Reaching "The Other Half": Teacher Referral Increases Inclusivity in Intervention Research for Neurodivergent School-Age Children.

OBJECTIVE: Researchers employed two recruitment strategies in a school-based comparative effectiveness trial for students with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) or autism. This study assessed the: 1) effectiveness of school-based referrals for identifying students meeting diagnostic criteria and 2) impact of eliminating requirements for existing diagnoses on recruitment, sample characteristics, and intervention response. METHOD: Autistic students and students with ADHD in schools serving underresourced communities were recruited for an executive functioning (EF) intervention trial over 2 years. In Year 1, school staff nominated students with previous diagnoses. In Year 2, school staff nominated students demonstrating EF challenges associated with ADHD or autism; previous diagnosis was not required. Study staff then confirmed diagnoses. RESULTS: More students were included in Year 2 (N = 106) than Year 1 (N = 37). In Year 2, 96% of students referred by school staff met diagnostic criteria for ADHD or autism, 53% of whom were not previously diagnosed. Newly identified students were less likely than previously diagnosed students to be receiving services and, for those with ADHD, were more likely to speak primarily Spanish at home. Previously diagnosed and newly identified students did not differ on other demographic variables or intervention response. Caregivers of previously diagnosed students reported more symptoms than caregivers of newly identified students for both diagnostic groups. Previously diagnosed students with ADHD had more researcher-rated symptoms than newly identified students. CONCLUSIONS: Recruitment for an intervention study using behavior-based referrals from school staff enhanced enrollment without compromising the sample's diagnostic integrity and engaged children who otherwise would have been excluded.

Defining the Semiclassical Limit of the Quantum Rabi Hamiltonian.

The crossover from quantum to semiclassical behavior in the seminal Rabi model of light-matter interaction still, surprisingly, lacks a complete and rigorous understanding. A formalism for deriving the semiclassical model directly from the quantum Hamiltonian is developed here. Working in a displaced Fock-state basis |α,n⟩, the semiclassical limit is obtained by taking |α|→∞ and the coupling to zero. This resolves the discrepancy between coherent-state dynamics and semiclassical Rabi oscillations in both standard and ultrastrong coupling and driving regimes. Furthermore, it provides a framework for studying the quantum-to-semiclassical transition, with potential applications in quantum technologies.

Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes.

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10-26, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.

Pathway level alterations rather than mutations in single genes predict response to HER2-targeted therapies in the neo-ALTTO trial.

Background: We performed whole-exome sequencing of pretreatment biopsies and examined whether genome-wide metrics of overall mutational load, clonal heterogeneity or alterations at variant, gene, and pathway levels are associated with treatment response and survival. Patients and Methods: Two hundred and three biopsies from the NeoALTTO trial were analyzed. Mutations were called with MuTect, and Strelka, using pooled normal DNA. Associations between DNA alterations and outcome were evaluated by logistic and Cox-proportional hazards regression. Results: There were no recurrent single gene mutations significantly associated with pathologic complete response (pCR), except PIK3CA [odds ratio (OR) = 0.42, P = 0.0185]. Mutations in 33 of 714 pathways were significantly associated with response, but different genes were affected in different individuals. PIK3CA was present in 23 of these pathways defining a 'trastuzumab resistance-network' of 459 genes. Cases with mutations in this network had low pCR rates to trastuzumab (2/50, 4%) compared with cases with no mutations (9/16, 56%), OR = 0.035; P < 0.001. Mutations in the 'Regulation of RhoA activity' pathway were associated with higher pCR rate to lapatinib (OR = 14.8, adjusted P = 0.001), lapatinib + trastuzumab (OR = 3.0, adjusted P = 0.09), and all arms combined (OR = 3.77, adjusted P = 0.02). Patients (n = 124) with mutations in the trastuzumab resistance network but intact RhoA pathway had 2% (1/41) pCR rate with trastuzumab alone (OR = 0.026, P = 0.001) but adding lapatinib increased pCR rate to 45% (17/38, OR = 1.68, P = 0.3). Patients (n = 46) who had no mutations in either gene set had 6% pCR rate (1/15) with lapatinib, but had the highest pCR rate, 52% (8/15) with trastuzumab alone. Conclusions: Mutations in the RhoA pathway are associated with pCR to lapatinib and mutations in a PIK3CA-related network are associated with resistance to trastuzumab. The combined mutation status of these two pathways could define patients with very low response rate to trastuzumab alone that can be augmented by adding lapatinib or substituting trastuzumab with lapatinib.

Universal quantum fluctuations of a cavity mode driven by a Josephson junction.

