fourteen patients were castration resistant at enrolment. The proportion of patients not requiring treatment escalation 2 years following SBRT was 51.7% (95% CI: 44.1-59.3%). The median length of treatment escalation-free survival over the entire follow-up period was 27.1 months (95% CI; 21.8-29.4 months). Prior androgen deprivation therapy (ADT) predicted a significantly lower rate of freedom from treatment escalation at 2 years compared to no prior ADT (odds ratio = 0.21, 95% CI: 0.08-0.54, p = 0.001). There was no difference in the efficacy of SBRT when treating 4-5 vs. 1-3 initial lesions. A prostate-specific antigen (PSA) decline was induced in 75% of patients, with PSA readings falling to an undetectable level in six patients. No late grade three toxicities were observed. These interim results suggest that SBRT can be used to treat up to five synchronous PCa oligometastases to delay treatment escalation.

Elav-Mediated Exon Skipping and Alternative Polyadenylation of the Dscam1 Gene Are Required for Axon Outgrowth.

Many metazoan genes express alternative long 3' UTR isoforms in the nervous system, but their functions remain largely unclear. In Drosophila melanogaster, the Dscam1 gene generates short and long (Dscam1-L) 3' UTR isoforms because of alternative polyadenylation (APA). Here, we found that the RNA-binding protein Embryonic Lethal Abnormal Visual System (Elav) impacts Dscam1 biogenesis at two levels, including regulation of long 3' UTR biogenesis and skipping of an upstream exon (exon 19). MinION long-read sequencing confirmed the connectivity of this alternative splicing event to the long 3' UTR. Knockdown or CRISPR deletion of Dscam1-L impaired axon outgrowth in Drosophila. The Dscam1 long 3' UTR was found to be required for correct Elav-mediated skipping of exon 19. Elav thus co-regulates APA and alternative splicing to generate specific Dscam1 transcripts that are essential for neural development. This coupling of APA to alternative splicing might represent a new class of regulated RNA processing.

Small-molecule anticancer agents kill cancer cells by harnessing reactive oxygen species in an iron-dependent manner.

In the course of generating a library of open-chain epothilones, we discovered a new class of small molecule anticancer agents that has no effect on tubulin but instead kills selected cancer cell lines by harnessing reactive oxygen species in an iron-dependent manner. Results of the preliminary studies are consistent with the recently described cell death mechanism ferroptosis. Studies are in progress to confirm ferroptosis as the cell death mechanism and to identify the specific molecular targets of these small molecule anticancer agents.

Evaluation of the preimplantation worksheet in determining Calypso eligibility for men prescribed postprostatectomy radiotherapy with electromagnetic transponder guidance.

This study aimed to assess the design and performance of the preimplant suitability worksheet in determining Calypso eligibility for prostate cancer patients prescribed postprostatectomy radiotherapy with electromagnetic transponder guidance. The medical records and radiotherapy planning datasets of 75 patients prospectively recruited between June 2015 and September 2016 to a Phase 2 trial evaluating electromagnetic transponder-guided postprostatectomy radiotherapy were retrospectively examined. Correlation and differences between computed tomography (CT)-defined greater trochanter and prostatic fossa landmarks were evaluated. Receiver operating characteristic curves were also generated to assess the expected and observed accuracy of the worksheet in determining Calypso eligibility. Strong correlation was demonstrated between anterior surface to planning CT-defined greater trochanter and prostate bed center distances (r = 0.95, p <0.001), with a mean difference between measurements of 1.1 cm (95% confidence interval [CI]: 0.9 to 1.3). A similar correlation coefficient was found for surface to greater trochanter location and posterior beacon location (r = 0.92, p <0.001) but with a reduced mean difference of 0.4 cm (95% CI: 0.1 to 0.6). Performance of the worksheet as assessed by planning CT data demonstrated excellent accuracy as a test to determine eligibility (area under the curve: 0.97; 95% CI: 0.92 to 1.00); however, this was not replicated using the same data captured clinically (area under the curve 0.83; 95% CI: 0.68 to 0.98). Although the greater trochanter is a good surrogate for the prostate bed center, it is better associated with the posterior beacon location. As a result, the worksheet will underestimate the truly eligible population if performed accurately and according to manufacturer guidelines. Theoretically, the worksheet could be improved if a cut off of 20 cm is used and the greater trochanter is accurately identified; however, the latter appears to be difficult to achieve in practice.

Radiotherapy in anaplastic thyroid carcinoma: An Australian experience.

INTRODUCTION: Anaplastic thyroid cancer is a rare and fatal malignancy, associated with significant local tumour and often treatment related morbidity. We report our experience in treating this cancer over a 20-year period. METHODS: A retrospective review of prospectively collected data from a single Australian Institution (Alfred Health Radiation Oncology) was carried out on patients referred with anaplastic thyroid carcinoma between 1992 and 2013. RESULTS: Thirty patients (17 females and 13 males) were identified with a median age at presentation of 72 years. At presentation, six (20%), 14 (47%) and 10 (33%) patients had stage IVA, IVB and IVC disease respectively. Thirteen patients underwent radical surgical resection with five having microscopic residual (R1) and eight having macroscopic residual (R2) disease. Twenty-eight patients were offered radiotherapy with 27 proceeding with treatment. Of those who received radiotherapy, three, six and 18 were treated with adjuvant, definitive and palliative intent respectively. Six patients had concomitant chemotherapy of which three received trimodality therapy. Only one patient experienced a grade 3 toxicity (oesophagitis). Median survival was 5.3 months and at last follow-up or time of death, 19 of 27 (70.4%) maintained loco-regional control. All patients who had R1 surgical resections and radiotherapy had loco-regional control. Seven of nine (77.8%) and 12 of 18 (66.7%) achieved loco-regional control after receiving definitive or palliative radiotherapy, respectively. CONCLUSIONS: Our study suggests that radiotherapy with or without surgery or chemotherapy is well-tolerated and results in durable loco-regional control in a high proportion of patients with anaplastic thyroid carcinoma.

