Skeletal phenotype amelioration in mucopolysaccharidosis VI requires intervention at the earliest stages of postnatal development.

Mucopolysaccharidosis VI (MPS VI) is a rare lysosomal disease arising from impaired function of the enzyme arylsulfatase B (ARSB). This impairment causes aberrant accumulation of dermatan sulfate, a glycosaminoglycan (GAG) abundant in cartilage. While clinical severity varies along with age at first symptom manifestation, MPS VI usually presents early and strongly affects the skeleton. Current enzyme replacement therapy (ERT) does not provide effective treatment for the skeletal manifestations of MPS VI. This lack of efficacy may be due to an inability of ERT to reach affected cells or to the irreversibility of the disease. To address the question of reversibility of skeletal phenotypes, we generated a conditional by inversion (COIN) mouse model of MPS VI, ArsbCOIN/COIN, wherein Arsb is initially null and can be restored to WT using Cre. We restored Arsb at different times during postnatal development, using a tamoxifen-dependent global Cre driver. By restoring Arsb at P7, P21, and P56-P70, we determined that skeletal phenotypes can be fully rescued if Arsb restoration occurs at P7, while only achieving partial rescue at P21 and no significant rescue at P56-P70. This work has highlighted the importance of early intervention in patients with MPS VI to maximize therapeutic impact.

Supraclavicular block evaluation in oncoorthopedic patients under general anesthesia using perfusion index: A prospective cohort study.

Background: Supraclavicular brachial plexus blocks (SCBPB) are routinely placed prior to anaesthetic induction for post-operative pain relief after prolonged orthopaedic oncosurgery, since patients are required to remain awake for sensorimotor evaluation of block. If the window period after surgery but before anesthesia-reversal is employed for administering SCBPB, it bestows the quadruple advantage of being painless, not augmenting surgical bleed, longer post-operative analgesia and reduced opioid-related side effects. The problem spot is assessing SCBPB-efficacy under general anesthesia. Methods: This prospective, single-centric, observational cohort study included 30 patients undergoing upper limb orthopaedic oncosurgery under general anesthesia. Perfusion index (PI) was assessed using two separate units of Radical-7™ finger pulse co-oximetry devices simultaneously in both the upper limbs and PI ratios calculated. Skin temperature was noted. Results: After successful block, PI values in blocked limb suddenly increased after 5 min, progressively increasing for next 10 min, whereas PI failed to increase further above that attained post anaesthetic-induction in unblocked limb. PI values in the blocked limb were 4.32, 4.49, 4.95, 7.25, 7.71, 7.90, 7.94, 7.89, and 7.93 at 0, 2, 3, 5, 10, and 15 min post block-institution at reversal and 2 min, 5 min post-reversal, respectively. PI ratios at 2, 3, 5, 10, and 15 min post block-administration in the blocked limb, taking PI at local anaesthetic injection as denominator were 1.04, 1.15, 1.67, 1.78, and 1.83, respectively. Correlation between PI and skin temperature in the blocked limb gave a repeated measures correlation coefficient of 0.79. Conclusion: Monitoring trends in PI and PI-ratio in the blocked limb is a quantitative, non-invasive, inexpensive, simple, effective technique to monitor SCBPB-onset in anaesthetised patients.

Prognostic value of initial electrocardiography in predicting long-term all-cause mortality in COVID-19.

