Efficacy of Cyclooxygenase-2 Inhibitors for Headache in Acute Brain Injury: A Systematic Review.

Background: Headache management after acute brain injury (ABI) is challenging. While opioids are commonly used, selective cyclooxygenase-2 inhibitors (COXIBs) may be promising alternatives. However, concerns about cardiovascular effects and bleeding risk have limited their use. We aimed at summarizing available data on efficacy of COXIBs for headache management following ABI. Methods: A systematic review was conducted through MEDLINE and Embase for articles published through 09/2023 (PROSPERO CRD42022320453). No language filters were applied to the initial searches. Interventional or observational studies and systematic reviews assessing efficacy of COXIBs for headache in adults with ABI were eligible. Article selection was performed by two independent reviewers using Distiller SR®. Descriptive statistics were used for data analysis, while meta-analysis was unfeasible due to study heterogeneity. Results: Of 3190 articles identified, six studies met inclusion criteria: four randomized controlled trials and two retrospective cohort studies, all conducted in neurosurgical patients (total n=738) between 2006-2022. Five studies used COXIBs in the intervention group only. Of the six studies, four found a reduction in overall pain scores in the intervention group, while one showed improvement only at 6 hours postoperative, and one did not find significant differences. Pain scores decreased between 4-15%, the largest shift being from moderate to mild severity. Three studies found an overall opioid use reduction throughout hospitalization in the intervention group, while one reported a reduction at 12 hours postoperative only. Opioid consumption decreased between 9-90%. Two studies found a decrease in hospital-length-of-stay by ~1 day in the intervention group. The one study reporting postoperative hemorrhage found a statistically non-significant 3% reduction in the intervention group. Conclusions: In adults with ABI, COXIBs may serve as opioid-sparing adjunctive analgesics for headache control, with limited but pointed data to indicate efficacy in the post-neurosurgical setting. However, further safety data remains to be elucidated.

Sarcopenia and its effects on outcome of lumbar spine surgeries.

PURPOSE: Sarcopenia, defined as progressive impairment of muscle function secondary to loss of skeletal muscle mass, has prevalence of 24-56% in patients > 60 years. Forty-four per cent of elderly patients undergoing orthopaedic surgery are found to be sarcopenic. It is a known risk factor for fall, fractures, disability, increased post-operative morbidity and mortality. If diagnosed pre-operatively, it can help prepare the patient and surgical team to foresee complications and thereby reduce morbidity and mortality. In the present study, we evaluated and correlated sarcopenia with the surgical outcome of operated patients with lumbar spine pathology. MATERIALS AND METHODS: A prospective, observational study was conducted on 114 patients > 40 years undergoing lumbar spine surgeries, who were studied and followed up for 3 months. They were segregated into 5 groups based on age (40-50 year, 50-60 year, 60-70 year, 70-80 year, and > 80 year) and were assessed separately. Data on demography, grip strength analysis, 30-s chair stand test, Psoas muscle index (calculated on pre-operative MRI), pre- and post-operative ODI (Oswestry Disability Index) scores at 2 weeks and 3 months, Dindo-Clavien Classification of peri-operative complications, 90-day readmission rates and mortality (if any) were included. Patients were segregated into sarcopenic and non-sarcopenic groups based on the definition and set parameters as per the European Working Group on Sarcopenia in Older People (EWGSOP). A comparative analysis between these groups was performed. RESULTS: Of 114 patients, there were 18 patients in 40-49 years, 24 in 50-59 years, 33 in 60-69 years, 30 in 70-79 years and 9 in > 80 years age group. Statistically significant difference in peri-operative ODI scores was seen in sarcopenic vs non-sarcopenic patients in all age groups (p < 0.05) except 40-49 years. The results showed that sarcopenic group had higher rate of peri-operative complications, delayed mobilisation, longer stay and mortality compared to non-sarcopenic group. CONCLUSION: We conclude that sarcopenic patients have poor outcome in lumbar spine surgery compared to those without. So, by diagnosing sarcopenia using tests routinely done as pre-operative requirement, one can reduce radiation exposure and cost of treatment. The management can be revolutionised by predicting those who are at high risk of developing post-operative complications and poor surgical outcomes by mere diagnosis of sarcopenia. This knowledge will benefit both the patients and the surgeons.

