Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

Safety and Efficacy of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem From a Phase 2, Randomized Clinical Trial in Pediatric Participants With Complicated Intra-abdominal Infection.

BACKGROUND: Ceftolozane/tazobactam, a cephalosporin-ß-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections (cIAI). The safety and efficacy of ceftolozane/tazobactam in pediatric participants with cIAI were assessed. METHODS: This phase 2 study (NCT03217136) randomized participants to either ceftolozane/tazobactam+metronidazole or meropenem for treatment of cIAI in pediatric participants (<18 years). The primary objective was to assess the safety and tolerability of intravenous ceftolozane/tazobactam+metronidazole. Clinical cure at end of treatment (EOT) and test of cure (TOC) visits were secondary end points. RESULTS: The modified intent-to-treat (MITT) population included 91 participants (ceftolozane/tazobactam+metronidazole, n = 70; meropenem, n = 21). Complicated appendicitis was the most common diagnosis (93.4%); Escherichia coli was the most common pathogen (65.9%). Adverse events (AEs) occurred in 80.0% and 61.9% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, drug-related AEs occurred in 18.6% and 14.3% and serious AEs occurred in 11.4% and 0% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, respectively. No drug-related serious AEs or discontinuations due to drug-related AEs occurred. Rates of the clinical cure for ceftolozane/tazobactam+metronidazole and meropenem at EOT were 80.0% and 95.2% (difference: -14.3; 95% confidence interval: -26.67 to 4.93) and at TOC were 80.0% and 100.0% (difference: -19.1; 95% confidence interval: -30.18 to -2.89), respectively; 6 of the 14 clinical failures for ceftolozane/tazobactam+metronidazole at TOC were indeterminate responses imputed as failures per protocol. CONCLUSION: Ceftolozane/tazobactam+metronidazole was well tolerated in pediatric participants with cIAI and had a safety profile similar to the established safety profile in adults. In this descriptive efficacy analysis, ceftolozane/tazobactam+metronidazole appeared efficacious.

Complex combined steroid mix of the female tract modulates human sperm.

Human spermatozoa interact with a complex biochemical environment in the female reproductive tract en route to the site of fertilisation. Ovarian follicular fluid contributes to this complex milieu and is known to contain steroids such as progesterone, whose effects on sperm physiology have been widely characterised. We have previously reported that progesterone stimulates intracellular calcium concentration ([Ca2+]i) signalling and acrosome reaction in human spermatozoa. To characterise the effects of the unified complete follicular fluid steroid hormone complement on human spermatozoa, a comprehensive, data-based, 'physiological standard' steroid hormone balance of follicular fluid (shFF) was created from individual constituents. shFF induced a rapid biphasic [Ca2+]i elevation in human spermatozoa. Using population fluorimetry, we compared [Ca2+]i signal amplitude in cells exposed to serial applications of shFF (6 steps from 10-5X up to 1X shFF) with responses to the equivalent progesterone component alone (6 steps from 135 pM - 13.5µM). Threshold for the response to shFF was right-shifted (≈10-fold) compared to progesterone alone, but the maximum response to shFF was greatly enhanced. An acrosome reaction assay was used to assess functional effects of shFF-induced sperm calcium signalling. shFF as well as progesterone-treated spermatozoa showed a significant increase in % acrosome reaction (P < 0.01). All of this evidence suggests the modulation of progesterone-mediated responses by other follicular fluid steroids.

Unintentional Window Falls in Children and Adolescents.

