Human parainfluenza virus 3 vaccine candidates attenuated by codon-pair deoptimization are immunogenic and protective in hamsters.

Human parainfluenza virus type 3 (HPIV3) is a major pediatric respiratory pathogen lacking available vaccines or antiviral drugs. We generated live-attenuated HPIV3 vaccine candidates by codon-pair deoptimization (CPD). HPIV3 open reading frames (ORFs) encoding the nucleoprotein (N), phosphoprotein (P), matrix (M), fusion (F), hemagglutinin-neuraminidase (HN), and polymerase (L) were modified singly or in combination to generate 12 viruses designated Min-N, Min-P, Min-M, Min-FHN, Min-L, Min-NP, Min-NPM, Min-NPL, Min-PM, Min-PFHN, Min-MFHN, and Min-PMFHN. CPD of N or L severely reduced growth in vitro and was not further evaluated. CPD of P or M was associated with increased and decreased interferon (IFN) response in vitro, respectively, but had little effect on virus replication. In Vero cells, CPD of F and HN delayed virus replication, but final titers were comparable to wild-type (wt) HPIV3. In human lung epithelial A549 cells, CPD F and HN induced a stronger IFN response, viral titers were reduced 100-fold, and the expression of F and HN proteins was significantly reduced without affecting N or P or the relative packaging of proteins into virions. Following intranasal infection in hamsters, replication in the nasal turbinates and lungs tended to be the most reduced for viruses bearing CPD F and HN, with maximum reductions of approximately 10-fold. Despite decreased in vivo replication (and lower expression of CPD F and HN in vitro), all viruses induced titers of serum HPIV3-neutralizing antibodies similar to wt and provided complete protection against HPIV3 challenge. In summary, CPD of HPIV3 yielded promising vaccine candidates suitable for further development.

Evaluation of the management of intestinal perforation in very low birth infants, a 10-year review.

AIM: The aim of this study was to assess outcomes of peritoneal drainage and laparotomy in the management of intestinal perforation secondary to necrotizing enterocolitis (NEC) and spontaneous intestinal perforation. METHODS: A retrospective review of all preterm infants (birthweight ≤1500 g) who underwent surgical intervention (peritoneal drainage and/or laparotomy) for intestinal perforation between March 2010 and March 2020. RESULTS: A total of 43 infants who underwent surgical intervention for intestinal perforation were included [19 (44%) with NEC and 24 (56%) with spontaneous intestinal perforation]. Peritoneal drainage was more commonly placed as the initial surgical procedure for management of spontaneous intestinal perforation compared with surgical NEC [23 (96%) vs. 11 (58%), p = 0.003]. Mortality was greater for infants who were initially managed with peritoneal drainage [11 (32%)] compared with those who underwent primary laparotomy [2 (22%), p = 0.5]. CONCLUSION: Initial surgical management of intestinal perforation is more often according to underlying pathology. Our data support primary laparotomy for infants with perforated NEC.

Outcomes and characteristics in term infants with necrotising enterocolitis and CHD.

BACKGROUND: CHD is a significant risk factor for the development of necrotising enterocolitis. Existing literature does not differentiate between term and preterm populations. Long-term outcomes of these patients are not well understood. The aim was to investigate the baseline characteristics and outcomes of term normal birth weight infants with CHD who developed necrotising enterocolitis. METHODS: A retrospective review was performed of infants from a single tertiary centre with CHD who developed necrotising enterocolitis of Bell's Stage 1-3, over a ten-year period. Inclusion criteria was those born greater than 36 weeks' gestation and birth weight over 2500g. Exclusion criteria included congenital gastro-intestinal abnormalities. Sub-group analysis was performed using Fisher's exact test. RESULTS: Twenty-five patients were identified, with a median gestational age of 38 weeks. Patients with univentricular physiology accounted for 32% (n = 8) and 52% of patients (n = 13) had a duct-dependent lesion. Atrioventricular septal defect was the most common cardiac diagnosis (n = 6, 24%). Patients with trisomy 21 accounted for 20% of cases. Mortality within 30 days of necrotising enterocolitis was 20%. Long-term mortality was 40%, which increased with increasing Bell's Stage. In total, 36% (n = 9) required surgical management of necrotising enterocolitis, the rate of which was significantly higher in trisomy 21 cases (p < 0.05). CONCLUSION: Not previously described in term infants is the high rate of trisomy 21 and atrioventricular septal defect. This may reflect higher baseline incidence in our population. Infants with trisomy 21 were more likely to develop surgical necrotising enterocolitis. Mortality at long-term follow-up was high in patients with Bell's Stage 2-3.

