Deep brain stimulation in pediatric dystonia: calls for therapeutic realism over nihilism.

PURPOSE: Pediatric dystonia (PD) has a significant negative impact on the growth and development of the child. This study was done retrospectively to analyze functional outcomes in pediatric patients with dystonia who underwent deep brain stimulation. METHODS: In this retrospective analytical study, all the patients of age less than 18 years undergoing deep brain stimulation (DBS) for dystonia between 2012 and 2020 in a single center were analyzed and their functional outcomes were measured by the Burke-Fahn-Marsden-dystonia-rating-scale (BFMDRS). RESULTS: A total of 10 pediatric patients were included with a mean age of onset, duration of disease, and age at surgery being 5.75 years, 7.36 years, and 13.11 years, respectively, with a mean follow-up of 23.22 months. The mean pre-DBS motor score was 75.44 ± 23.53 which improved significantly at 6-month and 12-month follow-up to 57.27 (p value 0.004) and 50.38 (p value < 0.001), respectively. Limbs sub-scores improved significantly at both the scheduled intervals. There was a significant improvement in disability at 1-year follow-up with significant improvement in feeding, dressing, and walking components. There was a 27.34% and 36.64% improvement in dystonia with a 17.37% and 28.86% reduction in disability at 6 months and 12 months, respectively. There was a positive correlation between the absolute reduction of the motor score and improvement in disability of the patients at 6 months (rho = 0.865, p value 0.003). CONCLUSIONS: DBS in PD has an enormous role in reducing disease burden and achieving a sustainable therapeutic goal.

Minimally invasive foramen magnum decompression using tubular retractors (MIFT) for Chiari I malformations.

BACKGROUND: Chiari malformation type 1 has been traditionally treated with foramen magnum decompression and C1 arch excision with or without duroplasty depending on the surgeon's preference. Each of the various surgical modifications has its advantages and disadvantages. METHODS: We describe a minimally invasive tubular retractor-based approach to achieve bony decompression in these cases. We have had good results comparable to the open approach. CONCLUSIONS: Strict orientation to the midline using soft tissue landmarks in between the muscles and bony landmarks in the deeper planes is important to achieve good surgical results. Operative time decreases with expertise and is comparable to the open technique. Minimal blood loss and decreased hospital stay and an excellent cosmetic scar make this procedure more appealing.

Xanthogranulomatous Colloid Cyst in a 13-Year-Old Boy: A Case Report and Surgical Implications.

INTRODUCTION: Colloid cysts are relatively uncommon lesions in the pediatric population. The xanthogranulomatous (XG) variant is very rare with less than 30 reported cases. CASE REPORT: In this report, the patient was a 13-year-old boy who presented with transient episodes of headache with blurring of vision. His MRI brain showed a T2 hyperintense well-defined cystic lesion, with an eccentrically located T2 hypointense partially enhancing nodule, at the foramen of Monro. He underwent middle frontal gyrus transcortical, transchoroidal gross total excision of the cyst. The histopathology of the lesion revealed an XG colloid cyst. The patient recovered well from the procedure and was relieved of the symptoms. CONCLUSION: XG colloid cyst may present with altered radiological features compared to the normal variant. This can pose a diagnostic dilemma, and it is important to differentiate it from a craniopharyngioma or a parasitic cyst, as in our case. When considered preoperatively, surgeons should be conscious to review their surgical strategies. Stereotactic aspiration of the XG cyst should be avoided as contents are thicker and heterogeneous than the usual. The spillage of cyst contents should be prevented. Also, the XG cysts are likely to have a poor cyst-fornix or -choroid plexus interface due to inflammation limiting complete resection.

Sella Bugged! Abscess Inside a Craniopharyngioma: Case Report with Literature Review.