OBJECTIVE: Unintentional window falls represent a preventable source of injury and death in children. Despite major campaigns in some larger cities, there continue to be unintentional falls from windows throughout the United States. We aimed to identify risk factors and trends in unintentional window falls in the pediatric population in a national and regional sample. METHODS: A retrospective analysis of annual emergency department (ED) visits from the National Electronic Injury Surveillance System using product codes specific to windows, as well as patient encounters for unintentional window falls from January 2007 to August 2017 using site-specific trauma registries from 10 tertiary care children's hospitals in New England. National and state-specific census population estimates were used to compute rates per 100,000 population. RESULTS: There were 38,840 ED visits and 496 regional patients who unintentionally fell from a window across the study period between 0 and 17 years old. The majority of falls occurred in children under the age of 6 and were related to falls from a second story or below. A decreased trend in national ED visits was seen, but no change in rates over time for regional trauma center encounters. A high number of falls was found to occur in smaller cities surrounding metropolitan areas and from single family residences. CONCLUSIONS: Falls from windows represent a low proportion of overall types of unintentional sources of injury in children but are a high risk for severe disability. These results provide updated epidemiologic data for targeted intervention programs, as well as raise awareness for continued education and advocacy.

Comparative analysis of traumatic esophageal injury in pediatric and adult populations.

PURPOSE: Distribution and outcomes of traumatic injury of the esophagus (TIE) in pediatric versus adult populations are unknown. Our study sought to perform a descriptive analysis of TIE in children and adults. METHODS: We reviewed the National Trauma Data Bank (NTDB) for the years 2010-2015. Demographics, characteristics, and outcomes of pediatric (age < 16 years) and adult TIE patients were described and compared. RESULTS: Among 526,850 pediatric and 3,838,895 adult trauma patients, 90 pediatric (0.02%) and 1,411 (0.04%) adult TIE patients were identified. Demographics and esophageal injury severity did not differ. Children were more likely to sustain blunt trauma (63% versus 37%), with the most common mechanism being transportation-related accidents, were less-severely injured (median ISS 14 versus 22), and had fewer associated injuries (79% versus 95%) and complications (30% versus 51%) (all p < 0.001). Children had shorter hospitalizations (median 5 versus 10 days) and were more likely to be discharged home (84% versus 64%) (both p = 0.01). In-hospital mortality did not differ significantly between children and adults (10% versus 19%, p = 0.09). CONCLUSION: TIE in the pediatric population has unique characteristics compared to adults: it is more likely to be a result of blunt trauma, has lower injury burden, and has more favorable clinical outcomes.

The MINDVIEW project: First results.

We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from 11C-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that 11C-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naïve, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia.

Esophageal duplication cysts and closure of the muscle layer.

BACKGROUND: Foregut duplication cysts are rare congenital anomalies that require surgical intervention with approximately 10%-15% of all gastrointestinal duplication cysts originating from the esophagus. Consensus is lacking among surgeons regarding closure of the esophageal muscle layer after resection of an esophageal duplication cyst and long-term outcomes are poorly documented. Therefore, we conducted the first study comparing complication rates in patients undergoing closure versus nonclosure of the esophageal muscle layer after esophageal duplication cyst resection. MATERIALS AND METHODS: A retrospective cohort study at Boston Children's Hospital, Massachusetts General Hospital, Brigham and Women's Hospital, and the Floating Hospital for Children at Tufts Medical Center was conducted. Patients undergoing resection of esophageal duplication cysts between 1990 and 2012 were classified according to whether the esophageal muscle layer was closed or left open. Demographic data, surgical technique, preoperative symptoms, and both short-term (<30 d) and long-term (≥30 d) complication rates were abstracted from patient medical records. RESULTS: Twenty-five patients were identified with a median age of 15-y old (range, 2 mo to 68-y old) and an average follow-up of 1 y. Eleven patients had the esophageal muscle layer closed after surgical resection (44%). Of those 11 patients, one developed a short-term complication, dysphagia (9%, 95% CI: 2%, 38%). Only one patient returned to the operating room, after 30 d, for an upper endoscopy after developing symptoms of gastroesophageal reflux disease. Of the 14 patients who had their muscle layer left open, three patients (21%, 95% CI: 8%, 48%) developed short-term complications, two of whom required surgical intervention within 30 d. Furthermore, two additional patients required surgical intervention after 30 d for a long-term complication (diverticulum and cyst recurrence). CONCLUSIONS: Surgical complications occurred more frequently in patients who had the muscle layer left open after resection of an esophageal duplication cyst. In addition, most patients requiring reoperation for both short-term and long-term complications occurred in this group. Though small, this study is the first to evaluate the complications after resecting esophageal duplication cysts. Our results suggest that closing the esophageal muscle layer after removal of an esophageal duplication cyst may be indicated to prevent both complications and the need for reoperations.