A 2-Year Outcomes and Complications of Various Techniques of Lumbar Discectomy: A Multicentric Prospective Study.

STUDY DESIGN: Prospective Study. OBJECTIVES: There are numerous techniques for performing lumbar discectomy, each with its own rationale and stated benefits. The authors set out to evaluate and compare the perioperative variables, results, and complications of each treatment in a group of patients provided by ten hospitals and operated on by experienced surgeons. METHODS: This prospective study comprised of 591 patients operated between February-2017 to February-2019. The procedures included open discectomy, microdiscectomy, tubular microdiscectomy, interlaminar endoscopic lumbar discectomy, transforaminal endoscopic lumbar discectomy and Destandau techniques with a follow-up of minimum 2 years. VAS (Visual Analogue Score) for back and leg pain, ODI (Oswestry Disability Index), duration of surgery, hospital stay, length of scar, operative blood loss and peri-operative complications were recorded in each group. RESULTS: Post-operatively, there was a significant improvement in the VAS score for back pain as well as leg pain, and ODI scores spanning all groups, with no significant distinction amongst them. When compared to open procedures (open discectomy and microdiscectomy), minimally invasive surgeries (tubular discectomy, interlaminar endoscopic lumbar discectomy, transforaminal endoscopic lumbar discectomy, and Destandau techniques) reported shorter operative time, duration of hospital stays, better cosmesis, and lower blood loss. Overall, the complication rate was reported to be 8.62%. Complication rates differed slightly across approaches. CONCLUSION: Minimally invasive surgeries have citable advantages over open approaches in terms of perioperative variables. However, all approaches are successful and provide comparable pain relief with similar functional outcomes at long term follow up.

Idiopathic hypereosinophilic syndrome presenting as cardiac tamponade and multiorgan dysfunction.

Idiopathic hypereosinophilic syndrome is characterised by the overproduction of eosinophils with tissue infiltration, leading to multiorgan dysfunction. Its heterogenous presentation makes the diagnosis challenging and easy to miss. A woman in her 70s was admitted with chest pain and shortness of breath. Diagnostic testing showed elevated cardiac enzymes, an ejection fraction of 45% and pericardial effusion. Pericardiocentesis helped her symptoms significantly. Cardiac catheterisation revealed patent coronary arteries. She was diagnosed with myopericarditis and discharged on non-steroidal anti-inflammatory drugs. She returned the following week with worsening chest pain, dyspnoea and diarrhoea. Chest imaging showed bilateral infiltrates. Diagnostic testing showed eosinophilic predominance in peripheral blood (59%), pericardial fluid (37%) and bronchoalveolar lavage (31%). After a negative infectious workup, she was started on glucocorticoids and responded favourably. She was discharged on steroids. Mepolizumab was initiated outpatient, and steroids were discontinued. Mepolizumab was discontinued after 2 years while monitoring her symptoms and eosinophil counts.

The flowering time regulator FLK controls pathogen defense in Arabidopsis thaliana.

Plant disease resistance is a complex process that is maintained in an intricate balance with development. Increasing evidence indicates the importance of posttranscriptional regulation of plant defense by RNA binding proteins. In a genetic screen for suppressors of Arabidopsis (Arabidopsis thaliana) accelerated cell death 6-1 (acd6-1), a small constitutive defense mutant whose defense level is grossly in a reverse proportion to plant size, we identified an allele of the canonical flowering regulatory gene FLOWERING LOCUS K HOMOLOGY DOMAIN (FLK) encoding a putative protein with triple K homology (KH) repeats. The KH repeat is an ancient RNA binding motif found in proteins from diverse organisms. The relevance of KH-domain proteins in pathogen resistance is largely unexplored. In addition to late flowering, the flk mutants exhibited decreased resistance to the bacterial pathogen Pseudomonas syringae and increased resistance to the necrotrophic fungal pathogen Botrytis cinerea. We further found that the flk mutations compromised basal defense and defense signaling mediated by salicylic acid (SA). Mutant analysis revealed complex genetic interactions between FLK and several major SA pathway genes. RNA-seq data showed that FLK regulates expression abundance of some major defense- and development-related genes as well as alternative splicing of a number of genes. Among the genes affected by FLK is ACD6, whose transcripts had increased intron retentions influenced by the flk mutations. Thus, this study provides mechanistic support for flk suppression of acd6-1 and establishes that FLK is a multifunctional gene involved in regulating pathogen defense and development of plants.

