Theory-based implementation of an enhanced recovery protocol for cranial surgery.

OBJECTIVE: There is growing evidence for the use of enhanced recovery protocols (ERPs) in cranial surgery. As they become widespread, successful implementation of these complex interventions will become a challenge for neurosurgical teams owing to the need for multidisciplinary engagement. Here, the authors describe the novel use of an implementation framework (normalization process theory [NPT]) to promote the incorporation of a cranial surgery ERP into routine neuro-oncology practice. METHODS: A baseline audit was conducted to determine the degree of implementation of the ERP into practice. The Normalization MeAsure Development (NoMAD) questionnaire was circulated among 6 groups of stakeholders (neurosurgeons, anesthetists, intensivists, recovery nurses, preoperative assessment nurses, and neurosurgery ward staff) to examine barriers to implementation. Based on these findings, a theory-guided implementation intervention was delivered. A repeat audit and NoMAD questionnaire were conducted to assess the impact of the intervention on the uptake of the ERP. RESULTS: The baseline audit (n = 24) demonstrated limited delivery of the ERP elements. The NoMAD questionnaire (n = 32) identified 4 subconstructs of the NPT as barriers to implementation: communal specification, contextual integration, skill set workability, and relational integration. These guided an implementation intervention that included the following: 1) teamwork-focused training; 2) ERP promotion; and 3) procedure simplification. The reaudit (n = 21) demonstrated significant increases in the delivery of 5 protocol elements: scalp block (12.5% of patients before intervention vs 76.2% of patients after intervention, p < 0.00001), recommended analgesia (25.0% vs 100.0%, p < 0.00001) and antiemetics (12.5% vs 100.0%, p < 0.00001), trial without catheter (13.6% vs 88.9%, p < 0.00001), and mobilization on the 1st postoperative day (45.5% vs 94.4%, p < 0.00001). There was a significant reduction in the mean hospital length of stay from 6.3 ± 3.4 to 4.2 ± 1.7 days (p = 0.022). Two months after implementation, a repeat NoMAD survey demonstrated significant improvement in communal specification. CONCLUSIONS: Here, the authors have demonstrated the successful implementation of a cranial surgery ERP by using a systematic theory-based approach.

The Carbon Catalogue, carbon footprints of 866 commercial products from 8 industry sectors and 5 continents.

Product carbon footprints (PCFs) are playing an increasing role in decisions around sustainability for companies and consumers. Using data reported to CDP, we have previously built a dataset of 866 PCFs, from 145 companies, 30 industry groups, and 28 countries, showing trends of how upstream and downstream emissions vary by industry and how life cycle assessment (LCA) appears to aid companies in achieving steeper carbon reductions through improvements throughout a product's value chain. Here, we present the greenhouse gas emissions and respective meta data for every product in this dataset. The Carbon Catalogue provides each product with name and description, PCF (in kg CO2e) and the respective LCA protocol/standard, product weight, as well as the name, industry, and country of incorporation of its manufacturer. For a subset of 421 products, the Carbon Catalogue further includes the PCF's reported breakdown into two to nine separate stages of the product's life cycle. For another subset of 250 products, the Carbon Catalogue includes how the respective PCFs changed and why the changes occurred.

Azithromycin for Poorly Controlled Asthma in Children: A Randomized Controlled Trial.