Quantifying drug overdose deaths: A troubled path from start to finish.

Between 1999 and 2019, according to the Centers for Disease Control and Prevention (CDC), nearly 450,000 people died from overdoses involving prescribed opioids. This review examines how drug overdose deaths are compiled by the CDC using the coding system of the International Classification of Diseases (ICD). When it comes to drug-involved deaths, the ICD may not tell the whole story or even the right story. To learn why, the authors examined the CDC's source data and the standard death certificate. In fatal drug overdose cases, death certificates are issued often before the results of post-mortem toxicology are known by the certifier. The CDC believes that this delay in the death investigation process may account for errors when, for example, certifiers list ambiguous terms such as "suspected acute drug intoxication" or "possible drug overdose" as a cause of death. When incomplete data are coded according to the ICD, the error is passed along while potentially useful information is lost. The result may reflect accurately the annual total of drug-involved overdose deaths while obscuring the lethality of individual substances, consumed alone or in combination, which contributed to, or caused, drug-involved deaths. The true cause of most fatal drug overdoses-polysubstance abuse-often is lost in this process. A key objective of this paper is to describe the process used by the CDC to report drug-involved mortality and how the current iteration of the ICD may be ill-suited for this important task.

A novel report of a fertile female with partial Y chromosome gain completing a healthy pregnancy.

We present a female patient with a complex sex chromosomal rearrangement [GRCh38] Xp22.33(10701_981101)x1,Yq11.221q11.23(13948013_26483746)x1 who conceived spontaneously and carried a healthy pregnancy to term. The patient presented with extreme short stature (more than 4SD below expected) and a bilateral Madelung deformity suggesting a possible SHOX deletion. The patient was otherwise medically well. This patient's short stature was found to be a result of a complex chromosome rearrangement involving a partial X chromosome deletion, which included the SHOX gene and a gain of Y chromosomal material. The Y chromosome material did not contain the SRY gene locus. This is the first recorded case to date of this rearrangement in a female who spontaneously conceived which resulted in a live birth. This patient had normal external and internal anatomy and normal endocrine evaluation with normal puberty. X-inactivation studies revealed no evidence of skewed inactivation.

Substance Use Disorders: Basic Overview for the Anesthesiologist.

Substance use disorders (SUDs) represent a current major public health concern in the United States and around the world. Social and economic stressors secondary to the coronavirus disease 2019 (COVID-19) pandemic have likely led to an increase in SUDs around the world. This chronic, debilitating disease is a prevalent health problem, and yet many clinicians do not have adequate training or clinical experience diagnosing and treating SUDs. Anesthesiologists and other perioperative medical staff frequently encounter patients with co-occurring SUDs. By such, through increased awareness and education, physicians and other health care providers have a unique opportunity to positively impact the lives and improve the perioperative outcomes of patients with SUDs. Understanding commonly used terms, potentially effective perioperative screening tools, diagnostic criteria, basics of treatment, and the perioperative implications of SUDs is essential to providing adequate care to patients experiencing this illness.

The cost of rejection: an internal audit of the clinical genetics service active triage pathway at CHI Crumlin, Ireland.

