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In traditional clinical trial design, efficacy is typically assessed using a single primary endpoint in a randomized controlled trial to detect an expected treatment effect of a therapy in a narrowly selected patient population. This accepted paradigm is based on clinical evaluations that may not actually capture the breadth of the impact of a disease, which is especially true in the setting of complex, multisystem, rare diseases with small, extremely heterogeneous patient populations. The multi-domain responder index (MDRI) is a novel approach that accommodates complex and heterogeneous disease manifestations and evaluates a broad array of clinical disease without impairing the power or rigor of a study to fully understand a treatment. The MDRI sums the scores corresponding to clinically significant thresholds of change for each component domain in each individual patient, capturing the mean clinically meaningful change across multiple domains within individuals. This novel approach combines and then sums the results of independent domain endpoint responder analyses into one responder score to provide a broad basis for the assessment of efficacy. The impact of a treatment across multiple, physiologically independent domains, can be assessed clinically, reducing the adverse impact of heterogeneity on trial outcomes and allowing eligibility criteria to enroll a wider range of patients, ultimately resulting in efficacy and safety assessments of a therapy across a broad group of heterogeneous patients in rare disease programs. Trial registration The following studies are referenced within this manuscript (CLINICALTRIALS.GOV registration numbers): NCT00912925; NCT00146770; NCT00067470; NCT00104234; NCT00069641; NCT02230566; NCT02377921; NCT02432144.

Occasionally there may be other congenital anomalies of the central nervous system associated with the encephalocoele. [...]one of our patients had a congenital dermal sinus 3 to 4 cm. above an occipital encephalocoele. The herniating mass lies deep to the nasal bone, making its appearance at the junction of the nasal bone and the nasal cartilage. [...]both frontal poles are seen herniating through the defect.

Good outcomes are expected with normal head size at birth, absence of hydrocephalus and an intact initial neurological examination. The principles of surgical treatment of encephaloceles are reduction of the herniation with preservation of as much viable brain as possible, water-tight dural closure with adequate skin coverage, repair of any cosmetic deformity, and cranial or craniofacial reconstruction. [...]majority of these patients require open surgical approaches.

First of all, let me congratulate Dr. Sanjay Behari, the erstwhile Editor of this journal to bring it to its present state of excellence and wish Dr. P. Sarat Chandra who is taking over this onerous responsibility to take it to greater heights. During the whole exercise from the diagnosis to the operation and the postoperation period, the type of facilities that were used were mostly not available at the time I ended my neurosurgical career, and certainly not available to Cushing, Penfield, Dandy, or even to Jules Hardy, one of the later neuropioneers of neurosurgery. [...]the ready availability of CT and MR scan, image-guided support, endoscopy, high magnification microscope, and an ultra-fine array of instruments no doubt helped make surgery safe. [...]during the Institute Review Committee headed by Dr. S.J. Mehta, I was questioned whether it was justified in operating under the then prevailing conditions at the Institute.

[...]it was difficult to be sure of the diagnosis preoperative ly. Between 2012 and 2016, among the 18 827 CNS 'tumours' submitted to biopsy there were only 95 tubercular lesions-50 intracranial and 45 spinal. [...]barring a few exceptions, the standard treatment for ICtm now is medical therapy and not surgery. [...]tuberculosis had not read the books' and 'the books failed to keep up' with its 'devious ways of evading its eradication'. [...]we ended up re-exploring practically all aspects of neuro tuberculosis- its pathology, pathogenesis, clinical manifestations, diagnosis and management of diverse syndromes had to be redefined and elaborated and new strategies for treatment evaluated. While no revolutionary discoveries were made, we had the satisfaction of adding some valuable new information and improving the management of our patients. [...]we were able to develop an experimental model of the disease in Rhesus monkeys, and were pioneers in studying its diverse effects on CSF pathways and flow dynamics, and were among the first to describe its image morphology on CT.