The Construction of Biologically Relevant Fiber-Reinforced Hydrogel Geometries Using Air-Assisted Dual-Polarity Electrospinning.

Fiber-reinforced hydrogels are a class of soft composite materials that have seen increased use across a wide variety of biomedical applications. However, existing fabrication techniques for these hydrogels are unable to realize biologically relevant macro/mesoscale geometries. To address this limitation, this paper presents a novel air-assisted, dual-polarity electrospinning printhead that converges high-strength electric fields, with low velocity air flow to remove the collector dependency seen with traditional far-field electrospinning setups. The use of this printhead in conjunction with different configurations of deformable collection templates has resulted in the production of three classes of fiber-reinforced hydrogel prototype geometries, viz., (i) tubular geometries with bifurcations and mesoscale texturing; (ii) hollow, nontubular geometries with single and dual-entrances; and (iii) three-dimensional (3D) printed flat geometries with varying fiber density. All three classes of prototype geometries were mechanically characterized to have properties that were in line with those observed in living soft tissues. With the realization of this printhead, biologically relevant macro/mesoscale geometries can be realized using fiber-reinforced hydrogels to aid a wide array of biomedical applications.

Prevalence and risk factors of neck pain in spine surgeons - Are we our own patients?

Aim: This survey of spine surgeons aimed to determine the prevalence of neck pain and identify the associated risk factors. The prevalence of neck pain has been reported in various medical sub-specialities including laparoscopy surgeons, dentists, plastic surgeons, ophthalmologist, urologist and orthopaedic surgeons. However, the literature is lacking on prevalence and risk factors for neck pain in spine surgeons. Methods: A survey questionnaire containing demographic, Neck pain and work practice details was administered to 300 spine surgeons (members of an online group) via text message and e-mail. Results: One hundred and eighty surgeons responded to the survey (response rate, 60%). Three spine surgeons had previous cervical spine surgeries. The 1-month prevalence rate of neck pain was 74.4% (134/180 surgeons). One hundred and eighteen surgeons (88%) reported only neck pain, 16 surgeons (11.9%) had neck pain with radicular arm pain. Only 20.5% of surgeons used a loupe, 18% of surgeons used a microscope, and 24% of surgeons used operating table height at umbilicus during surgery. There was no significant difference between the mean age (p = 0.65), work experience (p = 0.8), time spent in surgery (p = 0.7), and operating table height preference (p = 0.4) when symptomatic and asymptomatic groups were compared. However, a significantly greater percentage of surgeons had a sedentary lifestyle (p = 0.002) & used loupes as compared to microscopes (p = 0.04) in the symptomatic group. There was significant correlation between the surgeon's lifestyle & use of loupe and the incidence of neck pain. Conclusion: Spine surgeons have a higher prevalence of neck pain than general populations and surgeons from other specialties. Considering the high prevalence of neck pain, general health, work, and ergonomic guidelines and recommendations must be formulated to help prevent and decrease the burden of neck pain among spine surgeons.

Outcomes of patients presenting with Guillain-Barre Syndrome at a tertiary care center in India.