Radiotherapy in well-differentiated thyroid cancer: is it underutilized?

BACKGROUND: The usual management of thyroid cancer is surgery and radioactive iodine. The role of external beam radiotherapy (EBRT) in well-differentiated thyroid carcinoma remains controversial. Indications for the use of EBRT, contained within both the American and British Thyroid Association published guidelines, include unresectable or non-iodine avid disease, extra-thyroidal extension or distant metastatic disease. METHODS: A retrospective review of prospectively collected data from a single Australian institution was conducted, analysing patients referred and treated with EBRT for well-differentiated thyroid carcinoma between November 1992 and July 2013. RESULTS: Of 36 patients referred, 32 were treated with EBRT. Sixteen patients in total received locoregional treatment (six radical, 10 palliative), of whom 81% (13/16) had gross disease and 88% (14/16) had recurrent disease (eight with multiple recurrences). Additionally, 63% (10/16) had multiple surgical resections and 50% (8/16) had previously received multiple courses of radioactive iodine. Overall, 67% (4/6) of patients treated with radical intent had no locoregional recurrence or progression. Thirteen of the 16 patients who received locoregional EBRT remained asymptomatic from their locoregional disease at the time of last follow-up or death. The most commonly treated distant metastatic disease site was bone, with a total of 45 sites irradiated. Of these patients, 93% and 78% were symptom-free at two and four years, respectively. CONCLUSION: Our study suggests that in a select group of patients with well-differentiated thyroid carcinoma, EBRT treatment appears to provide durable tumour and symptom control.

MBD4-mediated glycosylase activity on a chromatin template is enhanced by acetylation.

The ability of the MBD4 glycosylase to excise a mismatched base from DNA has been assessed in vitro using DNA substrates with different extents of cytosine methylation, in the presence or absence of reconstituted nucleosomes. Despite the enhanced ability of MBD4 to bind to methylated cytosines, the efficiency of its glycosylase activity on T/G mismatches was slightly dependent on the extent of methylation of the DNA substrate. The reduction in activity caused by competitor DNA was likewise unaffected by the methylation status of the substrate or the competitor. Our results also show that MBD4 efficiently processed T/G mismatches within the nucleosome. Furthermore, the glycolytic activity of the enzyme was not affected by the positioning of the mismatch within the nucleosome. However, histone hyperacetylation facilitated the efficiency with which the bases were excised from the nucleosome templates, irrespective of the position of the mismatch relative to the pseudodyad axis of symmetry of the nucleosome.

Relationship between sleep/wake patterns, temperament and overall development in term infants over the first year of life.

BACKGROUND: This study sought to assess the relationship between the development of infant sleep/wake patterns, temperament and overall mental, motor and behavioural development over the first year of life. We hypothesised that infants with more regular sleep/wake patterns and longer sleep durations would have an easier temperament and higher developmental scores. STUDY DESIGN: Sleep/wake characteristics were recorded with the use of both parental sleep diary and actigraphy (Actiwatch AW64, Mini Mitter Company Inc, Sunriver, OR, USA) in 20 healthy term infants at monthly intervals over the first year of life. Temperament was assessed using the Early Infant Temperament Questionnaire (EITQ) at 3 months and the Revised Infant Temperament Questionnaire (RITQ) at 6 and 11 months and mental, motor and behavioural development at 12 months using the Bayley Scales of Infant Development II (BSID-II). RESULTS: At all 3 ages studied increased nocturnal sleep was correlated with increased approachability. In addition, at 11 months increased diurnal sleep duration was also correlated with increased rhythmicity and adaptability. At 12 months of age decreased daytime sleep duration was correlated with emotional regulation. CONCLUSIONS: Our findings highlight the importance of considering maturational and regulatory aspects of sleep when evaluating infant daytime behaviour. We suggest that concerns regarding sleep characteristics should become a significant aspect of clinical assessment and diagnosis of developmental delay or behaviour problems, particularly in the first year of life.

The use of actigraphy for assessment of the development of sleep/wake patterns in infants during the first 12 months of life.

Maturation of sleep/wake patterns is one of the most important physiological developments during the first year of life. In this study, we aimed to compare the use of actigraphy and parental sleep diaries (SD) for recording the development of sleep/wake patterns longitudinally in term infants in their own home environments over the first 12 months of life. Twenty healthy term infants (7F/13M) were studied for 3 days each month in their own homes over the first 12 months of life. Sleep/wake patterns were recorded using both SD and actigraphy (AW) (AW64, Mini Mitter Co. Inc., Sunriver, OR, USA). The development of sleep and wake was analysed over 24 h, during the day (08:00-20:00 hours) and during the night (20:00-08:00 hours). A total of 186 studies had complete data sets for both analysis methods. Overall, there was no difference between methods of measurement for determination of the total percentage of sleep or wake over 24 h, or for the total percentage of sleep or wake during the day. However, at night, AW scored less time asleep (73.3 +/- 0.9%) and more time awake (26.7 +/- 0.9%) compared with the SD (80.7 +/- 1.04% and 19 +/- 1.0%, respectively, P < 0.001). Mean percentage sleep during the day decreased from 51% at 1 month to 28% at 12 months with the 1-month values being significantly higher than all other ages, while mean percentage sleep at night was only different between 1 month and 11 and 12 months. In conclusion actigraphy provides a useful tool for assessing the development infant sleep.