BACKGROUND: The electrocardiography (ECG) has short-term prognostic value in coronavirus disease 2019 (COVID-19), yet its ability to predict long-term mortality is unknown. This study aimed to elucidate the predictive role of initial ECG on long-term all-cause mortality in patients diagnosed with COVID-19. METHODS: In this prospective cohort study, adults with COVID-19 who underwent ECG testing within a 17-hospital health system in Northeast Ohio and Florida between 03/2020-06/2020 were identified. An expert ECG reader analyzed all studies blinded to patient status. The associations of ECG characteristics with long-term all-cause mortality and intensive care unit (ICU) admission were assessed using Cox proportional hazards regression model and multivariable logistic regression models, respectively. Status of long-term mortality was adjudicated on 01/07/2022. RESULTS: Of 837 patients (median age 65 years, 51% female, 44% Black), 683 (81.6%) were hospitalized, 281 (33.6%) required ICU admission, 67 (8.0%) died in-hospital, and 206 (24.6%) died at final follow-up after a median (IQR) of 21 (9-103) days after ECG. Overall, 179 (20.7%) patients presented with sinus tachycardia, 12 (1.4%) with atrial flutter, and 45 (5.4%) with atrial fibrillation (AF). After multivariable adjustment, sinus tachycardia (E-value for HR=3.09, lower CI=2.2) and AF (E-value for HR=3.13, lower CI=2.03) each independently predicted all-cause mortality. At final follow-up, patients with AF had 64.5% probability of death compared with 20.5% for those with normal sinus rhythm (P<.0001). CONCLUSIONS: Sinus tachycardia and AF on initial ECG strongly predict long-term all-cause mortality in COVID-19. The ECG can serve as a powerful long-term prognostic tool in COVID-19.

Cardiac considerations in liver transplantation.

Cardiovascular events have a major impact on overall outcomes after liver transplantation. Today's transplant patients are older than those in the past and therefore are more likely to have coexisting cardiac comorbidities. In addition, pathophysiologic effects of advanced liver disease on the circulatory system pose challenges in perioperative management. This review discusses important preoperative, intraoperative, and postoperative cardiac considerations in patients undergoing liver transplant.

Implementation of a Myocardial Perfusion Imaging Risk Algorithm to Inform Appropriate Downstream Invasive Testing and Treatment.

BACKGROUND: To risk stratify patients undergoing single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) in accordance with appropriate use criteria for referral to coronary angiography, we developed a risk classification algorithm incorporating appropriate use criteria-defined risk features. We evaluated the association between this algorithm with downstream angiography, revascularization, and all-cause mortality. METHODS: We studied consecutive patients who underwent SPECT-MPI from January 1, 2015, to December 31, 2017, and assigned a scan risk of low, intermediate, high, or indeterminate. With this stratification, we assessed referral for angiography and revascularization within 3 months of SPECT-MPI and intermediate-term mortality. RESULTS: Among 12 799 patients, the mean age was 66 years, and a majority were men (56.8%). Most patients were low risk (83.6%) followed by intermediate (9.9%) and high risk (5.2%). Compared with low-risk patients, intermediate- and high-risk patients were more frequently referred for angiography (14.8% and 13.6% versus 2.0%; P<0.001) and revascularization (7.7% and 6.8% versus 0.7%; P<0.001). In 1008 propensity-matched patients, scan risk was independently associated with angiography after adjustment for ischemia, scar, or stress ejection fraction. At a mean follow-up of 2.3 years, mortality was higher with increased scan risk (high, 10.4%; intermediate, 7.1%; low, 4.1%; P<0.001). Compared with low scan risk, intermediate (hazard ratio, 1.37 [95% CI, 1.09-1.72]; P=0.008) and high scan risk (hazard ratio, 1.98 [95% CI, 1.53-2.56]; P<0.001) were associated with mortality in multivariable analysis. Similar findings were observed for those undergoing pharmacological and exercise SPECT-MPI with comparatively worse prognosis among pharmacological patients. CONCLUSIONS: This appropriate use criteria-derived risk classification algorithm for SPECT-MPI guided referral for coronary angiography and revascularization and was significantly associated with mortality. This algorithm may serve as an important tool to reaffirm appropriate use criteria and direct management of patients with stable ischemic heart disease undergoing stress testing.

Crosstalk with lung epithelial cells regulates Sfrp2-mediated latency in breast cancer dissemination.