BACKGROUND: The Guillain-Barre Syndrome (GBS), also known as acute idiopathic polyneuritis, is a critical acquired condition associated with preceding nonspecific infection or triggering factors like trauma, surgery, or vaccination. GBS is currently the most frequent cause of acute flaccid paralysis in India. This study evaluates the short-term and in-hospital outcomes in different subtypes of GBS. METHODS: A prospective observational study was conducted at V.S. Hospital, Ahmedabad, from September 2015 to December 2017. Patients above the age of 12 were included. Patients having other underlying neurological conditions, as well as immunodeficiency disorders, were excluded. The patients were classified into different subtypes of GBS, and functional outcomes were recorded on admission and discharge according to Hughes Scoring System. All statistical analyses were performed by using SPSS software. RESULTS: Out of 50 patients, 35 (70%) were males. The mean age was of 37.18 +/- 18.35 years. 25 (50%) patients had a preceding infection. 88% of patients presented with cranial nerve (CN) involvement had a Hughes Score of >/= 3 (p = 0.0087). They had less improvement of Hughes Score on discharge (0.13 +/- 0.04) as compared to the patients without cranial nerve involvement (0.38 +/- 0.08) (p = 0.008). Respiratory involvement was associated with a higher Hughes Score (p = 0.005) on admission. 85% of patients diagnosed with an axonal subtype of GBS had a Hughes Score of >/= 3 (p = 0.06) compared to 74% patients with demyelinating subtype. Axonal subtype required double period (11 +/- 2.34) to show improvement as compared to demyelinating subtype (6 +/- 1.2) (p = 0.020). Irrespective of the subtypes, in two different treatment cohorts (PLEX vs IVIG), there was no difference in short term functional outcomes measured by improvement in the Hughes scores (p = 0.89). CONCLUSIONS: Early cranial nerve and respiratory involvement in patients presenting with GBS are associated with poor outcomes warranting immediate critical care involvement. In our study, amongst all the subtypes, axonal had poor clinical outcomes. Further clinical trials on the Indian subpopulation will help us evaluate the impact of different treatment modalities on this disease.

Clinical Pharmacology in Drug Development for Rare Diseases in Neurology: Contributions and Opportunities.

Several challenges are associated with rare disease drug development in neurology. In this article, we summarize the US Food and Drug Administration's experience with clinical drug development for rare neurological diseases and discuss clinical pharmacology's critical contributions to drug development for rare diseases. We used publicly available information to identify and screen drug products approved for rare neurological indications between 1983 and 2019. We highlighted cases in which clinical pharmacology contributed to the evidence of drug efficacy, dose selection for pivotal clinical trials, dose optimization based on intrinsic and extrinsic factors, pharmacokinetic bridging for formulations, and efficacy bridging across different racial groups. Fifty-one approved drug products were identified since the introduction of the Orphan Drug Act in 1983. Interestingly, the number of approvals in the last few years increased significantly, probably due to advances in genomic research and targeted drug modalities. Evaluation of dose selection in patient populations showed that in 52% of cases, the sponsors did not evaluate efficacy for more than one or two dose levels throughout the development program. Clinical pharmacology studies to evaluate the effect of intrinsic or extrinsic factors were adequately characterized in most of the applications. With the expansion of model informed drug development applications, (e.g., quantitative systems pharmacology and deep learning neural network models), the role and impact of clinical pharmacology is expected to grow exponentially in the next decade and enhance the development of novel treatment modalities for neurological rare diseases.

A 2-Year Outcomes and Complications of Various Techniques of Lumbar Discectomy: A Multicentric Retrospective Study.

OBJECTIVES: Various techniques of performing lumbar discectomy are prevalent, each having its rationale and claimed benefits. The authors ventured to assess the perioperative factors, outcomes, and complications of each procedure and compare among them with 946 patients contributed by 10 centers and operated by experienced surgeons. METHODS: This was a retrospective study of patients operated using open discectomy, microdiscectomy, microendoscopic discectomy, interlaminar endoscopic lumbar discectomy, transforaminal endoscopic lumbar discectomy, and Destandau techniques with a follow-up of minimum 2 years. The inclusion criteria were age >18 years, failed conservative treatment for 4-6 weeks, and the involvement of a single lumbar level. RESULTS: There was a significant improvement in the visual analog scale score of back, leg, and Oswestry Disability Index scores postoperatively across the board, with no significant difference between them. Minimally invasive procedures (microendoscopic discectomy, interlaminar endoscopic lumbar discectomy, transforaminal endoscopic lumbar discectomy, and Destandau techniques) had shorter operation time, hospital stay, better cosmesis, and decreased blood loss compared with open procedures (open discectomy and microdiscectomy). The overall complication rate was 10.1%. The most common complication was recurrence (6.86%), followed by reoperation (4.3%), cerebrospinal fluid leak (2.24%), wrong level surgery (0.74%), superficial infection (0.62%), and deep infection (0.37%). There were minor differences in incidence of complications between techniques. CONCLUSION: Although minimally invasive techniques have some advantages over the open techniques in the perioperative factors, all the techniques are effective and provide similar pain relief and functional outcomes at the end of 2 years. The various rates of individual complications provide a reference value for future studies.