Characterization of Large-Area SiPM Array for PET Applications.

The performance of an 8 × 8 array of 6.0 × 6.0 mm2 (active area) SiPMs was evaluated for PET applications using crystal arrays with different pitch sizes (3.4 mm, 1.5 mm, 1.35 mm and 1.2 mm) and custom designed five-channel front-end readout electronics (four channels for position information and one channel for timing information). The total area of this SiPM array is 57.4 × 57.4 mm2, and the pitch size is 7.2 mm. It was fabricated using enhanced blue sensitivity SiPMs (MicroFB-60035-SMT) with peak spectral sensitivity at 420 nm. The performance of the SiPM array was characterized by measuring flood histogram decoding quality, energy resolution, timing resolution and saturation at several bias voltages (from 25.0 V to 30.0 V in 0.5 V intervals) and two different temperatures (5 °C and 20 °C). Results show that the best flood histogram was obtained at a bias voltage of 28.0 V and 5 °C and an array of polished LSO crystals with a pitch as small as 1.2 mm can be resolved. No saturation was observed up to a bias voltage of 29.5 V during the experiments, due to adequate light sharing between SiPMs. Energy resolution and timing resolution at 5 °C ranged from 12.7 ± 0.8% to 14.6 ± 1.4 % and 1.58 ± 0.13 ns to 2.50 ± 0.44 ns, for crystal array pitch sizes of 3.4 mm and 1.2 mm respectively. Superior flood histogram quality, energy resolution and timing resolution were obtained with larger crystal array pitch sizes and at lower temperature. Based on our findings, we conclude that this large-area SiPM array can serve as a suitable photodetector for high-resolution small-animal PET or dedicated human brain PET scanners.

The ABCC4 membrane transporter modulates platelet aggregation.

Controlling the activation of platelets is a key strategy to mitigate cardiovascular disease. Previous studies have suggested that the ATP-binding cassette (ABC) transporter, ABCC4, functions in platelet-dense granules. Using plasma membrane biotinylation and super-resolution microscopy, we demonstrate that ABCC4 is primarily expressed on the plasma membrane of both mouse and human platelets. Platelets lacking ABCC4 have unchanged dense-granule function, number, and volume, but harbor a selective impairment in collagen-induced aggregation. Accordingly, Abcc4 knockout (KO) platelet attachment to a collagen substratum was also faulty and associated with elevated intracellular cyclic AMP (cAMP) and reduced plasma membrane localization of the major collagen receptor, GPVI. In the ferric-chloride vasculature injury model, Abcc4 KO mice exhibited markedly impaired thrombus formation. The attenuation of platelet aggregation by the phosphodiesterase inhibitor EHNA (a non-ABCC4 substrate), when combined with Abcc4 deficiency, illustrated a crucial functional interaction between phosphodiesterases and ABCC4. This was extended in vivo where EHNA dramatically prolonged the bleeding time, but only in Abcc4 KO mice. Further, we demonstrated in human platelets that ABCC4 inhibition, when coupled with phosphodiesterase inhibition, strongly impaired platelet aggregation. These findings have important clinical implications because they directly highlight an important relationship between ABCC4 transporter function and phosphodiesterases in accounting for the cAMP-directed activity of antithrombotic agents.

Early Closure of Gastroschisis After Silo Placement Correlates with Earlier Enteral Feeding.