INTRODUCTION: Abscess within a craniopharyngioma (CPG) is extremely rare and only 8 such cases have been reported in literature. Most patients present with hypopituitarism and visual disturbances. We report the first ever case of a CPG with abscess in a pediatric patient. CASE REPORT: A 10-year-old girl presented with visual deterioration and bitemporal hemianopia. Her CT and MRI brain suggested of a sellar-suprasellar CPG. Due to ill-developed sino-nasal anatomy, a transcranial approach was made for the lesion. The lesion was well capsulated, thick walled, and appeared inflamed. Upon incising the wall, thick yellowish pus was drained out in a controlled manner. This was followed by a partial resection of the CPG wall and eccentric, adhered, calcified residue was left behind with an Ommaya drain. The abscess culture grew Enterococcus species and histopathology revealed adamantinomatous CPG. Patient underwent culture sensitive antibiotics course followed by radiation for the residue. She was doing well at 1-year follow-up with clinical and radiological improvement. CONCLUSION: This is the first report of a pediatric case with secondary abscess in CPG. Operative management of such a case includes controlled drainage of pus without dissemination into the surrounding arachnoid space. The tumor and abscess have to be addressed as separate surgical entities; infection control and wherever complete resection is not feasible, partial safe resection followed by radiotherapy is a viable option.

Management of a Persistent Oblique Occipital Sinus with Staged Ligation in a Case of Medulloblastoma: A Case Report.

INTRODUCTION: A patent persistent occipital sinus (OS) can be seen in 10% of adults. The presence of such a dominant draining OS can present as a challenge for posterior fossa surgeries. Occlusion or division of the sinus can cause venous hypertension, causing a cerebellar bulge or increased intra-op bleeding. CASE REPORT: A 3-and-a-half-year-old female child presented with a vermian medulloblastoma with hydrocephalus. MR venography (MRV) revealed a large patent OS draining from the torcula to the right sigmoid sinus. She underwent a left Frazier's point VP shunt followed by a midline suboccipital craniotomy for the lesion. The OS was divided during a "Y"-shaped durotomy. Following the sinus ligation, there was a significant cerebellar bulge and excessive bleeding from the lesion. We released cisternal CSF and punctured the tumor cysts to allow the brain bulge to settle. Hemostasis was secured, and surgery was deferred, an augmented duroplasty was done, and bone flap was removed to allow for intracranial pressure decompression. The patient was electively ventilated for 24 h and weaned off gradually. A repeat MRV at 7 days showed the reorganization of the venous outflow at the torcula. Reexploration with tumor resection was done on post-op day 10. The patient recovered well from the surgery and was referred for adjuvant therapy. CONCLUSION: Surgeons should carefully analyze venous anatomy before posterior fossa surgeries. The persistent dominant OS, when present, should be taken care of while planning the durotomy. A hypoplastic but persistent transverse sinus allowed us to ligate and divide the OS. By doing a staged division of the sinus, reorganization of the venous outflow from the torcula can be allowed to occur, and the lesion can be resected.

Trapped fourth ventricle-treatment options and the role of open posterior fenestration in the surgical management.

BACKGROUND: Trapped fourth ventricle (TFV) is a rare and difficult to treat condition. Most patients have a past inciting event (infection, IVH, trauma) and history of prior CSF diversion. The symptoms are due to the mass effect on brainstem and cerebellum. Rarely, TFV can also be associated with syrinx formation due to a dissociated craniospinal CSF flow near the fourth ventricle outlets. We present our experience and outcomes of open posterior fenestration in 11 cases, along with an overview of the surgical management of TFV. METHODS: Between 2011 and 2018, 11 patients of TFV were operated by the posterior approach fenestration of the fourth ventricle outlets and arachnoid dissection. The clinical and radiological findings of the patients were retrieved from the hospital database. The surgical technique is described in detail. The patients' neurological status and imaging findings in the follow-up were recorded and compared. RESULTS: The average age of the patients was 23.55 years. The most common presenting symptoms were headache (9/11) and gait imbalance (7), with TB meningitis being the commonest etiology. Ten patients had a history of prior CSF diversion with two presenting with shunt malfunction. Mean follow-up duration was 33.33 months. The improvement in neurological status was observed in 9/11 patients, 2 remained status quo. On follow-up imaging, 8/11 (72.72%) patients had a decrease in the size of TFV while syrinx improved in 3/5 (60%). CONCLUSION: Multiple surgical approaches have been described for TFV. Endoscopic fourth ventriculostomy with aqueductoplasty is gaining popularity in the past two decades. However, an open posterior fenestration of the midline fourth ventricle outlet (magendieplasty) along with sharp arachnoid dissection (adhesiolysis) along the cerebello-medullary cisterns and paracervical gutters is relatively simple and provides physiological fourth ventricular CSF outflow. This is especially useful in TFV with syrinx as the craniospinal CSF circulation is established.