NP-ALT, a Liposomal:Peptide Drug, Blocks p27Kip1 Phosphorylation to Induce Oxidative Stress, Necroptosis, and Regression in Therapy-Resistant Breast Cancer Cells.

Resistance to cyclin D-CDK4/6 inhibitors (CDK4/6i) represents an unmet clinical need and is frequently caused by compensatory CDK2 activity. Here we describe a novel strategy to prevent CDK4i resistance by using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. We find that NP-ALT blocks proliferation in HR+ breast cancer cells, as well as CDK4i-resistant cell types, including triple negative breast cancer (TNBC). The peptide ALT is not as stable in primary mammary epithelium, suggesting that NP-ALT has little effect in nontumor tissues. In HR+ breast cancer cells specifically, NP-ALT treatment induces ROS and RIPK1-dependent necroptosis. Estrogen signaling and ERα appear required. Significantly, NP-ALT induces necroptosis in MCF7 ESRY537S cells, which contain an ER gain of function mutation frequently detected in metastatic patients, which renders them resistant to endocrine therapy. Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant, and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance. IMPLICATIONS: This study reveals that blocking p27 tyrosine phosphorylation inhibits CDK4 and CDK2 activity and induces ROS-dependent necroptosis, suggesting a novel therapeutic option for endocrine and CDK4 inhibitor-resistant HR+ tumors.

Estradiol induces allosteric coupling and partitioning of sex-hormone-binding globulin monomers among conformational states.

Sex-hormone-binding globulin (SHBG) regulates the transport and bioavailability of estradiol. The dynamics of estradiol's binding to SHBG are incompletely understood, although it is believed that estradiol binds to each monomer of SHBG dimer with identical affinity (Kd ∼2 nM). Contrary to the prevalent view, we show that estradiol's binding to SHBG is nonlinear, and the "apparent" Kd changes with varying estradiol and SHBG concentrations. Estradiol's binding to each SHBG monomer influences residues in the ligand-binding pocket of both monomers and differentially alters the conformational and energy landscapes of both monomers. Monomers are not energetically or conformationally equivalent even in fully bound state. Estradiol's binding to SHBG involves bidirectional, inter-monomeric allostery that changes the distribution of both monomers among various energy and conformational states. Inter-monomeric allostery offers a mechanism to extend the binding range of SHBG and regulate hormone bioavailability as estradiol concentrations vary widely during life.

A district-level susceptibility and vulnerability assessment of the COVID-19 pandemic's footprint in India.

In this study, we trace the COVID-19 pandemic's footprint across India's districts. We identify its primary epicentres and the outbreak's imprint in India's hinterlands in four separate time-steps, signifying the different lockdown stages. We also identify hotspots and predict areas where the pandemic may spread next. Significant clusters in the country's western and northern parts pose risk, along with the threat of rising numbers in the east. We also perform epidemiological and socioeconomic susceptibility and vulnerability analyses, identifying resident populations that may be physiologically weaker, leading to a high incidence of cases and pinpoint regions that may report high fatalities due to ambient poor demographic and health-related factors. Districts with a high share of urban population and high population density face elevated COVID-19 risks. Aspirational districts have a higher magnitude of transmission and fatality. Discerning such locations can allow targeted resource allocation to combat the pandemic's next phase in India.

Plasma cell leukaemia with t(11;14) not responsive to venetoclax.