OBJECTIVES: Gastroschisis is a congenital anomaly affecting 2.3-4.4/10,000 births. Previous studies show initiation of early enteral feeds predicts improved outcomes. We hypothesize that earlier definitive closure after silo placement; can lead to earlier enteral feed initiation. Design/ Setting/ Duration: Retrospective review of patients with gastroschisis from 2005 and 2014 at a single institution. MATERIAL AND METHODS: The data, including ethnicity, gestational age, birth weight, time to definitive closure, and time of first and full feeds, were analyzed using both Spearman's rho and the Kruskal-Wallis rank sum test where appropriate; a p value less than 0.05 was considered significant. RESULTS: Forty-three patients (24 males, 19 females) born with gastroschisis were identified. Overall survival rate was 88% (38/43). Forty of the 43 patients had a silo placed prior to definitive closure. Median days to closure were 6 (0 to 85) days. First feeds on average began on day of life (DOL) 17, and full feeds on DOL 25. Earlier closure of gastroschisis correlated with early initiation of feeds (p=0.0001) and shorter time to full feeds (p=0.018), closure by DOL4 showed a trend toward earlier feeding (p=0.13). CONCLUSION: Earlier closure of gastroschisis after silo placement was associated with earlier feed initiation and shorter time to full feeds.

Evaluation of Matrix9 silicon photomultiplier array for small-animal PET.

PURPOSE: The MatrixSL-9-30035-OEM (Matrix9) from SensL is a large-area silicon photomultiplier (SiPM) photodetector module consisting of a 3 × 3 array of 4 × 4 element SiPM arrays (total of 144 SiPM pixels) and incorporates SensL's front-end electronics board and coincidence board. Each SiPM pixel measures 3.16 × 3.16 mm(2) and the total size of the detector head is 47.8 × 46.3 mm(2). Using 8 × 8 polished LSO/LYSO arrays (pitch 1.5 mm) the performance of this detector system (SiPM array and readout electronics) was evaluated with a view for its eventual use in small-animal positron emission tomography (PET). METHODS: Measurements of noise, signal, signal-to-noise ratio, energy resolution, flood histogram quality, timing resolution, and array trigger error were obtained at different bias voltages (28.0-32.5 V in 0.5 V intervals) and at different temperatures (5 °C-25 °C in 5 °C degree steps) to find the optimal operating conditions. RESULTS: The best measured signal-to-noise ratio and flood histogram quality for 511 keV gamma photons were obtained at a bias voltage of 30.0 V and a temperature of 5 °C. The energy resolution and timing resolution under these conditions were 14.2% ± 0.1% and 4.2 ± 0.1 ns, respectively. The flood histograms show that all the crystals in the 1.5 mm pitch LSO array can be clearly identified and that smaller crystal pitches can also be resolved. Flood histogram quality was also calculated using different center of gravity based positioning algorithms. Improved and more robust results were achieved using the local 9 pixels for positioning along with an energy offset calibration. To evaluate the front-end detector readout, and multiplexing efficiency, an array trigger error metric is introduced and measured at different lower energy thresholds. Using a lower energy threshold greater than 150 keV effectively eliminates any mispositioning between SiPM arrays. CONCLUSIONS: In summary, the Matrix9 detector system can resolve high-resolution scintillator arrays common in small-animal PET with adequate energy resolution and timing resolution over a large detector area. The modular design of the Matrix9 detector allows it to be used as a building block for simple, low channel-count, yet high performance, small animal PET or PET/MRI systems.

Management of patients with combined tracheoesophageal fistula, esophageal atresia, and duodenal atresia.