BACKGROUND: Azithromycin has immunomodulatory actions, and its beneficial effects have been demonstrated in asthmatic adults. Data on children are limited. RESEARCH QUESTION: Does the addition of oral azithromycin to standard therapy in children with poorly controlled asthma improve asthma control compared with standard treatment alone? STUDY DESIGN AND METHODS: This open-label randomized controlled trial included children (5-15 years of age) with poorly controlled asthma defined by Asthma Control Test (ACT) and Childhood Asthma Control Test (CACT) score of ≤ 19. They were randomized to receive azithromycin (10 mg/kg) three times weekly for 3 months along with standard treatment or standard treatment alone. The primary outcome was the ACT and CACT scores at 3 months. Secondary outcomes were asthma control according to Global Initiative for Asthma (GINA) guidelines, the number of exacerbations, change in spirometry parameters, change in fractional exhaled nitric oxide (Feno) level, positive throat swab results, and side effects. RESULTS: The trial included 120 children (89 boys; 60 in each group). The mean ± SD age was 9.9 ± 3 years. The baseline parameters were similar between the groups. Mean ± SD ACT and CACT scores (available for 115 children) at 3 months of intervention were 21.71 ± 2.17 vs 18.33 ± 2.19 (P < .001) in the azithromycin and control groups, respectively. The numbers of children with well-controlled asthma according to GINA guidelines were 41 of 56 vs 10 of 56 in the azithromycin and control groups, respectively (P < .001). The median number of exacerbations requiring emergency visit and steroid use were fewer in the azithromycin group: 0 (interquartile range [IQR], 3) vs 1 [IQR, 6]; P < .001). No difference was found in Feno level, spirometry parameters, positive throat swab results, and adverse effects between the groups. INTERPRETATION: The use of azithromycin in children with poorly controlled asthma resulted in improved asthma control and reduced exacerbations. TRIAL REGISTRY: Clinical Trials Registry - India; No.: CTRI/2019/06/019727; URL: www.ctri.nic.in.

Foramen magnum osteochondroma causing myelopathy in a patient with hereditary multiple exostoses.

BACKGROUND: Osteochondromas are commonly occurring benign bone tumors which may be either a solitary lesion or occur due to association with hereditary multiple exostoses (HMEs). There have been several reported cases of spinal osteochondromas, but intracranial lesions are rare. CASE DESCRIPTION: A 51-year-old male with a history of multiple osteochondromas presented with myelopathy. He had an exostosis arising from the foramen magnum causing compression of the cervical spinal cord that was successfully removed. Genetic testing revealed that he had HMEs. CONCLUSION: Osteochondromas of the skull are extremely rare. However, parts of the foramen magnum ossify in cartilage and can give rise to an osteochondroma. Here, we present a patient with HMEs who developed cervical myelopathy due to an osteochondroma arising from the foramen magnum. Due to the cartilaginous ossification of the foramen magnum, clinicians should be aware that osteochondromas can occur in this location and potentially give rise to cervical myelopathy.

Indian Academy of Cytologists National Guidelines for Cytopathology Laboratories for Handling Suspected and Positive COVID-19 (SARS-CoV-2) Patient Samples.

COVID-19, caused by the SARS-CoV-2 virus, has been declared a pandemic by the World Health Organization. This scenario has impacted the way we practice cytopathology. Cytology laboratories receive fresh and potentially infectious biological samples including those from the respiratory tract, from COVID-19 positive or suspected patients. Hence, the Indian Academy of Cytologists thought it necessary and fit to bring forth appropriate guidelines starting from transportation, receipt, processing, and reporting of samples in the COVID-19 era. The guidelines are prepared with the aim of safeguarding and protecting the health care personnel including laboratory staff, trainees and cytopathologists by minimizing exposure to COVID-19 so that they remain safe, in order to able to provide a continuous service. We hope that these national guidelines will be implemented across all cytopathology laboratories effectively.

Carbon emissions embodied in product value chains and the role of Life Cycle Assessment in curbing them.

Life cycle-based analyses are considered crucial for designing product value chains towards lower carbon emissions. We have used data reported by companies to CDP for public disclosure to build a database of 866 product carbon footprints (PCFs), from 145 companies, 30 industries, and 28 countries. We used this database to elucidate the breakdown of embodied carbon emissions across products' value chains, how this breakdown varies by industry, and whether the reported emission reductions vary with the granularity of the PCF. For the 866 products, on average 45% of total value chain emissions arise upstream in the supply chain, 23% during the company's direct operations, and 32% downstream. This breakdown varies strongly by industry. Across their lifecycle, the 866 products caused average total emissions of 6 times their own weight, with large variation within and across industries. Reported achievements to reduce emissions varied depending on whether a company had reported a PCF's breakdown to life cycle stages or only the total emissions (10.9% average reduction with breakdown versus 3.7% without). We conclude that a sector-level understanding of emissions, absent of individual PCFs, is insufficient to reliably quantify carbon emissions, and that higher reported emission reductions go hand in hand with more granular PCFs.