A 70-year-old man with medical history of IgG kappa multiple myeloma, initially diagnosed in 2017, underwent induction therapy with carfilzomib, lenalidomide and dexamethasone followed by autologous haematopoietic stem cell transplantation. Nine months following transplant, disease relapsed in the form of plasma cell leukaemia. Fluorescent in situ hybridisation of malignant plasma cells revealed t(11;14). A combination therapy including venetoclax was used based on efficacy data for Bcl-2 inhibitor venetoclax from available early-phase clinical trials in patients with relapsed multiple myeloma with t(11;14) and other published case studies. Unfortunately, the disease was primary refractory, and after further ineffective therapies, the patient did not have a successful outcome.

Gauging the effects of the COVID-19 pandemic lockdowns on atmospheric pollution content in select countries.

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Does Three-Dimensional Printed Patient-Specific Templates Add Benefit in Revision Surgeries for Complex Pediatric Kyphoscoliosis Deformity with Sublaminar Wires in Situ? A Clinical Study.

STUDY DESIGN: Case-control study. PURPOSE: To evaluate the accuracy of three-dimensional (3D) printed patient-specific templates (PSTs) for placement of pedicle screws (PAs) in patients undergoing revision surgeries for complex kyphoscoliosis deformity with sublaminar wires in situ. OVERVIEW OF LITERATURE: Revision kyphoscoliosis correction surgery in pediatric patients is a challenging task for the treating surgeon. In patients with sublaminar wires in situ, the native anatomical landmarks are obscured, thus making the freehand screw placement technique a highly specialized task. Hence, the concept of using PSTs for insertion of PAs in such surgeries is always intriguing and attractive. METHODS: Five consecutive patients undergoing revision deformity correction with sublaminar wires in situ were included in this study. Patients were divided in two groups based on the technique of PA insertion. A total of 91 PAs were inserted using either a freehand technique (group A) or 3D printed templates (group B) (34 vs. 57). The placement of PAs was classified according to a postoperative computed tomography scan using Neo's classification. Perforation beyond class 2 (>2 mm) was termed as a misplaced screw. The average time required for the insertion of screws was also noted. RESULTS: Mean age, surgical time, and blood loss were recorded. The change in mean Cobb's angle in both groups was also recorded. The difference in rates of misplaced screws was noted in group A and group B (36.21% vs. 2.56%); however, the mean number of misplaced PAs per patient in group A and group B was statistically insignificant (6.5±3.54 vs. 4.67±1.53, p =0.4641). The mean time required to insert a single PA was also statistically insignificant (120±28.28 vs. 90±30 seconds, p =0.3456). CONCLUSIONS: Although 3D printed PSTs help to avoid the misplacement of PAs in revision deformity correction surgeries with sublaminar wires in situ, the mean number of misplaced screws per patient using this technique was found to be statistically insignificant when compared with the freehand technique in this study.

Some respite for India's dirtiest river? Examining the Yamuna's water quality at Delhi during the COVID-19 lockdown period.

The Yamuna's stretch within Delhi is considered as the dirtiest river reach in India and despite numerous restoration plans, pollution levels have risen unabated. However, the enforcement of a nationwide lockdown due to the ongoing COVID-19 pandemic can possibly provide a ray of hope. We analyze the lockdown's impact on the water quality status of this stretch using a combination of measured parameters and satellite image derived indices. Class C Water Quality Index estimates of nine stations indicate an improvement of 37% during the lockdown period. The Biological Oxygen Demand and Chemical Oxygen Demand values reduced by 42.83% and 39.25%, respectively, compared to the pre-lockdown phase, while Faecal Coliform declined by over 40%. Similar analysis of 20 major drains that meet the Yamuna revealed declining effluent loads and discernable improvements in drain contaminant status were ascertained via a hierarchical cluster analysis. Reach-wise suspended particulate matter content, turbidity and algal signatures were derived from multi-temporal Landsat-8 images of prior and ongoing lockdown periods for 117 channel segment zones. These parameters also declined notably within most stretches, although their extents were spatially varied. While the partial/non-operational status of most industries during the lockdown enabled significant reduction in effluent loads and a consequent betterment in the river water quality, its spatial variations and even deterioration in some locations resulted from the largely undiminished inflow of domestic sewage through multiple drains. This study provides an estimate of possible river recovery extents and degree of improvement if deleterious polluting activities and contaminants are regulated properly.