The process of metastasis is complex1. In breast cancer, there are frequently long time intervals between cells leaving the primary tumour and growth of overt metastases2,3. Reasons for disease indolence and subsequent transition back to aggressive growth include interactions with myeloid and fibroblastic cells in the tumour microenvironment and ongoing immune surveillance4-6. However, the signals that cause actively growing cells to enter an indolent state, thereby enabling them to survive for extended periods of time, are not well understood. Here we reveal how the behaviour of indolent breast cancer cells in the lung is determined by their interactions with alveolar epithelial cells, in particular alveolar type 1 cells. This promotes the formation of fibronectin fibrils by indolent cells that drive integrin-dependent pro-survival signals. Combined in vivo RNA sequencing and drop-out screening identified secreted frizzled-related protein 2 (SFRP2) as a key mediator of this interaction. Sfrp2 is induced in breast cancer cells by signals from lung epithelial cells and promotes fibronectin fibril formation and survival, whereas blockade of Sfrp2 expression reduces the burden of indolent disease.

Goal-directed fluid therapy using transoesophageal echocardiographic inferior venacaval index in patients with low left ventricular ejection fraction undergoing major cytoreductive surgery: A clinical trial.

BACKGROUND AND AIMS: This study aims to trans oesophageal echo cardiographically (TOE) measure inferior venacava diameter (IVCD) during inspiration and expiration in poor left ventricular ejection fraction (LVEF) patients undergoing cytoreductive oncosurgery, to ascertain if any correlation exists between, caval index (DeltaIVCD), and stroke volume variation (SVV), and to compare DeltaIVCD-guided versus SVV-guided fluid therapy. METHODS: In this prospective, parallel group, interventional study, seventy American Society of Anesthesiologists-III patients, aged 30-75 years, weighing 40-90 kg, with LVEF ≤40% undergoing cytoreductive surgery were included and randomised to group-D (DeltaIVCD-guided fluid therapy) and group-S (SVV-guided fluid therapy). Patients with oesophageal lesions were excluded. After standard endotracheal anaesthesia, arterial and internal jugular vein catheters were placed. A TOE probe was inserted in the interventional group-D. Quantification of IVCD respiratory variations was done. Heart rate (HR), arterial oxygen saturation (SPO2), mean arterial pressure, end tidal carbondioxide (EtCO2), central venous pressure, SVV, IVCD, and urine output (UO) were recorded every 30 min. Post-operative arterial blood gas analysis, lung-ultrasound, chest-radiograph, and serum creatinine were done. STATISTICAL ANALYSIS: Pearson's correlation coefficient as measure of strength of linear relationship, calculation of regression equation, and unpaired t-test for normally distributed continuous variables were used. RESULTS: A positive correlation between DeltaIVCD and SVV (r = 0.751) was observed. A regression equation was obtained for SVV (SVV = [0.317 × DeltaIVCD] + 5.877). Serum lactate, estimated glomerular filtration rate, HR, and UO were within normal limits in group-D. There was no pulmonary oedema. CONCLUSION: DeltaIVCD-guided intravenous fluid therapy is valuable in low LVEF patients where tight fluid control is essential and any fluid overload may precipitate cardiac failure.

Comparison of pectoralis plane blocks with ketamine-dexmedetomidine adjuncts and opioid-based general anaesthesia in patients undergoing modified radical mastectomy.