Hypersensitivity Reactions to Obinutuzumab in Cynomolgus Monkeys and Relevance to Humans.

Obinutuzumab (GA101, Gazyva™, Gazyvaro®, F. Hoffmann-La Roche AG, Basel, Switzerland) is a humanized, glycoengineered type II antibody targeted against CD20. The preclinical safety evaluation required to support clinical development and marketing authorization of obinutuzumab included repeat-dose toxicity studies in cynomolgus monkeys for up to 6-month dosing with a 9-month recovery period. Results from those studies showed decreases in circulating B cells and corresponding B-cell depletion in lymphoid tissues, consistent with the desired pharmacology of obinutuzumab. Hypersensitivity reactions were noted at all doses in the 6-month study and were attributed to the foreign recognition of the drug construct in cynomolgus monkeys. Findings in monkeys were classified as acute hypersensitivity reactions that were evident immediately after dosing, such as excessive salivation, erythema, pruritus, irregular respiration, or ataxia, or chronic hypersensitivity reactions characterized by glomerulonephritis, arteritis/periarteritis, and inflammation in several tissues including serosal/adventitial inflammation. Immune complex deposits were demonstrated in tissues by immunohistochemistry, immunofluorescence, and electron microscopy. Some of, but not all, the animals that developed these reactions had detectable antidrug antibodies or circulating immune complexes accompanied by loss of drug exposure and pharmacodynamic effect. On the basis of clinical evidence to date, hypersensitivity reactions following obinutuzumab are rare, further supporting the general view that incidence and manifestation of immunogenicity in nonclinical species are generally not predictive for humans.

Discovery of siRNA lipid nanoparticles to transfect suspension leukemia cells and provide in vivo delivery capability.

As a powerful research tool, siRNA's therapeutic and target validation utility with leukemia cells and long-term gene knockdown is severely restricted by the lack of omnipotent, safe, stable, and convenient delivery. Here, we detail our discovery of siRNA-containing lipid nanoparticles (LNPs) able to effectively transfect several leukemia and difficult-to-transfect adherent cell lines also providing in vivo delivery to mouse spleen and bone marrow tissues through tail-vein administration. We disclose a series of novel structurally related lipids accounting for the superior transfection ability, and reveal a correlation between expression of Caveolins and successful transfection. These LNPs, bearing low toxicity and long stability of >6 months, are ideal for continuous long-term dosing. Our discovery represents the first effective siRNA-containing LNPs for leukemia cells, which not only enables high-throughput siRNA screening with leukemia cells and difficult-to-transfect adherent cells but also paves the way for the development of therapeutic siRNA for leukemia treatment.