BACKGROUND: Clinical genetics is an under-resourced service in the Republic of Ireland. There can be a number of avenues that lead to barriers in patient triage noted within the department. AIMS: To evaluate the reasons for referral rejection in the triage pathway. To identify the time and cost implications. METHODS: A retrospective analysis of rejected referrals consecutively triaged by one consultant was undertaken over an 18-month period. Calculation of costs used data from a previous study. RESULTS: The consultant rejected 128/1581 (8.3%) of referrals. The rejection reasons included the following: 75% had not included the family/patient genetic report, 10% were conditions not accepted by our service, 8% redirected to other specialities, 3% given written advice in lieu of appointment and 4% for other reasons. Follow-up information was requested on 78% of rejected referrals. For 57% this was received; in 43% no response was received, and these cases remain closed. Median response time was 33 days. Of those who sent back appropriate information, 39% remain on waiting list, 50% attended OPD or were given appropriate advice, 5% did not attend and 4% had alternative follow-up pathways. The estimated time cost of rejected referrals equated to 88.5 h (59 h/year). Using this as our cost of rejection letter, it equated €11,878.4/year departmental cost. CONCLUSION: The majority of referrals are rejected for non-enclosure of patient genetic reports. Many referrals would have accepted to the waiting list if the appropriate report had been attached. This means patients at risk of genetic disorders are not accessing clinical services because the referrer is not providing the necessary information to allow triage. Active management of the waiting list via upfront letters is costly, with a 57% response rate. Should similar rejection rates exist in other specialities, we estimate this would equate to a cost of €2,714,214.40/year to the HSE.

Outcomes of Percutaneous Tracheostomy for Patients With SARS-CoV-2 Respiratory Failure.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause severe respiratory failure leading to prolonged mechanical ventilation. Data are just emerging about the practice and outcomes of tracheostomy in these patients. We reviewed our experience with tracheostomies for SARS-CoV-2. METHODS: We retrospectively reviewed the demographics, comorbidities, timing of mechanical ventilation, tracheostomy, and intensive care unit and hospital lengths of stay in SARS-CoV-2 patients who received tracheostomies performed by the interventional pulmonary team. A tertiary care, teaching hospital in Chicago, Illinois. From March 2020 to April 2021, our center had 473 patients intubated for SARS-CoV-2, and 72 (15%) had percutaneous bedside tracheostomy performed by the interventional pulmonary team. RESULTS: Median time from intubation to tracheostomy was 20 (interquartile range: 16 to 25) days. Demographics and comorbidities were similar between early and late tracheostomy, but early tracheostomy was associated with shorter intensive care unit lengths of stay and a shorter total duration of ventilation. To date, 39 (54%) patients have been decannulated, 17 (24%) before hospital discharge; median time to decannulation was 22 (IQR: 18 to 36) days. Patients that were decannulated were younger (56 vs. 69 y). The rate of decannulation for survivors was 82%. No providers developed symptoms or tested positive for SARS-CoV-2. CONCLUSION: Tracheostomy enhances care for patients with prolonged respiratory failure from SARS-CoV-2 since early tracheostomy is associated with shorter duration of critical care, and decannulation rates are high for survivors. It furthermore appears safe for both patients and operators.

How, when and why to establish preoperative surgical risk in thoracic surgery.

PURPOSE OF REVIEW: Emphasizing a systems-based approach, we discuss the timing for referral for perioperative surgical consultation. This review then highlights several types of comorbidities that may complicate thoracic procedures, and references recent best practices for their management. RECENT FINDINGS: Patients requiring thoracic surgeries present some of the most challenging cases for both intraoperative and postoperative management. The recent SARS-CoV-2 pandemic has only exacerbated these concerns. Effective preoperative optimization, however, provides for identification of patient comorbidities, allowing for mitigation of surgical risks. This kind of planning is multidisciplinary by nature. We believe patients benefit from early engagement of a dedicated preoperative clinic experienced for caring for complex surgical patients. SUMMARY: Optimizing patients for thoracic surgery can be challenging for small and large health systems alike. Implementation of evidence-based guidelines can improve care and mitigate risk. As surgical techniques evolve, future research is needed to ensure that perioperative care continues to progress.

Comparing bupivacaine alone to liposomal bupivacaine plus bupivacaine in interscalene blocks for total shoulder arthroplasty: a randomized, non-inferiority trial.