Indian Academy of Cytologists Guidelines for Collection, Preparation, Interpretation, and Reporting of Serous Effusion Fluid Samples.

Cytological examination plays an important role in the initial work-up of the serous cavity effusion fluids to find out the possible etiology as benign or malignant. Among malignant effusions, cytology is helpful in determining the exact type, site, and stage of the tumor. However, for reporting effusion cytology specimens, there is no consistent and reproducible reporting system. AIMS: The aim of these guidelines is to provide a standardized format for effusion cytopathology right from sample receipt to its ultimate report sign-out for implementation in all cytopathology laboratories. The Indian Academy of Cytologists in consultation with experts across the country has prepared guidelines pertaining to collection, preparation, and diagnostic categories of effusion specimens to reduce reporting variability. The guidelines are made keeping in mind the different areas of practices in India, especially low- and medium-resource settings. The guidelines are broadly divided into essential, optimal, and optional categories for best usage and appropriate allocation of the precious specimens. In referral centers or well-established setups, essential ancillary techniques can be done for accurate and final diagnosis. By adhering to and implementing these uniform guidelines, it is hoped that clinical patient care and management in India will improve and be of uniformly good quality by enabling and facilitating good laboratory practices.

Intraoperative Magnetic Resonance Imaging-Guided Glioma Resections in Awake or Asleep Settings and Feasibility in the Context of a Public Health System.

BACKGROUND: Despite the most recent surgical aids and tools, surgical removal of infiltrating brain tumors remains a challenge. Unclear margins, edematous areas, and infiltrative behavior are the main causes for failing gross total removals. Also, excessive resection of peri-tumoral tissue often carries risks of damaging the nearby functioning cortical and subcortical structures with an unacceptable decrease in patient's quality of life and postoperative functional status, and the risk of making patients not eligible to adjuvant treatments. Awake surgery and intraoperative magnetic resonance imaging (ioMRI) are among the most effective aids in preventing damage to functional brain while maximizing the extent of resection. METHODS: We present our series of 46 patients operated on at Southmead Hospital (North Bristol NHS Trust) in between July 2014 and February 2017 using ioMRI plus or minus awake surgery. Setting, patient features, indications, type and size of tumors, surgical times, extent of resection, morbidity, and survival are analyzed and discussed. RESULTS: Overall, ioMRI check led to a +43% resections in Group 1 and +58% in Group 2. In grade 2 tumors, GTR was 46% in Group 1 and 55% in Group 2 (41% in control group). In grade 3 tumors, GTR was 57% in Group 1 and 66% in Group 2 (30% in control group). In Grade 4 tumors, GTR was 63% in Group 1, 66% in Group 2 (36% in control group). In terms of theatre occupation, the use of ioMRI added 1/2 operative session; the addition of awake surgery implied the use of another 1/2 operative session. Morbidity did not differ among the groups, with low incidence of permanent post-operative deficits (<5%). Group 2 OS was statistically longer when compared to the control group. CONCLUSIONS: Using ioMRI together with awake surgery is demanding for the anesthetic team, staff nurses, and for the patient. Nevertheless, low morbidity, greater total resections rates, and longer survival suggest its use is effective in making more approachable gliomas of all grades that we would consider "complex" due to their intrinsic features or locations.

Urocytological evaluation of pemphigus patients on long term cyclophosphamide therapy: A cross sectional study.