Assessment of Brd4 inhibition in idiopathic pulmonary fibrosis lung fibroblasts and in vivo models of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of high unmet medical need. Although bromodomain (Brd) and extra terminal domain isoforms have recently been implicated in mediating inflammatory and oncologic indications, their roles in lung fibrosis have not been comprehensively assessed. We investigated the role of Brd on the profibrotic responses of lung fibroblasts (LFs) in patients with rapidly progressing IPF and a mouse bleomycin model of lung fibrosis. The enhanced migration, proliferation, and IL-6 release observed in LFs from patients with rapidly progressing IPF are attenuated by pharmacologic inhibition of Brd4. These changes are accompanied by enhanced histone H4 lysine5 acetylation and association of Brd4 with genes involved in the profibrotic responses in IPF LFs as demonstrated using chromatin immunoprecipitation and quantitative PCR. Oral administration of 200 mg/kg per day Brd4 inhibitor JQ1 in a therapeutic dosing regimen substantially attenuated lung fibrosis induced by bleomycin in C57BL/6 mice. In conclusion, this study shows that the Brd4 inhibitor JQ1, administered in a therapeutic dosage, is capable of inhibiting the profibrotic effects of IPF LFs and attenuates bleomycin-induced lung fibrosis in mice. These results suggest that Brd4 inhibitors may represent a novel therapy for the treatment of rapidly progressing IPF.

Progression of degenerative mitral stenosis: insights from a cohort of 254 patients.

BACKGROUND AND AIM OF THE STUDY: Degenerative mitral stenosis (DMS) is an increasingly common echocardiographic finding, yet the clinical and biological behavior and rate of progression of the condition are unknown. METHODS: A total of 254 patients was identified from the authors' echocardiographic database with DMS, defined as severe mitral annular calcification with extension into the mitral leaflets resulting in transmitral flow acceleration with a mean diastolic gradient of >2 mmHg in the absence of commissural fusion. Each patient required paired echocardiograms to have been recorded at least three months apart. Clinical, biochemical and pharmacological data were collected from each patient and related to the annualized rate of increase in mean diastolic mitral gradient and stenosis severity on a scale of 0 to 3. RESULTS: The characteristics of the patients were as follows: mean age 71 +/- 15 years; female gender 73%; and left ventricular ejection fraction 66 +/- 13%. Diabetes was present in 50% of patients, renal insufficiency in 40%, and coronary artery disease in 50%. Over a follow up period of 2.6 +/- 2.2 years, the mean gradient was increased by 0.8 +/- 2.4 mmHg (range: 0-15 mmHg) per year, while the stenosis grade was increased by 0.18 +/- 0.5 (range: 0-3) per year. The rate of progression was faster in patients with lesser degrees of stenosis (p = 0.01) and low serum albumen levels (p = 0.04), and slower in those receiving beta-blockers (p = 0.01). Milder stenosis, diabetes mellitus and lack of beta-blocker use were independent predictors of faster DMS progression. CONCLUSION: DMS progression is highly variable, but generally slow; its progression is accelerated in the presence of diabetes mellitus, but is retarded by beta-blocker use. DMS may be an active biological process offering potentially modifiable targets for intervention.

Role of Optical Coherence Tomography in Predicting Visual Outcome after Surgery for Sellar and Supra-Sellar Tumors.

BACKGROUND: Almost one-fifth of patients undergoing surgery for sellar/supra-sellar tumors do not gain a significant improvement in their vision. Various methods have been described to predict prospective visual outcomes in them, although they lack uniformity. OBJECTIVE: The study was conducted to predict visual outcomes following surgery for sellar and supra-sellar tumors compressing the anterior optic pathway based on pre-operative optical coherence tomography (OCT) parameters. METHODS AND MATERIALS: This was a record-based observational descriptive longitudinal study done in a tertiary care center in India. Thirty-seven patients (74 eyes) diagnosed with sellar supra-sellar lesions were included in the study. Patients' ophthalmic evaluations, done pre-operatively and 3 months post-operatively, were reviewed. Spectral-domain OCT and segmentation were done using the automated segmentation technology of Spectralis software. The thickness of the respective layers was measured. RESULTS AND CONCLUSIONS: The mean age of the study population was 42.68 years. Eyes with a pre-operative visual acuity component of VIS (visual impairment score) ≤61, pre-operative ganglion cell layer thickness ≥26.31 um, a pre-operative inner plexiform layer thickness of ≥25.69 um, a pre-operative ganglion cell inner plexiform layer thickness of 52.00 um, pre-operative ganglion cell complex thickness ≥84.47 µm, and a pre-operative inner retinal layer thickness of ≥205.25 µm were more likely to have an improved visual outcome. Eyes with a pre-operative duration of visual symptoms of ≥15 months, VIS ≥126.50, a pre-operative decimal visual acuity of <0.035, a pre-operative visual field index of ≤8%, a pre-operative macular thickness of ≤287.06 um, a pre-operative macular RNFL (retinal nerve fiber layer) thickness ≤66.00 µm, and a pre-operative peri-papillary RNFL thickness ≤64.62 µm were unlikely to have visual improvement.

