Longitudinal Assessment of BNT162b2- and mRNA-1273-Induced Anti-SARS-CoV-2 Spike IgG Levels and Avidity Following Three Doses of Vaccination.

SARS-CoV-2 vaccination-induced protection against infection is likely to be affected by functional antibody features. To understand the kinetics of antibody responses in healthy individuals after primary series and third vaccine doses, sera from the recipients of the two licensed SARS-CoV-2 mRNA vaccines were assessed for circulating anti-SARS-CoV-2 spike IgG levels and avidity for up to 6 months post-primary series and 9 months after the third dose. Following primary series vaccination, anti-SARS-CoV-2 spike IgG levels declined from months 1 to 6, while avidity increased through month 6, irrespective of the vaccine received. The third dose of either vaccine increased anti-SARS-CoV-2 spike IgG levels and avidity and appeared to enhance antibody level persistence-generating a slower rate of decline in the 3 months following the third dose compared to the decline seen after the primary series alone. The third dose of both vaccines induced significant avidity increases 1 month after vaccination compared to the avidity response 6 months post-primary series vaccination (p ≤ 0.001). A significant difference in avidity responses between the two vaccines was observed 6 months post-third dose, where the BNT162b2 recipients had higher antibody avidity levels compared to the mRNA-1273 recipients (p = 0.020).

Buprenorphine Facilitates Rapid Weaning From Very-High-Dose Intrathecal Hydromorphone.

Pain management in patients on chronic opioid therapy is a common clinical challenge. The phenomena of opioid-induced hyperalgesia and tolerance are important contributors to that challenge. There are multiple strategies described to wean opioid doses and/or transition patients off opioids altogether. However, there is very little data to guide transitions off chronic intrathecal opioids. Here, we report on two patients with intractable post-laminectomy pain syndrome, resulting in severe functional limitation in the setting of opioid escalation culminating in the intrathecal delivery of hydromorphone to daily doses as high as 20 mg/day. We describe their rapid successful weaning off opioids using low-dose buprenorphine, which resulted in a dramatic improvement in pain and function.

Evidence-based target setting informs blue carbon strategies for nationally determined contributions.

The magnitude and pace of global climate change demand ambitious and effective implementation of nationally determined contributions (NDCs). Nature-based solutions present an efficient approach to achieving mitigation, adaptation and resilience goals. Yet few nations have quantified the diverse benefits of nature-based solutions to evaluate and select ecosystem targets for their NDCs. Here we report on Belize's pursuit of innovative, evidence-based target setting by accounting for multiple benefits of blue carbon strategies. Through quantification of carbon storage and sequestration and optimization of co-benefits, we explore time-bound targets and prioritize locations for mangrove protection and restoration. We find increases in carbon benefits with larger mangrove investments, while fisheries, tourism and coastal risk-reduction co-benefits grow initially and then plateau. We identify locations, currently lacking protected status, where prioritizing blue carbon strategies would provide the greatest delivery of co-benefits to communities. These findings informed Belize's updated NDCs to include an additional 12,000 ha of mangrove protection and 4,000 ha of mangrove restoration, respectively, by 2030. Our study serves as an example for the more than 150 other countries that have the opportunity to enhance greenhouse gas sequestration and climate adaptation by incorporating blue carbon strategies that provide multiple societal benefits into their NDCs.

SARS-CoV-2 IgG Spike antibody levels and avidity in natural infection or following vaccination with mRNA-1273 or BNT162b2 vaccines.

Certain aspects of the immunogenicity and effectiveness of the messenger ribonucleic acid (mRNA) vaccines (mRNA-1273 and BNT162b2) developed in response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are still uncharacterized. Serum or plasma samples from healthy donor recipients of either vaccine (BNT162b2 n = 53, mRNA-1273 n = 49; age 23-67), and individuals naturally infected with SARS-CoV-2 (n = 106; age 18-82) were collected 0-2 months post-infection or 1- and 4 months after second dose of vaccination. Anti-Spike antibody levels and avidity were measured via an enzyme-linked immunosorbent assay (ELISA). Overall, vaccination induced higher circulating anti-Spike protein immunoglobulin G (IgG) antibody levels and avidity compared to infection at similar time intervals. Both vaccines produced similar anti-Spike IgG concentrations at 1 month, while mRNA-1273 demonstrated significantly higher circulating antibody concentrations after 4 months. mRNA-1273 induced significantly higher avidity at month 1 compared to BNT162b2 across all age groups. However, the 23-34 age group was the only group to maintain statistical significance by 4 months. Male BNT162b2 recipients were approaching statistically significant lower anti-Spike IgG avidity compared to females by month 4. These findings demonstrate enhanced anti-Spike IgG levels and avidity following vaccination compared to natural infection. In addition, the mRNA-1273 vaccine induced higher antibody levels by 4 months compared to BNT162b2.