BACKGROUND: Cyclophosphamide therapy is associated with several urological complications including urinary bladder malignancy. Data on urologic complications of chronic cyclophosphamide therapy for dermatologic conditions is not available. OBJECTIVES: To study the urocytological profile of pemphigus patients on long-term cyclophosphamide therapy. MATERIALS AND METHODS: In a cross-sectional study, consecutive patients who had received cyclophosphamide therapy for pemphigus for more than 12 months were included. All patients were subjected to urinalysis including microscopy, culture, and urine cytology. Immunocytochemical staining for cytokeratin 20 (CK-20) on urine sediments and ELISA (enzyme-linked immunosorbent assay) for nuclear membrane protein-22 (NMP-22) were performed in all cases. In patients with urinary symptoms, microscopic hematuria, or those detected with abnormal urine sediment cytology, NMP-22, and CK-20 positivity, cystoscopy, and other relevant investigations were also done. RESULTS: A total of 44 patients (43 of pemphigus vulgaris and one of pemphigus foliaceus) were recruited. Mean duration of cyclophosphamide intake was 2.9 ± 1.7 years (range 1-8 years) with a mean cumulative dose of 53 ± 28.4 g (range 6.5-141 g). Twenty-one cases (47.7%) each were asymptomatic and symptomatic with episodic urinary symptoms [of which two had urinary tract infection (UTI)] and two patients had gross hematuria. Urine cytology revealed mild urothelial nucleomegaly with hyperchromasia in four patients. However, CK-20 and NMP-22 were negative in all samples. Cystoscopy was performed in 21 cases and did not reveal any sign of bladder malignancy. LIMITATIONS: A relatively small sample size and lack of long-term follow-up were limitations. CONCLUSIONS: In our study, no serious urologic complications were found in pemphigus cases on chronic cyclophosphamide therapy.

Fine needle aspiration cytology diagnosis of metastatic malignant diffuse type tenosynovial giant cell tumor.

Tenosynovial giant cell tumors (TGCTs) arise from the synovium of joint, bursa, and tendon sheath, and are classified into localized and diffuse types. Diffused type often affects the large joint, and has more recurrence, metastasis, and malignant transformation potential compared to the localized type. Malignant diffused TGCT (D-TGCT) usually occurs as a large tumor (>5 cm), in older patients, and its histopathologic features include necrosis, cellular anaplasia, prominent nucleoli, high nuclear cytoplasmic ratio, brisk mitosis, discohesion of tumor cells, paucity of giant cells, and a diffuse growth pattern. At least five of these criteria are required for the histopathologic diagnosis of malignant TGCT because the benign TGCT also shares many of these morphological features. We describe the cytomorphologic features of a malignant D-TGCT from an unusual case of pulmonary metastasis in an adult patient. Fine needle aspiration cytologic features of malignant D-TGCT have not been described earlier in the English literature.

Dyad content is reduced in cardiac myocytes of mice with impaired calmodulin regulation of RyR2.

In cardiac muscle, calmodulin (CaM) regulates the activity of several membrane proteins involved in Ca(2+) homeostasis (CaV1.2; RyR2, SERCA2, PMCA). Three engineered amino acid substitutions in the CaM binding site of the cardiac ryanodine receptor (RyR2) in mice (Ryr2 (ADA/ADA) ) strongly affect cardiac function, with impaired CaM inhibition of RyR2, reduced SR Ca(2+) sequestration, and early cardiac hypertrophy and death (Yamaguchi et al., J Clin Invest 117:1344-1353, 2007). We have examined the ultrastructure and RyR2 immunolocalization in WT and Ryr2 (ADA/ADA) hearts at ~10 days after birth. The myocytes show only minor evidence of structural damage: some increase in intermyofibrillar space, with occasional areas of irregular SR disposition and an increase in frequency of smaller myofibrils, despite an increase of about 15 % in average myocyte cross sectional area. Z line streaming, a sign of myofibrillar stress, is limited and fairly rare. Immunolabeling with an anti-RyR2 antibody shows that RyR-positive foci located at the level of the Z lines are less frequent in mutant hearts. A dramatic decrease in the frequency and size of dyads, accompanied by a decrease in occupancy of the gap by RyR2, but without obvious alterations in location and general structure is a notable ultrastructural feature. The data suggest that the uneven distribution of dyads or calcium release sites within the cells resulting from an overall reduction in RyR2 content may contribute to the poor cardiac performance and early death of Ryr2 (ADA/ADA) mice. An unusual fragmentation of mitochondria, perhaps related to imbalances in free cytoplasmic calcium levels, accompanies these changes.

Overexpression of junctophilin-2 does not enhance baseline function but attenuates heart failure development after cardiac stress.