BACKGROUND AND AIMS: Regional anaesthesia attenuates surgical stress-response, provides superior analgesia, reduces recovery time with early mobilisation and is opioid-sparing [addresses post-operative nausea vomiting (PONV), constipation, immunosuppression and cancer-progression concerns with opioids]. Hence, we studied pectoralis (PECS) blocks for modified radical mastectomy (MRM). METHODS: A prospective, interventional, double-blind, randomised, parallel-arm, active-controlled study comparing two anaesthetic techniques for post-operative pain relief in70 adult American Society of Anesthesiologists grade I/II carcinoma breast patients undergoing MRM was conducted. Patients were randomised to Group-O (opioids, sevoflurane) and Group-P (PECS-block, pre-incisional intravenous (IV) ketamine (0.5 mg/kg), pre-incisional IVdexmedetomidine (1 µg/kg over 10 min, then 0.6 µg/kg/h). Data were subjected to statistical analysis using the Statistical Package for Social Sciences, version-23 and independent sample t-test/Welch test for equality of means and expressed as dotted box-whisker plots. Nominal categorical intergroup data was compared using Chi-squared test/Fisher's exact test. P<0.05 was considered statistically significant. Clinical significance was calculated. RESULTS: Higher Visual Analogue Scale (VAS)-scores were recorded in Group-O versus Group-P, immediately post-extubation [mean (SD) 3.6 ± 1.5 and 0.76 ± 0.6] and at 1h (3.1 ± 1.2 and1.4 ± 0.5), 2h (2.5 ± 0.9 and 1.2 ± 0.6) and 4h (2.2 ± 0.5 and 1.7 ± 0.9) respectively. At 8h and 24h post-surgery VAS was comparable. Cumulative-VAS was lower in Group-P. Intraoperative haemodynamics were comparable. Incidence of PONV and constipation was higher in Group-O where each patient received average 27.46 mg morphine-equivalents of opioids. Time to discharge from surgical intensive care unit was 2h shorter in Group-P. CONCLUSION: Pre-emptive PECS-blocks supplemented with low-dose ketamine and dexmedetomidine comprise a practical and useful alternative technique to the standard opioid-based general anaesthetic technique for MRM.

Convolutional neural networks for reconstruction of undersampled optical projection tomography data applied to in vivo imaging of zebrafish.

Optical projection tomography (OPT) is a 3D mesoscopic imaging modality that can utilize absorption or fluorescence contrast. 3D images can be rapidly reconstructed from tomographic data sets sampled with sufficient numbers of projection angles using the Radon transform, as is typically implemented with optically cleared samples of the mm-to-cm scale. For in vivo imaging, considerations of phototoxicity and the need to maintain animals under anesthesia typically preclude the acquisition of OPT data at a sufficient number of angles to avoid artifacts in the reconstructed images. For sparse samples, this can be addressed with iterative algorithms to reconstruct 3D images from undersampled OPT data, but the data processing times present a significant challenge for studies imaging multiple animals. We show here that convolutional neural networks (CNN) can be used in place of iterative algorithms to remove artifacts-reducing processing time for an undersampled in vivo zebrafish dataset from 77 to 15 minutes. We also show that using CNN produces reconstructions of equivalent quality to compressed sensing with 40% fewer projections. We further show that diverse training data classes, for example, ex vivo mouse tissue data, can be used for CNN-based reconstructions of OPT data of other species including live zebrafish.

Cardiac output monitoring: A comparative prospective observational study of the conventional cardiac output monitor Vigileo™ and the new smartphone-based application Capstesia™.

BACKGROUND AND AIMS: Capstesia is a software designed for smartphones (AndroidTM/iOSTM) to estimate the cardiac output and other haemodynamic variables from the waveform obtained from an invasive arterial cannula. The technology has been validated by studies in simulated environmental conditions. We compared the cardiac output (CO) and stroke volume variation (SVV) obtained by conventional cardiac output monitor VigileoTM with CO and pulse pressure variation (PPV) extracted from CapstesiaTM, under clinical conditions, intraoperatively. METHODS: In a Samsung smartphone in which the Capstesia software had been downloaded, the application was opened and a snapshot of the arterial waveform from the monitor screen of anaesthesia workstation was taken. The application instantaneously calculates the CO and PPV after inputting the heart rate and the systolic and diastolic blood pressure variables. These values were then compared with readings from the VigileoTM monitor. Data was collected from 53 patients and analysed. RESULTS: Five hundred and thirty data pairs of CO and an equal number of SVV and PPV pairs were analysed. Cardiac index by Capstesia (CIcap) was found to have a positive correlation with cardiac index by Vigileo (CIvig) using the intraclass correlation for raters, the strength of correlation being 0.757. Upper and lower 95% confidence limits were 1.43 l/min/m2 and - 1.14 l/min/m2 (Bland Altman's plot). A positive correlation was found between SVV and PPV using the Pearson's correlation (r = 0.732). CONCLUSION: CapstesiaTM is a reliable and feasible alternative to VigileoTM for intraoperative CO monitoring in oncosurgical patients.

