Short-term variations in response distribution to cortical stimulation

Patterns of responses in the cerebral cortex can vary, and are influenced by pre-existing cortical function, but it is not known how rapidly these variations can occur in humans. We investigated how rapidly response patterns to electrical stimulation can vary in intact human brain. We also investigated whether the type of functional change occurring at a given location with stimulation would help predict the distribution of responses elsewhere over the cortex to stimulation at that given location. We did this by studying cortical afterdischarges following electrical stimulation of the cortex in awake humans undergoing evaluations for brain surgery. Response occurrence and location could change within seconds, both nearby to and distant from stimulation sites. Responses might occur at a given location during one trial but not the next. They could occur at electrodes adjacent or not adjacent to those directly stimulated or to other electrodes showing afterdischarges. The likelihood of an afterdischarge at an individual site after stimulation was predicted by spontaneous electroencephalographic activity at that specific site just prior to stimulation, but not by overall cortical activity. When stimulation at a site interrupted motor, sensory or language function, afterdischarges were more likely to occur at other sites where stimulation interrupted similar functions. These results show that widespread dynamic changes in cortical responses can occur in intact cortex within short periods of time, and that the distribution of these responses depends on local brain states and functional brain architecture at the time of stimulation. Similar rapid variations may occur during normal intracortical communication and may underlie changes in the cortical organization of function. Possibly these variations, and the occurrence and distribution of responses to cortical stimulation, could be predicted. If so, interventions such as stimulation might be used to alter spread of epileptogenic activity, accelerate learning or enhance cortical reorganization after brain injury

cGMP production of astatine-211-labeled anti-CD45 antibodies for use in allogeneic hematopoietic cell transplantation for treatment of advanced hematopoietic malignancies.

The objective of this study was to translate reaction conditions and quality control methods used for production of an astatine-211(211At)-labeled anti-CD45 monoclonal antibody (MAb) conjugate, 211At-BC8-B10, from the laboratory setting to cGMP production. Five separate materials were produced in the preparation of 211At-BC8-B10: (1) p-isothiocyanato-phenethyl-closo-decaborate(2-) (B10-NCS), (2) anti-CD45 MAb, BC8, (3) BC8-B10 MAb conjugate, (4) [211At]NaAt, and (5) 211At-BC8-B10. The 211At-labeling reagent, B10-NCS, was synthesized as previously reported. BC8 was produced, then conjugated with B10-NCS under cGMP conditions to form BC8-B10. [211At]NaAt was produced by α-irradiation of Bi targets, followed by isolation of the 211At using a "wet chemistry" method. The clinical product, 211At-BC8-B10, was prepared by reacting [211At]NaAt with BC8-B10 in NH4OAc buffer (pH 5.5) for 2 min at room temperature, followed by size-exclusion chromatography purification. Quality control tests conducted on the 211At-BC8-B10 included evaluations for purity and identity, as well as pyrogen and sterility tests. Stability of the 211At-BC8-B10 in 25 mg/mL sodium ascorbate solution was evaluated at 1, 2, 4, 6 and 21 h post isolation. For qualification, three consecutive 211At-BC8-B10 clinical preparations were successfully conducted in the cGMP suite, and an additional cGMP clinical preparation was carried out to validate each step required to deliver 211At-BC8-B10 to a patient. These cGMP preparations provided 0.80-1.28 Gbq (21.5-34.5 mCi) of 211At-BC8-B10 with radiochemical purity of >97%. The preparations were found to be sterile and have a pyrogen level 95% for up to 21 h at room temperature. The experiments conducted have defined conditions for translation of 211At-BC8-B10 production from the laboratory to cGMP suite. This study has allowed the initiation of a phase I/II clinical trial using 211At-BC8-B10 (NCT03128034)

Hysteroscopy before in-vitro fertilisation (inSIGHT) : A multicentre, randomised controlled trial

BACKGROUND: Hysteroscopy is often done in infertile women starting in-vitro fertilisation (IVF) to improve their chance of having a baby. However, no data are available from randomised controlled trials to support this practice. We aimed to assess whether routine hysteroscopy before the first IVF treatment cycle increases the rate of livebirths. METHODS: We did a pragmatic, multicentre, randomised controlled trial in seven university hospitals and 15 large general hospitals in the Netherlands. Women with a normal transvaginal ultrasound of the uterine cavity and no previous hysteroscopy who were scheduled for their first IVF treatment were randomly assigned (1:1) to either hysteroscopy with treatment of detected intracavitary abnormalities before starting IVF (hysteroscopy group) or immediate start of the IVF treatment (immediate IVF group). Randomisation was done with web-based concealed allocation and was stratified by centre with variable block sizes. Participants, doctors, and outcome assessors were not masked to the assigned group. The primary outcome was ongoing pregnancy (detection of a fetal heartbeat at >12 weeks of gestation) within 18 months of randomisation and resulting in livebirth. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01242852. FINDINGS: Between May 25, 2011, and Aug 27, 2013, we randomly assigned 750 women to receive either hysteroscopy (n=373) or immediate IVF (n=377). 209 (57%) of 369 women eligible for assessment in the hysteroscopy group and 200 (54%) of 373 in the immediate IVF group had a livebirth from a pregnancy during the trial period (relative risk 1·06, 95% CI 0·93-1·20; p=0·41). One (<1%) woman in the hysteroscopy group developed endometritis after hysteroscopy. INTERPRETATION: Routine hysteroscopy does not improve livebirth rates in infertile women with a normal transvaginal ultrasound of the uterine cavity scheduled for a first IVF treatment. Women with a normal transvaginal ultrasound should not be offered routine hysteroscopy. FUNDING: The Dutch Organisation for Health Research and Development (ZonMW)