We analyze the quantum dynamics of a superconducting cavity coupled to a voltage-biased Josephson junction. The cavity is strongly excited at resonances where the voltage energy lost by a Cooper pair traversing the circuit is a multiple of the cavity photon energy. We find that the resonances are accompanied by substantial squeezing of the quantum fluctuations of the cavity over a broad range of parameters and are able to identify regimes where the fluctuations in the system take on universal values.

Cooling a nanomechanical resonator with quantum back-action.

Quantum mechanics demands that the act of measurement must affect the measured object. When a linear amplifier is used to continuously monitor the position of an object, the Heisenberg uncertainty relationship requires that the object be driven by force impulses, called back-action. Here we measure the back-action of a superconducting single-electron transistor (SSET) on a radio-frequency nanomechanical resonator. The conductance of the SSET, which is capacitively coupled to the resonator, provides a sensitive probe of the latter's position; back-action effects manifest themselves as an effective thermal bath, the properties of which depend sensitively on SSET bias conditions. Surprisingly, when the SSET is biased near a transport resonance, we observe cooling of the nanomechanical mode from 550 mK to 300 mK--an effect that is analogous to laser cooling in atomic physics. Our measurements have implications for nanomechanical readout of quantum information devices and the limits of ultrasensitive force microscopy (such as single-nuclear-spin magnetic resonance force microscopy). Furthermore, we anticipate the use of these back-action effects to prepare ultracold and quantum states of mechanical structures, which would not be accessible with existing technology.

A macroscopic object passively cooled into its quantum ground state of motion beyond single-mode cooling.

The nature of the quantum-to-classical crossover remains one of the most challenging open question of Science to date. In this respect, moving objects play a specific role. Pioneering experiments over the last few years have begun exploring quantum behaviour of micron-sized mechanical systems, either by passively cooling single GHz modes, or by adapting laser cooling techniques developed in atomic physics to cool specific low-frequency modes far below the temperature of their surroundings. Here instead we describe a very different approach, passive cooling of a whole micromechanical system down to 500 µK, reducing the average number of quanta in the fundamental vibrational mode at 15 MHz to just 0.3 (with even lower values expected for higher harmonics); the challenge being to be still able to detect the motion without disturbing the system noticeably. With such an approach higher harmonics and the surrounding environment are also cooled, leading to potentially much longer mechanical coherence times, and enabling experiments questioning mechanical wave-function collapse, potentially from the gravitational background, and quantum thermodynamics. Beyond the average behaviour, here we also report on the fluctuations of the fundamental vibrational mode of the device in-equilibrium with the cryostat. These reveal a surprisingly complex interplay with the local environment and allow characteristics of two distinct thermodynamic baths to be probed.

Amplitude noise suppression in cavity-driven oscillations of a mechanical resonator.

We analyze the amplitude and phase noise of limit-cycle oscillations in a mechanical resonator coupled parametrically to an optical cavity driven above its resonant frequency. At a given temperature the limit-cycle oscillations have lower amplitude noise than states of the same average amplitude excited by a pure harmonic drive; for sufficiently low thermal noise a sub-Poissonian resonator state can be produced. We also calculate the linewidth narrowing that occurs in the limit-cycle states and show that while the minimum is set by direct phase diffusion, diffusion due to the optical spring effect can dominate if the cavity is not driven exactly at a sideband resonance.

Associations Between Medical History, Cognition, and Behavior in Youth With Down Syndrome: A Report From the Down Syndrome Cognition Project.

The cause of the high degree of variability in cognition and behavior among individuals with Down syndrome (DS) is unknown. We hypothesized that birth defects requiring surgery in the first years of life (congenital heart defects and gastrointestinal defects) might affect an individual's level of function. We used data from the first 234 individuals, age 6-25 years, enrolled in the Down Syndrome Cognition Project (DSCP) to test this hypothesis. Data were drawn from medical records, parent interviews, and a cognitive and behavior assessment battery. Results did not support our hypothesis. That is, we found no evidence that either birth defect was associated with poorer outcomes, adjusting for gender, race/ethnicity, and socioeconomic status. Implications for study design and measurement are discussed.

The influence of exogenous progestin on the occurrence of proestrous or estrous signs, plasma concentrations of luteinizing hormone and estradiol in deslorelin (GnRH agonist) treated anestrous bitches.