Pediatric shunt failure: finding predictability in the sea of uncertainty.

OBJECTIVE: Shunt malfunction is a complication that can have devastating implications. In this study, the authors aimed to evaluate the rate of shunt revision in a single institution over 5 years and to determine the factors associated with shunt revision in the pediatric population. METHODS: This retrospective report assimilated data from all patients ≤ 18 years old who underwent shunt surgery between January 2015 and April 2021 at the authors' institute with a minimum of 3 months of follow-up. Patient data regarding demographic characteristics, indications, clinical status, point of entry, operative and CSF findings, revision interval, and cause of failure were collected. RESULTS: Between January 2015 and April 2021, 1112 pediatric patients underwent initial shunt surgery at the authors' institute, among whom 934 patients met the inclusion criteria. Ninety-five patients underwent revision (shunt revision rate 10.2%). The cohort comprised 562 male and 368 female patients (no sex was recorded in 4 cases), with infratentorial tumors (37.8%) being the most common indication for the shunt. Multivariate analyses revealed that younger patient age, right-sided shunt, single surgeon, and shunt placement done in the evening and night were significantly associated with shunt failure. Among all the factors analyzed, female sex had the greatest risk of early shunt failure (OR 2.90 [95% CI 1.09-8.16], p = 0.037). The presence of prior external ventricular drainage was associated with an increased risk of multiple revisions (OR 6.67 [95% CI 1.60-32.52], p = 0.012). The most common cause of failure was obstruction, usually at the cranial end. The most common cause of distal failure was malposition of the abdominal end. CONCLUSIONS: This study identifies various factors associated with shunt failure. Various goal-directed strategies toward modifiable risk factors can significantly improve shunt survival.

Management of intracranial Rosai-Dorfman disease: An institutional experience.

OBJECTIVE: Rosai-Dorfman disease (RDD) is a rare benign proliferative disorder of histiocytes. The study discusses the intracranial RDD approach, its management, and its outcome. METHODS: It is a retrospective study performed in a tertiary center, the National Institute of Mental Health and Neuroscience, Bangalore, from January 2010 to December 2022. The biopsy-proven patients of RDD were recruited in the present cohort. Demographic and surgical details were collected from the record section, and radiology was collected from the internal storage system. Follow-up assessments were done clinically and telephonically. RESULTS: A total of 25 patients matched the criteria. The mean age was 32 ± 13.4 years, with male predominance. We have included only cranial cases (N=25). Among the intracranial lesions, 5/25 (20 %) patients had multicentric lesions. All the lesions were avidly enhancing on contrast, and 16 (64 %) lesions were hypointense on T2. Perilesional edema (T2/Flair hyperintensities in the surrounding white matter) was seen in 12 (48 %) patients. Gross total resection (GTR) was carried out in six (24 %) cases. Sub-total resection was in 14 (56 %), and biopsy was in five cases (20 %). Nineteen patients received adjuvant therapy, either only steroid (40 %), only low-dose radiotherapy (16 %), only Chemotherapy (4 %), or a combination of both. At follow-up,44 % of patients had stable disease,28 % had primary disease or recurrence growth, and regression in 12 % of cases. CONCLUSION: We demonstrate that surgical resection is an effective therapy for treating isolated intracranial RDD. Adjuvant therapy is an add-on treatment for skull base locations in multicentric locations or surgically inaccessible locations.