INTRODUCTION: Interscalene brachial plexus blocks are a commonly performed procedure to reduce pain following total shoulder arthroplasty. Liposomal bupivacaine has been purported to prolong the duration of brachial plexus blocks for up to 72 hours; however, there has been controversy surrounding the analgesic benefits of this drug. Our hypothesis was that an interscalene block performed with bupivacaine alone would be non-inferior to a combination of liposomal bupivacaine and bupivacaine with respect to opioid consumption following total shoulder arthroplasty. METHODS: Subjects presenting for primary total shoulder arthroplasty were randomized in a 1:1 ratio to an ultrasound-guided, single-injection interscalene block with either a combination of liposomal bupivacaine and bupivacaine (LB group) or bupivacaine without additive (Bupi group). The primary outcome of this study was 72-hour postoperative cumulative opioid consumption (in oral morphine equivalents) with a non-inferiority margin of 22.5 mg. Secondary outcomes included pain scores, patient satisfaction with analgesia and patient reported duration of sensory block. RESULTS: Seventy-six subjects, 38 from the Bupi group and 38 from the LB group, completed the study. Analysis of the primary outcome showed a 72-hour cumulative geometric mean oral morphine equivalent consumption difference of 11.9 mg (95% CI -6.9 to 30.8) between groups (calculated on the log scale). This difference constitutes approximately 1.5 tablets of oxycodone over 3 days. No secondary outcomes showed meaningful differences between groups. DISCUSSION: Interscalene brachial plexus blocks performed with bupivacaine alone did not demonstrate non-inferiority compared to a mixture of liposomal bupivacaine plus bupivacaine with regards to 72-hour cumulative opioid consumption following total shoulder arthroplasty. However, the difference between groups did not appear to be clinically meaningful.

Guided Approach to Implant Placement, Immediate Provisionalization, and Definitive Restoration: A Case Letter.

Replacement of missing teeth is becoming more prevalent, currently with more than 700,000 dental implants being placed every year. Patients seek out dental treatment with the expectations of having procedures performed in the least number of time/visits, for as inexpensive as possible, and at the highest quality. As this continues, clinicians can adapt with changing times and adopt the newer advancements in digital dentistry. This case letter aims to provide readers with insight to integration of digital workflows to optimize patient and clinician outcomes with single tooth implant therapy.

The Role of Long-Term Noninvasive Ventilation in Chronic Stable Hypercapnic Chronic Obstructive Pulmonary Disease.

Despite the heterogeneity of data on the role of noninvasive ventilation (NIV) in severe stable chronic obstructive pulmonary disease with chronic hypercapnia, the current evidence supports the use of NIV in select populations and phenotypes. The Center for Medicare and Medicaid Services reimbursement criteria are complex, and the practice of navigating the most efficient method to initiate NIV therapy continues to be challenging. These patients optimally require referral to a medical center that has physicians with specific training in pulmonary and sleep medicine, who can navigate the specific needs for the use of NIV.

The distribution of acquired peripheral nerve injuries associated with severe COVID-19 implicate a mechanism of entrapment neuropathy: a multicenter case series and clinical feasibility study of a wearable, wireless pressure sensor.

We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine this new data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of the feasibility for a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.

Nonhuman Primates Are Protected against Marburg Virus Disease by Vaccination with a Vesicular Stomatitis Virus Vector-Based Vaccine Prepared under Conditions to Allow Advancement to Human Clinical Trials.

Vaccines are needed to disrupt or prevent continued outbreaks of filoviruses in humans across Western and Central Africa, including outbreaks of Marburg virus (MARV). As part of a filovirus vaccine product development plan, it is important to investigate dose response early in preclinical development to identify the dose range that may be optimal for safety, immunogenicity, and efficacy, and perhaps demonstrate that using lower doses is feasible, which will improve product access. To determine the efficacious dose range for a manufacturing-ready live recombinant vesicular stomatitis virus vaccine vector (rVSV∆G-MARV-GP) encoding the MARV glycoprotein (GP), a dose-range study was conducted in cynomolgus macaques. Results showed that a single intramuscular injection with as little as 200 plaque-forming units (PFUs) was 100% efficacious against lethality and prevented development of viremia and clinical pathologies associated with MARV Angola infection. Across the vaccine doses tested, there was nearly a 2000-fold range of anti-MARV glycoprotein (GP) serum IgG titers with seroconversion detectable even at the lowest doses. Virus-neutralizing serum antibodies also were detected in animals vaccinated with the higher vaccine doses indicating that vaccination induced functional antibodies, but that the assay was a less sensitive indicator of seroconversion. Collectively, the data indicates that a relatively wide range of anti-GP serum IgG titers are observed in animals that are protected from disease implying that seroconversion is positively associated with efficacy, but that more extensive immunologic analyses on samples collected from our study as well as future preclinical studies will be valuable in identifying additional immune responses correlated with protection that can serve as markers to monitor in human trials needed to generate data that can support vaccine licensure in the future.