UNLABELLED: The objectives of this study were to confirm: (i) whether progestin treatment suppressed GnRH agonist-induced estrus in anestrous greyhound bitches; and (ii) the site of progestin action (i.e. pituitary, ovary). All bitches received a deslorelin implant on Day 0 and blood samples were taken from -1 h to +6 h. Five bitches were treated with megestrol acetate (2 mg/kg orally once daily) from -7 d to +6 d (Group 1) and 10 bitches were untreated controls (Group 2). Proestrous or estrous signs were observed in 4 of 5 bitches in Group 1, and 4 of 10 bitches in Group 2 (P = 0.28). The plasma LH responses (area under the curve from 0 to 6h after implantation) were higher (P = 0.008) in Group 2 than in Group 1. Plasma LH responses were similar (P = 0.59) in bitches showing signs of proestrus or estrus (responders) and in non-responders. The plasma estradiol responses (calculated as for LH response) were greater in Group 1 than in Group 2 (P = 0.048), and in responders than in non-responders (P = 0.02). IN CONCLUSION: (i) progestin treatment (a) did not suppress the incidence of bitches showing deslorelin-induced proestrus or estrus, and (b) was associated with a reduced pituitary responsiveness and an increased ovarian responsiveness to deslorelin treatment; (ii) the occurrence of proestrous or estrous signs reflected increased ovarian responsiveness to induced gonadotrophin secretion and not increased pituitary responsiveness to deslorelin.

No-carrier-added iodine-131-MIBG: evaluation of a therapeutic preparation.

UNLABELLED: Iodine-131-metaiodobenzylguanidine ([131I]MIBG) is a radiopharmaceutical for imaging as well as targeted radiotherapy of neuroblastoma. It is predicted that the use of no-carrier-added [131I]MIBG, rather than the conventional low specific activity preparation, will result in an enhanced therapeutic ratio because of different transport processes in neuroblastoma compared with most normal tissues. METHODS: The main aims of the study were: (1) to determine whether [131I]MIBG of substantially greater specific activity is transported into tumor cells by the same process as the existing compound; (2) to evaluate the effect of nonradiolabeled MIBG on the cytotoxicity of no-carrier-added [131I]MIBG; and (3) to compare the biodistribution of both preparations of the radiochemical in neuroblastoma xenografts. RESULTS: Active uptake of no-carrier-added [131I]MIBG was temperature-, sodium- and oxygen-dependent; ouabain- and desmethylimipramine-inhibitable; and could be blocked competitively by monoamine inhibitors of the noradrenaline transport mechanism. The rank order of specific uptake capacity in a panel of neuroblastoma cell lines was the same for both low and high specific activity drug. Neuroblastoma spheroid regrowth was 85% inhibited by no-carrier-added [131I]MIBG at 2 MBq.ml-1. Inhibitory potency was reduced in a dose-dependent manner by nonradiolabeled MIBG. The accumulation of no-carrier-added [131I]MIBG was significantly greater in tumor, adrenal, heart and skin of tumor-bearing mice than that of the conventional therapy preparation of [131I]MIBG. CONCLUSION: These data indicate that there may be clinical advantages in the use of no-carrier-added [131I]MIBG rather than conventional [131I]MIBG.

Dilutional hyponatraemia: a cause of massive fatal intraoperative cerebral oedema in a child undergoing renal transplantation.

A four year old boy with polyuric renal failure resulting from recurrent urinary tract infections and vesicoureteric reflux from birth underwent renal transplantation. In the past he had had five ureteric reimplant operations and a gastrostomy, as he ate nothing by mouth. He required peritoneal dialysis 13 hours a night, six nights a week. His fluid requirements were 2100 ml per day. This included a night feed of 1.5 litres Nutrizon. Before operation he received 900 ml of Dioralyte instead of the Nutrizon feed, and peritoneal dialysis was performed as usual. The operation itself was technically difficult and there was more blood loss than anticipated, requiring intravenous fluids and blood. The operation ended about four hours later but he did not wake up. Urgent computed tomography revealed gross cerebral oedema. He died the next day. At necropsy the brain was massively oedematous and weighed 1680 g.

Apoptosis in cervical squamous carcinoma: predictive value for survival following radiotherapy.

BACKGROUND: Apoptosis, or programmed cell death, can be induced by radiotherapy. The extent of apoptosis in a tumour before treatment may have important implications for response to radiotherapy and long term survival. AIM: To examine the extent of apoptosis in tumour tissue from patients with squamous carcinoma of the cervix before radiotherapy, and to correlate this with response to treatment and prognosis. METHODS: The percentage of apoptotic cells was assessed in 146 carcinomas of the cervix from patients scheduled to receive radiotherapy. The CAS 200 static image analysis system was used to count the number of tumour nuclei per high power field, while the numbers of apoptotic cells in the same field were visualised simultaneously on the image analyser and recorded manually. RESULTS: The median apoptotic level was 0.73%. Patients were divided into two groups around the median. There was no statistically significant difference in outcome between the two groups as determined by long term survival following radiotherapy. CONCLUSIONS: The CAS 200 static image analyser system can be used to assist in the rapid semiautomated assessment of apoptosis in conventionally prepared tissue. The results suggest that the apoptotic state of a tumour before treatment is of no value in predicting response to radiotherapy and subsequent prognosis. Tumour stage, size, and BrdU labelling index, as a measure of proliferation rate, remain the most important prognostic factors in terms of predicting local tumour control.