Perioperative Management of Extended-Release Buprenorphine: A Narrative Review and Case Series.

BACKGROUND: Perioperative management of formulations of buprenorphine used for the treatment of opioid use disorder and/or pain are common clinical challenges. Care strategies are increasingly recommending continuation of buprenorphine while administering multimodal analgesia including full agonist opioids. While this "simultaneous strategy" is relatively simple for the shorter-acting sublingual buprenorphine formulation, best practices are needed for the increasingly prescribed extended-release buprenorphine (ER-buprenorphine). To our knowledge there are no prospective data to guide perioperative management of patients on ER-buprenorphine. Herein we provide a narrative review, report on the perioperative experiences of a series of patients maintained on ER-buprenorphine, and propose recommendations for perioperative ER-buprenorphine management based on best evidence, clinical experience, and our judgments. CASES: Here we present clinical data describing the perioperative experiences of patients maintained on extended-release buprenorphine who recently underwent a variety of surgeries ranging from outpatient inguinal hernia repair to multiple inpatient surgeries for source control in sepsis, at different medical centers throughout the United States. These patients were identified via an email solicitation to substance use disorder treatment providers throughout a nationwide healthcare system, requesting cases of patients maintained on extended-release buprenorphine who had recently undergone surgery. We report here on all of the cases received. DISCUSSION: Extrapolating from these and recently published case reports, we describe an approach to perioperative management of extended-release buprenorphine.

Severe Pulmonary Hypertension Meets Intraperitoneal Surgery: No Place to Inflate?

Severe pulmonary hypertension (PH) is associated with poor operative outcomes; however, guidance for perioperative management of this population is lacking. Mechanical ventilation has known deleterious effects on right ventricular preload and cardiac output. Meanwhile, pneumoperitoneum results in further cardiopulmonary insults. We report the successful case management of a patient with severe PH scheduled for elective cholecystectomy. While patients undergoing this surgery typically benefit from the less invasive, laparoscopic approach, the risk-benefit ratio may tilt towards risk in the setting of severe PH. A multidisciplinary approach to optimize outcome included the decision to perform an open rather than laparoscopic procedure, which resulted in a favorable outcome.

Perioperative Management of Extended-release Buprenorphine.

Perioperative management of buprenorphine is increasingly characterized by continuation of buprenorphine throughout the perioperative period while coadministering full agonist opioids for analgesia. Although this "simultaneous strategy" is commonly used for the shorter-acting sublingual buprenorphine formulations, there is little to guide management of the extended-release formulations of buprenorphine. Here we report the perioperative experience of an individual maintained on extended-release buprenorphine who successfully underwent major surgeries utilizing a strategy of performing the surgeries at the time of the next scheduled dose.

Use of protective antigen of Bacillus anthracis as a model recombinant antigen to evaluate toll-like receptors 2, 3, 4, 7 and 9 agonists in mice using established functional antibody assays, antigen-specific antibody assays and cellular assays.

Toll-like receptor (TLR) agonists can act as immune stimulants alone or as part of alum or oil formulations. Humoral and cellular immune responses were utilized to assess quantitative and qualitative immune response enhancement by TLR agonists using recombinant protective antigen (rPA) of B. anthracis as a model antigen. To rPA, combined with aluminum hydroxide (Alhydrogel; Al(OH)3) or squalene (AddaVax™), was added one of 7 TLR agonists: TLR2 agonist Pam3CysSK4 (PamS), TLR3 agonist double stranded polyinosinic:polycytidylic acid (PolyIC), TLR4 agonists Monophosphoryl lipid A (MPLA) or glucopyranosyl lipid A (GLA), TLR7-8 agonists 3M-052 or Resiquimod (Resiq), or TLR9 agonist CPG 7909 (CPG). CD-1 or BALB/c mice received two intraperitoneal or intramuscular immunizations 14 days apart, followed by serum or spleen sampling 14 days later. All TLR agonists except PamS induced high levels of B. anthracis lethal toxin-neutralizing antibodies and immunoglobulin G (IgG) anti-PA. Some responses were >100-fold higher than those without a TLR agonist, and IP delivery (0.5 mL) induced higher TLR-mediated antibody response increases compared to IM delivery (0.05 mL). TLR7-8 and TLR9 agonists induced profound shifts of IgG anti-PA response to IgG2a or IgG2b. Compared to the 14-day immunization schedule, use of a shortened immunization schedule of only 7 days between prime and boost found that TLR9 agonist CPG in a squalene formulation maintained higher interferon-γ-positive cells than TLR4 agonist GLA. Variability in antibody responses was lower in BALB/c mice than CD-1 mice but antibody responses were higher in CD-1 mice. Lower serum 50% effective concentration (EC50) values were found for rPA-agonist formulations and squalene formulations compared to Al(OH)3 formulations. Lower EC50 values also were associated with low frequency detection of linear peptide epitopes. In summary, TLR agonists elicited cellular immune responses and markedly boosted humoral responses.