Heart failure is accompanied by a loss of the orderly disposition of transverse (T)-tubules and a decrease of their associations with the junctional sarcoplasmic reticulum (jSR). Junctophilin-2 (JP2) is a structural protein responsible for jSR/T-tubule docking. Animal models of cardiac stresses demonstrate that down-regulation of JP2 contributes to T-tubule disorganization, loss of excitation-contraction coupling, and heart failure development. Our objective was to determine whether JP2 overexpression attenuates stress-induced T-tubule disorganization and protects against heart failure progression. We therefore generated transgenic mice with cardiac-specific JP2 overexpression (JP2-OE). Baseline cardiac function and Ca(2+) handling properties were similar between JP2-OE and control mice. However, JP2-OE mice displayed a significant increase in the junctional coupling area between T-tubules and the SR and an elevated expression of the Na(+)/Ca(2+) exchanger, although other excitation-contraction coupling protein levels were not significantly changed. Despite similar cardiac function at baseline, overexpression of JP2 provided significantly protective benefits after pressure overload. This was accompanied by a decreased percentage of surviving mice that developed heart failure, as well as preservation of T-tubule network integrity in both the left and right ventricles. Taken together, these data suggest that strategies to maintain JP2 levels can prevent the progression from hypertrophy to heart failure.

Diagnosis of primary cerebral lymphomas: possible value of PCR testing in equivocal cases requiring rebiopsy.

INTRODUCTION. Rebiopsy rates as high as 12% have been reported in previous studies of Primary Central Nervous System Lymphoma (PCNSL). This can lead to secondary operations, increasing risks of morbidity to the patient and costs for the NHS. Polymerase Chain Reaction (PCR) testing for clonality in haematological malignancies has been applied to cases of lymphoma outwith the central nervous system (CNS), but is less commonly used in the diagnosis of CNS lymphomas. Clonality in B- and T-cell populations may indicate the presence of malignancy. We aimed to identify factors to reduce the rebiopsy rate in PCNSL. METHODS. We examined a cohort of 102 suspected cerebral lymphoma cases biopsied at Frenchay Hospital, Bristol over a 10-year period (2000-2010). Clinical data, including age, sex, location, pre-biopsy steroid use, the need for rebiopsy and histological diagnosis, were collected. We retrospectively reviewed rebiopsied cases and they subsequently underwent PCR testing for clonality. RESULTS. Overall, 96/102 (94%) cases achieved a histological diagnosis after one or more biopsies. 81/96 (84%) of these were lymphomas involving the brain and 15/96 (16%) were spinal lymphomas. The majority of these were B-cell lymphomas (95/96 (99%)), with one case of peripheral T-cell lymphoma (1/96 (1%)). Due to insufficient histological evidence of PCNSL after the first biopsy, 9/102 (9%) of cases had required rebiopsy. In 7/9 (78%) of these cases, we undertook PCR testing for clonality on tissue from the first biopsy. We found 3/7 (43%) cases were monoclonal for B or T populations, raising the possibility of PCNSL. CONCLUSIONS. We recommend that all CNS lymphoproliferative lesions be assessed by haematopathologists, with the inclusion of PCR testing particularly in equivocal cases. This would reduce the number of patients going for rebiopsy and reduce the patient morbidity and costs for the NHS.

Abnormal calcium cycling and cardiac arrhythmias associated with the human Ser96Ala genetic variant of histidine-rich calcium-binding protein.