Pericapsular nerve group (PENG) block for hip arthroscopy: a randomized, double-blinded, placebo-controlled trial.

INTRODUCTION: Arthroscopic hip surgery is associated with significant postoperative pain. Femoral nerve blocks have been shown to improve postoperative analgesia at the expense of quadriceps weakness. The pericapsular nerve group (PENG) block could be an alternative that may improve postoperative analgesia while preserving quadriceps strength. Our hypothesis was that a PENG block would provide superior postoperative analgesia compared with a sham block following arthroscopic hip surgery. METHODS: Subjects presenting for arthroscopic hip surgery were randomized in a 1:1 ratio to either an ultrasound-guided unilateral, single-injection PENG block (PENG group) with 20 mL of 0.5% ropivacaine or a sham injection with 5 mL of 0.9% normal saline (Sham group) prior to receiving general anesthesia. The primary outcome of this study was worst pain score within 30 min of emergence from anesthesia. Secondary outcomes included opioid consumption, patient satisfaction with analgesia, opioid-related adverse events, and persistent opioid use at 1 week. RESULTS: Sixty-eight subjects, 34 from the PENG group and 34 from the Sham group, completed the study per protocol. Analysis of the primary outcome demonstrated a mean difference in pain scores of -0.79 (95% CI -1.96 to 0.37; p=0.17) between the PENG and Sham groups immediately following surgery. No secondary outcomes showed statistically significant differences between groups. DISCUSSION: This study demonstrates that a preoperative PENG block does not improve analgesia following arthroscopic hip surgery. TRIAL REIGSTRATION NUMBER: NCT04508504.

Echoes of Past Contact: Venetian Influence on Cretan Greek Intonation.

Prosodic aspects of cross-linguistic contact are under-researched, especially past contact that has subsequently ceased. In this paper, we investigate declarative and polar question tunes of contemporary Cretan Greek, a regional variety of Greek whose speakers were in contact with Venetian speakers during the four and half centuries of Venetian rule on the island, from 1204 to 1669. The F0 contours of the Cretan tunes and alignment of peaks and troughs of interest with the nuclear vowel are compared to the corresponding tunes in Venetian dialect and Venetian Italian and to those in Athenian (Standard) Greek, which are used as control. The data (1610 declarative utterances and 698 polar questions) were drawn from natural speech corpora based on pragmatic criteria: broad focus for declaratives, broad focus, and information-seeking interpretation for polar questions. The pitch contour shapes of the tunes are modeled using polynomial basis functions, and the F0 alignment points are determined analytically. The results show the robustness of contact effects almost three and a half centuries after regular contact ceased and indicate that the shapes of the F0 contours of Cretan and Venetian declarative and polar question tunes are similar. In addition, Cretan alignment patterns are similar to Venetian and significantly different from Athenian. Insights are gained from research into how long prosodic characteristics may persist in a recipient language-decades or even centuries after the cessation of contact.

Use of epidurography in the perioperative and acute pain setting.

Ensuring proper placement of epidural catheters is critical to improving their reliability for pain control and maintaining confidence in their continued use. This article will seek to address the role of objective confirmation of successful epidural placement via either single view or continuous epidural contrast studies, each creating an 'epidurogram.' Furthermore, the pertinent anatomical corollaries of continuous fluoroscopy used frequently in chronic pain medicine, from which these techniques emerged, will be addressed. Technical radiographic information needed to better understand and troubleshoot these studies is also included. Image examples which highlight the patterns key for successful interpretation of epidurograms will be provided. The aim of this paper was to provide an anesthesiologist unfamiliar with fluoroscopic evaluation of epidural catheters with the tools necessary to successfully conduct and interpret such an examination.