The Use of Retraction Sutures in End-To-Side Microvascular Anastomosis-A Novel Technical Innovation in Experimental Rat Femoral Model with Successful Use in STA-MCA Bypass in Moyamoya Disease.

BACKGROUND: A narrow working space, small diameters, and the tendency to collapse with clamps make cerebral microvascular anastomosis challenging. A retraction suture (RS) is a novel technique to keep the recipient vessel lumen open during the bypass. OBJECTIVE: To provide a step-by-step overview of RS for end-to-side (ES) microvascular anastomosis on rat femoral vessels and successful use for superficial temporal artery to middle cerebral artery (STA-MCA) bypass in Moyamoya disease patients. METHODS: A prospective experimental study with approval from the Institutional Animal Ethics Committee. Femoral vessels ES anastomoses were performed on Sprague Daley rats. The rat model used 3 types of RS (adventitial, luminal, and flap RSs). An ES-interrupted anastomosis was done. The rats were observed for an average period of 16.18 ± 5.65 days; the patency was assessed by reexploration. The immediate patency on the STA-MCA bypasses was confirmed with intraoperative indocyanine green angiography and micro-Doppler; delayed patency with magnetic resonance imaging and digital subtraction angiography after 3-6 months. RESULTS: In the rat model, 45 anastomoses were performed, 15 each using the 3 subtypes. The immediate patency was 100%. Delayed patency was 42/43 (97.67%), and 2 rats died during observation. In the clinical series, 59 STA-MCA bypasses were done in 44 patients (average age, 18.14 ± 11.09 years) using RS. The follow-up imaging was available for 41/59 patients. Both immediate patency and delayed patency (41/41 at 6 months) were 100%. CONCLUSION: The RS allows continuous visualization of the vessel lumen, reduces the handling of intimal edges, and avoids incorporating the back wall in sutures, thus improving anastomosis patency.

Bioconcrete-Enabled Resilient Construction: a Review.

Concrete, the ubiquitous cementitious composite though immensely versatile, is crack-susceptible. Cracks let in deleterious substances causing durability issues. Superseding conventional crack-repair methods, the innovative application of microbially induced calcium carbonate precipitation (MICCP) stands prominent, being based on the natural phenomenon of carbonate precipitation. It is eco-friendly, self-activated, economical, and simplistic. Bacteria inside concrete get activated by contacting the environment upon the crack opening and filling the cracks with calcium carbonate-their metabolic waste. This work systematizes MICCP's intricacies and reviews state-of-the-art literature on practical technicalities in its materialization and testing. Explored are the latest advances in various aspects of MICCP, such as bacteria species, calcium sources, encapsulations, aggregates, and the techniques of bio-calcification and curing. Furthermore, methodologies for crack formation, crack observation, property analysis of healed test subject, and present techno-economic limitations are examined. The work serves as a succinct, implementation-ready, and latest review for MICCP's application, giving tailorable control over the enormous variations in this bio-mimetic technique.

Bleomycin induced lung fibrosis increases work of breathing in the mouse.

Bleomycin induces a transient lung fibrosis in mice that has been used to investigate mechanisms related to idiopathic pulmonary fibrosis. Our aim was to determine a sensitive method for assessing lung function in bleomycin treated mice that correlated with the degree of lung fibrosis as measured by collagen immunohistochemistry. Bleomycin (2 U/kg) or saline was intratracheally microsprayed to male C57BL/6 mice under isoflurane anesthesia. Lung function (single compartment model, constant phase model, and work of breathing) was assessed using the flexiVent system, and after euthanasia lungs were inflated with formalin in situ for histological analysis. The lung fibrosis histopathology score for the bleomycin treated animals on day 21 was indicative of mild-to-moderate fibrosis (Saline treated control: 0 ± 0, Bleomycin treated: 4.9 ± 0.4). There were at least three large areas of fibrosis in the peribronchial alveolar regions of the lung, but less than 50% of each lung was affected by fibrosis. Although changes in lung function were less obvious, volume normalized dynamic work of breathing measured at 30 ml/kg tidal volume (Saline treated control: 9.2 ± 0.1 J/l, Bleomycin treated: 10.6 ± 0.3 J/l) and the oscillatory mechanics constant phase model parameter tissue elastance (H; Saline treated control: 31 ± 2 cm H(2)O/ml, Bleomycin treated: 38 ± 3 cm H(2)O/ml) were significantly increased on day 21. The work of breathing (r = 0.83) correlated slightly better with fibrosis histopathology score than H (r = 0.64). Work of breathing can detect decrements in lung function due to pulmonary fibrosis, correlates well with the amount of collagen in the lungs, and may be a more sensitive quantitative measure of efficacy for drugs being developed to treat pulmonary fibrosis.