BACKGROUND: A human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine-rich Ca(2+)-binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy. However, the precise mechanisms affecting SR function and leading to arrhythmias remain elusive. METHODS AND RESULTS: We generated transgenic mice with cardiac-specific expression of human Ala96 HRC or Ser96 HRC in the null background to assess function in absence of endogenous protein. Ala96 HRC decreased (25% to 30%) cardiomyocyte contractility and Ca2+ kinetics compared with Ser96 HRC in the absence of any structural or histological abnormalities. Furthermore, the frequency of Ca2+ waves was significantly higher (10-fold), although SR Ca2+ load was reduced (by 27%) in Ala96 HRC cells. The underlying mechanisms involved diminished interaction of Ala96 HRC with triadin, affecting ryanodine receptor (RyR) stability. Indeed, the open probability of RyR, assessed by use of ryanodine binding, was significantly increased. Accordingly, stress conditions (5 Hz plus isoproterenol) induced aftercontractions (65% in Ala96 versus 12% in Ser96) and delayed afterdepolarizations (70% in Ala96 versus 20% in Ser96). The increased SR Ca2+ leak was accompanied by hyperphosphorylation (1.6-fold) of RyR at Ser2814 by calmodulin-dependent protein kinase II. Accordingly, inclusion of the calmodulin-dependent protein kinase II inhibitor KN93 prevented Ser2814 phosphorylation and partially reversed the increases in Ca2+ spark frequency and wave production. Parallel in vivo studies revealed ventricular ectopy on short-term isoproterenol challenge and increased (4-fold) propensity to arrhythmias, including nonsustained ventricular tachycardia, after myocardial infarction in Ala96 HRC mice. CONCLUSIONS: These findings suggest that aberrant SR Ca2+ release and increased susceptibility to delayed afterdepolarizations underlie triggered arrhythmic activity in human Ala96 HRC carriers.

Clinical profile of Langerhans Cell Histiocytosis at a tertiary centre: a prospective study.

OBJECTIVE: To study the varied presentations of Langerhans Cell Histiocytosis (LCH), the differential diagnosis of the varied presentations and the time lag in achieving the diagnosis. Prospective analysis of children diagnosed to have LCH over a period of 51 mo was done. A complete history and physical examination was undertaken in all patients, followed by relevant laboratory and radiological evaluation. Biopsy of the appropriate specimen was done. The extent of the disease was documented, accordingly treated and followed up. RESULTS: There were 16 children with LCH from October 2005 through December 2009. The age ranged from 8 mo to 72 mo. Diagnosis was confirmed by CD1a/S 100 in 15 children (93.75%). The mean time to arrive at the diagnosis was 9.9 mo. Multisystem disease was documented in 11 (68.75%) children and there were 4 (25.0%) cases of pulmonary LCH. The mean time of follow-up was 14.4 mo (range, 1 mo to 50.6 mo). Most common referral diagnoses in LCH patients was recurrent pneumonia and immunodeficiency. CONCLUSIONS: There is a need for high index of suspicion for diagnosis of LCH; misdiagnosis is frequent. Pulmonary involvement in children with LCH appears common. It is possibly still underdiagnosed. Nail changes are uncommon, but may act as a marker for multisystem disease. In addition to survival data and analysis of prognostic factors, the prospective collection of data on diverse presentations is essential, along with a high index of suspicion for the diagnosis of LCH.

Sudden cardiac death risk stratification in patients with heart failure.

The multiplicity of mechanisms contributing to arrhythmogenesis in patients with heart failure carries obvious implications for risk stratification. If patients having the propensity to develop arrhythmias by these different mechanisms are to be identified, tests must be devised that reveal the substrates or other factors that relate to each mechanism. In the absence of this, efforts to risk stratify patients are likely to be neither cost-effective nor accurate. This article reviews the current knowledge base of risk stratification for sudden death in patients with heart failure, while acknowledging several limitations in the studies examined.

Safety of nerve conduction studies in patients with peripheral intravenous lines.

Nerve conduction studies (NCS) may be deferred because of a perceived risk of cardiac arrhythmia in the presence of same-limb peripheral intravenous lines. Patients with implanted pacemakers or defibrillators provide a model in whom this risk can be assessed. Twenty patients, seven with pacemakers and 13 with defibrillators, had peripheral intravenous lines placed during routine care and underwent NCS in the same limb. NCS were performed with the intravenous line clamped and then with saline open to gravity. The implanted cardiac device was interrogated before and after the study. During NCS the surface electrocardiogram and intracardiac electrograms were monitored continuously. Electrical impulses generated during routine NCS were never detected by the sensing amplifiers of the pacemakers/defibrillators and did not affect the programmed settings or interfere with pacing of the device. Routine NCS are safe in patients with same-limb peripheral intravenous lines, even with saline open to gravity.