Robotic hysterectomy in Trendelenburg position in a severely anaemic JKa alloimmunised patient with impending high-output cardiac failure: An anaesthetic challenge.

Kidd blood group alloimmunisation, though extremely rare, may produce considerable morbidity, and even mortality. Severe anaemia and impending high-output cardiac failure requiring blood transfusion should be weighed against the risk of severe transfusion reactions even with fully cross-matched blood. Kidd antibodies are a common cause of delayed haemolytic transfusion reaction (DHTR) since they have a tendency remain undetectable in plasma. A low -grade DHTR (second hit) was grossly amplified by a second DHTR (third hit) superimposed on it in our patient leading to severe haemolysis with serum bilirubin reaching 68 mg%. Indirect antiglobulin test (indirect Coombs reaction) should ideally be performed in all patients (scheduled for major surgery requiring blood transfusion) who have experienced a previous pregnancy or blood transfusion. Non-invasive continuous haemoglobin monitoring and non-invasive cardiac output monitoring can prove invaluable tools in management.

A randomized controlled trial comparing C Mac D Blade and Macintosh laryngoscope for nasotracheal intubation in patients undergoing surgeries for head and neck cancer.

PURPOSE: Several devices are available to take care of difficult airway, but C-MAC D-Blade has scant evidence of its use in nasotracheal intubation in a difficult airway scenario. AIMS AND OBJECTIVES: We compared the C-MAC D-Blade videolaryngoscope™, and the standard Macintosh laryngoscope for nasal intubation in patients with difficult airways selected by El-Ganzouri risk index using parameters of time and attempts required for intubation, glottic view in terms of Cormack-Lehane grade, ease of intubation, success rate, use of accessory maneuvers, incidence of complications, and hemodynamic changes. METHODS: One hundred American Society of Anesthesiologists (ASA) I-III patients aged 20-70 years with EGRI score 1-≤7 scheduled for head and neck surgery requiring nasal intubation. ASA IV patients, patients with mouth opening <2.5 cm, patients difficult to mask ventilate, and patients with hyperkalemia and history of malignant hyperthermia were excluded from the study. Primary outcome was time taken to intubation, and secondary outcomes were a number of attempts, glottic view in terms of C/L grade, use of accessory maneuvers, success rate, incidence of trauma, ease of intubation, and hemodynamic changes before and after intubation. RESULTS: Time required for intubation was less (39.56 ± 15.65 s) in Group C than in Group M (50.34 ± 15.65 s). Cormack-Lehane Grade I and II view were more in C-MAC D-Blade group (P < 0.05). Success rate and ease of intubation were found to be more in C-MAC D-Blade group than in Macintosh group (P < 0.05). A number of attempts and incidence of complications such as trauma, bleeding, and failed intubation were greater in Macintosh group than in C-MAC D-Blade group. Hemodynamic changes were observed to be comparable in both the groups. CONCLUSION: C-MAC D-Blade videolaryngoscope™ is a better tool in anesthetic management of difficult airway for nasal intubation compared to conventional Macintosh laryngoscope.

Anesthesia for minimally invasive chest wall reconstructive surgeries: Our experience and review of literature.