Late radiation side-effects in three patients undergoing parotid irradiation for benign disease.

We report three patients in whom standard radiation therapy was given and serious late radiation damage was seen. The first patient suffered recurrent parotiditis and a parotid fistula. He was treated initially with 20 Gy in ten fractions via a 300 kV field. Further irradiation was required 1 year later and 40 Gy was given in 2 Gy fractions by an oblique anterior and posterior wedged photon pair. Ten years later he developed localized temporal bone necrosis. The second patient, with pleomorphic salivary adenoma, developed localized temporal bone necrosis 6 years after 60 Gy had been given using standard fractionation and technique. The third patient received 55 Gy in 25 fractions for a pleomorphic salivary adenoma and after 3 years developed temporal bone necrosis. Sixteen years later the same patient developed cerebellar and brainstem necrosis. All patients developed chronic persistent infection during or shortly after the radiation therapy, which increased local tissue sensitivity to late radiation damage. As a result, severe bone, cerebellar and brainstem necrosis was observed at doses that are normally considered safe. We therefore strongly recommend that any infection in a proposed irradiated area should be treated aggressively, with surgical debridement if necessary, before radiotherapy is administered, or that infection developing during or after irradiation is treated promptly.

A comparison of two methods of infiltration in breast reduction surgery.

The superwet technique has been shown in previous studies to dramatically reduce blood loss in breast reduction surgery, compared with standard infiltration. A retrospective chart review of 303 consecutive patients undergoing bilateral breast reduction surgery was undertaken to demonstrate additional differences in complication rate, operative time, or sponge use in the operating room. In this series, 132 consecutive patients received standard infiltration along incision lines (25 cc per breast of 1:100,000 epinephrine), and 171 patients received superwet infiltration with 240 cc per breast of 1:1,000,000 epinephrine. The average operative time was significantly reduced in the superwet group, from 78.5 minutes to 70.7 minutes (p < 0.01 level). The average number of sponges used intraoperatively was also decreased significantly (p < 0.01), from 26 to 20 sponges. Complication rates were equally low in both groups, demonstrating the safety of the superwet technique. In addition to limiting blood loss, the superwet infiltration effectively reduces operative time and sponge use without increasing complications in breast reduction surgery.

Ectopic cervical hamartomatous thymoma showing extensive myoid differentiation.

Ectopic 'hamartomatous' thymoma is a rare benign neoplasm. These tumours are found in the neck and are thought to be part of a spectrum of ectopic cervical thymic neoplasia. The clinical and histological features are discussed and the literature is reviewed. An attempt is made to explain in embryological terms why such lesions appear to occur more commonly on the left side.

A study of gunshot suicides in Northern Ireland from 1989 to 1993.

A study of 104 gunshot suicides, including six women, in Northern Ireland over a 5-year period. Forty-five suicides in the security forces are compared with 59 which took place in the civilian population. The former were commonly associated with marital problems and overwhelmingly occurred in young males under the age of 40, whereas the civilian deaths were predominantly associated with mental ill health, with a wider age range distribution. The security forces used rifled weapons in 44 cases, whereas civilians used shotguns in 46 cases. Twelve out of the 45 were witnessed, compared to one in the civilian population. The security forces favoured the head as site of entry in 40 cases compared to 35 in the civilian population. Alcohol consumption was involved in 23 of the security forces suicides and 18 civilian. Of the 6 women, one was in the security forces and 4 had a history of mental illness.

Nosological Inaccuracies in death certification in Northern Ireland. A comparative study between hospital doctors and general practitioners.

We aimed to audit nosological inaccuracies in death certification in Northern Ireland and to compare performance of hospital doctors and general practitioners. Nosology is the branch of medicine which treats of the classification of disease. 1138 deaths were registered in Northern Ireland in a 4-week period commencing 3/10/94. 195 of these were either registered by HM Coroners (HMC) or required further investigation by their staff; these cases were excluded from the study. The remaining 943 were analysed for wording and formulation inaccuracies according to the revised notes (1974), Northern Ireland Medical Certificate of Cause of Death. These are issued in book form by the Registrar of Births and Deaths. The commonest inaccuracies in death certification occur in the areas of poor terminology, sequence errors and unqualified mode. One or more inaccuracies were found in 317 (33.6%) of cases. In 13 of these (4%) cases, the inaccuracies were serious enough to warrant referral by the Registrar of Deaths to HM Coroner. The numbers of general practitioners and hospital doctors were recorded, with general practitioners being responsible for 122 (38%) and hospital doctors being responsible for 195 (62%) of inaccuracies.