INTRODUCTION: Patients with combined esophageal atresia (EA), tracheoesophageal fistula (TEF), and duodenal atresia (DA) pose a rare management challenge. PRESENTATION OF CASE: Three patients with combined esophageal atresia (EA), tracheoesophageal fistula (TEF), and duodenal atresia safely underwent a staged approach inserting a gastrostomy tube and repairing the EA/TEF first followed by a duodenoduodenostomy within one week. None of the patients suffered significant pre- or post-operative complications and our follow-up data (between 12 and 24 months) suggest that all patients eventually outgrow their reflux and respiratory symptoms. DISCUSSION: While some authors support repair of all defects in one surgery, we recommend a staged approach. A gastrostomy tube is placed first for gastric decompression before TEF ligation and EA repair can be safely undertaken. The repair of the DA can then be performed within 3-7 days under controlled circumstances. CONCLUSION: A staged approach of inserting a gastrostomy tube and repairing the EA/TEF first followed by a duodenoduodenostomy within one week resulted in excellent outcomes.

Sensory-motor deficits in children with fetal alcohol spectrum disorder assessed using a robotic virtual reality platform.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is associated with a large number of cognitive and sensory-motor deficits. In particular, the accurate assessment of sensory-motor deficits in children with FASD is not always simple and relies on clinical assessment tools that may be coarse and subjective. Here we present a new approach: using robotic technology to accurately and objectively assess motor deficits of children with FASD in a center-out reaching task. METHODS: A total of 152 typically developing children and 31 children with FASD, all aged between 5 and 18 were assessed using a robotic exoskeleton device coupled with a virtual reality projection system. Children made reaching movements to 8 peripheral targets in a random order. Reach trajectories were subsequently analyzed to extract 12 parameters that had been previously determined to be good descriptors of a reaching movement, and these parameters were compared for each child with FASD to a normative model derived from the performance of the typically developing population. RESULTS: Compared with typically developing children, the children with FASD were found to be significantly impaired on most of the parameters measured, with the greatest deficits found in initial movement direction error. Also, children with FASD tended to fail more parameters than typically developing children: 95% of typically developing children failed fewer than 3 parameters compared with 69% of children with FASD. These results were particularly pronounced for younger children. CONCLUSIONS: The current study has shown that robotic technology is a sensitive and powerful tool that provides increased specificity regarding the type of motor problems exhibited by children with FASD. The high frequency of motor deficits in children with FASD suggests that interventions aimed at stimulating and/or improving motor development should routinely be considered for this population.

Management of pediatric patients with refractory constipation who fail cecostomy.

BACKGROUND: Antegrade continence enema (ACE) is a recognized therapeutic option in the management of pediatric refractory constipation. Data on the long-term outcome of patients who fail to improve after an ACE-procedure are lacking. PURPOSE: To describe the rate of ACE bowel management failure in pediatric refractory constipation, and the management and long term outcome of these patients. METHODS: Retrospective analysis of a cohort of patients that underwent ACE-procedure and had at least 3-year-follow-up. Detailed analysis of subsequent treatment and outcome of those patients with a poor functional outcome was performed. RESULTS: 76 patients were included. 12 (16%) failed successful bowel management after ACE requiring additional intervention. Mean follow-up was 66.3 (range 35-95 months) after ACE-procedure. Colonic motility studies demonstrated colonic neuropathy in 7 patients (58%); abnormal motility in 4 patients (33%), and abnormal left-sided colonic motility in 1 patient (9%). All 12 patients were ultimately treated surgically. Nine patients (75%) had marked clinical improvement, whereas 3 patients (25%) continued to have poor function issues at long term follow-up. CONCLUSIONS: Colonic resection, either segmental or total, led to improvement or resolution of symptoms in the majority of patients who failed cecostomy. However, this is a complex and heterogeneous group and some patients will have continued issues.

Spontaneous hemothorax in multiple exostoses: a case report and review of literature.

Abstract Multiple hereditary exostoses is a rare autosomal dominant disorder characterized by the growth of multiple osteochondromas. We describe the thoracoscopic remodeling of a spiculated costal exostotic lesion responsible for spontaneous recurrent hemothoraces in a 17-year-old male patient with multiple hereditary exostoses.