Minimal access procedures have revolutionized the field of surgery and opened newer challenges for the anesthesiologists. Pectus carinatum or pigeon chest is an uncommon chest wall deformity characterized by a protruding breast bone (sternum) and ribs caused by an overgrowth of the costal cartilages. It can cause a multitude of problems, including severe pain from an intercostal neuropathy, respiratory dysfunction, and psychologic issues from the cosmetic disfigurement. Pulmonary function indices, namely, forced expiratory volume over 1 s, forced vital capacity, vital capacity, and total lung capacity are markedly compromised in pectus excavatum. Earlier, open surgical correction in the form of the Ravitch procedure was followed. Currently, in the era of minimally invasive surgery, Nuss technique (pectus bar procedure) is a promising step in chest wall reconstructive surgery for pectus excavatum. Reverse Nuss is a corrective, minimally invasive surgery for pectus carinatum chest deformity. A tailor-made anesthetic technique for this new procedure has been described here based on the authors' personal experience and thorough review of literature based on Medline, Embase, and Scopus databases search.

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity.

Intrinsically disordered proteins (IDPs) that lack a unique 3D structure and comprise a large fraction of the human proteome play important roles in numerous cellular functions. Prostate-Associated Gene 4 (PAGE4) is an IDP that acts as a potentiator of the Activator Protein-1 (AP-1) transcription factor. Homeodomain-Interacting Protein Kinase 1 (HIPK1) phosphorylates PAGE4 at S9 and T51, but only T51 is critical for its activity. Here, we identify a second kinase, CDC-Like Kinase 2 (CLK2), which acts on PAGE4 and hyperphosphorylates it at multiple S/T residues, including S9 and T51. We demonstrate that HIPK1 is expressed in both androgen-dependent and androgen-independent prostate cancer (PCa) cells, whereas CLK2 and PAGE4 are expressed only in androgen-dependent cells. Cell-based studies indicate that PAGE4 interaction with the two kinases leads to opposing functions. HIPK1-phosphorylated PAGE4 (HIPK1-PAGE4) potentiates c-Jun, whereas CLK2-phosphorylated PAGE4 (CLK2-PAGE4) attenuates c-Jun activity. Consistent with the cellular data, biophysical measurements (small-angle X-ray scattering, single-molecule fluorescence resonance energy transfer, and NMR) indicate that HIPK1-PAGE4 exhibits a relatively compact conformational ensemble that binds AP-1, whereas CLK2-PAGE4 is more expanded and resembles a random coil with diminished affinity for AP-1. Taken together, the results suggest that the phosphorylation-induced conformational dynamics of PAGE4 may play a role in modulating changes between PCa cell phenotypes. A mathematical model based on our experimental data demonstrates how differential phosphorylation of PAGE4 can lead to transitions between androgen-dependent and androgen-independent phenotypes by altering the AP-1/androgen receptor regulatory circuit in PCa cells.

Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation.

Signaling mediated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) is involved in numerous cellular processes. Mitogen-activated protein kinase kinases (MEK1/2) catalyze the phosphorylation of ERK1/2, converting it into an active kinase that regulates the expression of numerous genes and cellular processes. Inhibitors of MEK1/2 have demonstrated preclinical and clinical efficacy in certain cancers and types of cardiomyopathy. We report the synthesis of a novel, allosteric, macrocyclic MEK1/2 inhibitor that potently inhibits ERK1/2 activity in cultured cells and tissues of mice after systemic administration. Mice with dilated cardiomyopathy caused by a lamin A/C gene mutation have abnormally increased cardiac ERK1/2 activity. In these mice, this novel MEK1/2 inhibitor is well tolerated, improves left ventricular systolic function, decreases left ventricular fibrosis, has beneficial effects on skeletal muscle structure and pathology and prolongs survival. The novel MEK1/2 inhibitor described herein may therefore find clinical utility in the treatment of this rare cardiomyopathy, other types of cardiomyopathy and cancers in humans.