Surgical management of simultaneous supra- and infratentorial hemorrhages in a pediatric patient with multiple cavernomas.

Multiple intracranial cavernomas are rare and occur mostly in familial cases. Clinical presentation with simultaneous rupture of two or more lesions has only been reported in four cases to date. A 15-year-old boy presented with simultaneous right frontal and superior vermian hematomas with hydrocephalus. The patient underwent a ventriculoperitoneal shunt, and his magnetic resonance imaging (MRI) revealed multiple cavernomas with bleed in the above-mentioned locations. The patient underwent a midline suboccipital craniotomy and excision of the cavernoma. The supratentorial lesions were left in situ in lieu of small size, no history of seizures, mass effect, or other neurological deficits. The patient recovered well from surgery with significant improvement in truncal ataxia. He remained asymptomatic for supratentorial lesions at follow-up. Cavernomas should be considered as differential diagnoses in cases of multiple intraparenchymal hemorrhages, especially in pediatric patients. The surgical management should be rationalized based on the lesion location, the eloquence of the surrounding parenchyma, mass effect, and the risks of re-rupture. Due to the rarity of multiple simultaneous hemorrhages, the management of multiple cavernomas remains controversial. The patient's relatives can be screened with MRI to rule out the familial form of the disease. Strict clinical and radiological follow-up is a must in such patients.

Delayed Vasospasm in Endoscopic Transsphenoidal Pituitary Surgery: Two Case Reports and Reviews.

Background: Cerebral vasospasm (CVS) due to injuries to arteries of the circle of willies has been reported in transsphenoidal pituitary surgeries. However, the incidence of delayed vasospasm following endoscopic transsphenoidal surgery is rare. Materials and Methods: Total 569 pituitary adenomas were operated on by endoscopic transsphenoidal approach from January 2016 to February 2020. We retrospectively described two cases of vasospasm following pituitary surgery from our institution. Objective: To describe two cases of delayed cerebral vasospasm following endoscopic transsphenoidal surgery and review previous literature. Results: Out of two patients, the Glasgow outcome score (GOS) of one patient was favorable and the other was unfavorable. Conclusion: CVS is rare after transsphenoidal pituitary surgery, which makes its predictability difficult. The clinician should maintain a high index of suspicion in patients with suprasellar extension of the tumor and postoperative hematoma in the tumor bed. Similarly, care should be taken in patients with a subarachnoid hemorrhage in basal cistern, intraoperative arachnoid breach, and postoperative meningitis.

Functionally compensating coevolving positions are neither homoplasic nor conserved in clades.

We demonstrated that a pair of positions in phosphoglycerate kinase that score highly by three nonparametric covariation measures are important for function even though the positions can be occupied by aliphatic, aromatic, or charged residues. Examination of these pairs suggested that the majority of the covariation scores could be explained by within-clade conservation. However, an analysis of diversity showed that the conservation within clades of covarying pairs was indistinguishable from pairs of positions that do not covary, thus ruling out both clade conservation and extensive homoplasy as means to identify covarying positions. Mutagenesis showed that the residues in the covarying pair were epistatic, with the type of epistasis being dependent on the initial pair. The results show that nonconserved covarying positions that affect protein function can be identified with high precision.