Illusory force perception following a voluntary limb movement.

We present a novel illusion in which participants report constant forces on their hand as steadily increasing. Participants made discrete reaching movements perturbed by a lateral force that increased with the distance moved; when stationary at the end of the movement, a true constant force was perceived to increase. We tested perceived subjective equality by increasing or decreasing the force. The illusion was significantly stronger when the perturbation was applied during active movement. We conclude that the unusual context of moving against lateral spring forces results in participants failing to predict steady lateral forces at the end of their movement, and causes an illusion of increasing forces even after movement termination. This result further emphasizes the role of action prediction in sensory perception.

Spatially valid proprioceptive cues improve the detection of a visual stimulus.

Vision and proprioception are the main sensory modalities that convey hand location and direction of movement. Fusion of these sensory signals into a single robust percept is now well documented. However, it is not known whether these modalities also interact in the spatial allocation of attention, which has been demonstrated for other modality pairings. The aim of this study was to test whether proprioceptive signals can spatially cue a visual target to improve its detection. Participants were instructed to use a planar manipulandum in a forward reaching action and determine during this movement whether a near-threshold visual target appeared at either of two lateral positions. The target presentation was followed by a masking stimulus, which made its possible location unambiguous, but not its presence. Proprioceptive cues were given by applying a brief lateral force to the participant's arm, either in the same direction (validly cued) or in the opposite direction (invalidly cued) to the on-screen location of the mask. The d' detection rate of the target increased when the direction of proprioceptive stimulus was compatible with the location of the visual target compared to when it was incompatible. These results suggest that proprioception influences the allocation of attention in visual space.

Once-a-week psychiatric ward round or daily inpatient team meeting? A multidisciplinary mental health team's experience of new ways of working.

Evidence indicates that while service users are dissatisfied with current ward round practices, studies of how professionals experience this practice are sparse. This study highlights staff view of the once-a-week psychiatric ward round compared to a reformed ward round taking place every weekday. Interviews were conducted at one acute psychiatric ward in north-west England. Our analysis revealed a core theme, 'forming a new way of working', which could be understood from three themes. The theme, 'bound by tradition', emphasized how the traditional ward round represented a double-edged sword: it provided a safe structure, but it also highlighted a shared awareness of an urgent need to leave old ways of working behind. The process of change became discernable in the themes 'juggling the change' and 'light at the end of the tunnel', which showed that restructuring the traditional ward round was both possible and valued. We found that staff views on ward rounds are more complex than had been earlier understood, but new ways of working can be implemented, if the impact of tradition, the process of change, and the time to bed down are taken into account.

Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes.

We generated mice expressing a full-length Mpl transgene under the control of a 2-kb Mpl promoter in an Mpl(-/-) background, effectively obtaining mice that express full-length Mpl in the absence of other Mpl isoforms. These mice developed thrombocytosis with platelet levels approximately 5-fold higher than wild-type controls and markedly increased megakaryocyte numbers. The reintroduction of one wild-type Mpl allele restored normal platelet counts. We excluded the deletion of Mpl-tr, a dominant-negative isoform, as the underlying molecular cause for thrombocytosis. Instead, we found that transgene expression driven by the 2-kb Mpl promoter fragment was decreased during late megakaryocyte maturation, resulting in strongly diminished Mpl protein expression in platelets. Because platelets exert a negative feedback on thrombopoiesis by binding and consuming Tpo in the circulation through Mpl, we propose that the severe reduction of Mpl protein in platelets in Mpl-transgenic Mpl(-/-) mice shifts the equilibrium of this feedback loop, resulting in markedly elevated levels of megakaryocytes and platelets at steady state. Although the mechanism causing decreased expression of Mpl protein in platelets from patients with myeloproliferative disorders differs from this transgenic model, our results suggest that lowering Mpl protein in platelets could contribute to raising the platelet count.