Development and Validation of a Risk Prediction Model for Second Primary Lung Cancer.

BACKGROUND: With advancing therapeutics, lung cancer (LC) survivors are rapidly increasing in number. Although mounting evidence suggests LC survivors have high risk of second primary lung cancer (SPLC), there is no validated prediction model available for clinical use to identify high-risk LC survivors for SPLC. METHODS: Using data from 6325 ever-smokers in the Multiethnic Cohort (MEC) study diagnosed with initial primary lung cancer (IPLC) in 1993-2017, we developed a prediction model for 10-year SPLC risk after IPLC diagnosis using cause-specific Cox regression. We evaluated the model's clinical utility using decision curve analysis and externally validated it using 2 population-based data-Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and National Lung Screening Trial (NLST)-that included 2963 and 2844 IPLC (101 and 93 SPLC cases), respectively. RESULTS: Over 14 063 person-years, 145 (2.3%) ever-smoking IPLC patients developed SPLC in MEC. Our prediction model demonstrated a high predictive accuracy (Brier score = 2.9, 95% confidence interval [CI] = 2.4 to 3.3) and discrimination (area under the receiver operating characteristics [AUC] = 81.9%, 95% CI = 78.2% to 85.5%) based on bootstrap validation in MEC. Stratification by the estimated risk quartiles showed that the observed SPLC incidence was statistically significantly higher in the 4th vs 1st quartile (9.5% vs 0.2%; P < .001). Decision curve analysis indicated that in a wide range of 10-year risk thresholds from 1% to 20%, the model yielded a larger net-benefit vs hypothetical all-screening or no-screening scenarios. External validation using PLCO and NLST showed an AUC of 78.8% (95% CI = 74.6% to 82.9%) and 72.7% (95% CI = 67.7% to 77.7%), respectively. CONCLUSIONS: We developed and validated a SPLC prediction model based on large population-based cohorts. The proposed prediction model can help identify high-risk LC patients for SPLC and can be incorporated into clinical decision making for SPLC surveillance and screening.

Perioperative Buprenorphine Management: A Multidisciplinary Approach.

Buprenorphine formulations (including buprenorphine/naloxone) are effective treatments of pain and opioid use disorder (OUD). Historically, perioperative management of patients prescribed buprenorphine involved abstinence from buprenorphine sufficient to allow for unrestricted mu-opioid receptor availability to full agonist opioid (FAO) treatment. Evidence is mounting that a multimodal analgesic strategy, including simultaneous administration of buprenorphine and FAO, nonopioid adjuncts such as acetaminophen and nonsteroidal anti-inflammatory drugs, and regional anesthesia, is a safe and effective perioperative strategy for the patient prescribed long-term buprenorphine treatment of OUD. This strategy will likely simplify management and more seamlessly provide continuous buprenorphine treatment of OUD after hospital discharge.

Opioid-induced analgesia among persons with opioid use disorder receiving methadone or buprenorphine: A systematic review of experimental pain studies.

BACKGROUND: Treating acute pain among persons with opioid use disorder (OUD) on opioid agonist therapy (OAT) is complex, and the therapeutic benefits of opioids remain unclear when weighted against their abuse potential and respiratory depressant effects. METHODS: We conducted a systematic review of experimental pain studies examining opioid-induced analgesia among persons with OUD on OAT. We searched multiple databases from inception to July 30, 2021. Study quality was assessed by previously established validity measures. RESULTS: Nine studies were identified, with a total of 225 participants, of whom 63% were male, and 37% were female. Six studies included methadone-maintained persons with OUD; four studies included buprenorphine-maintained persons with OUD; and three studies included healthy persons as comparison groups. Either additional doses of OAT or other opioids - morphine, oxycodone, hydromorphone, or remifentanil - were administered. In seven studies, persons with OUD on OAT did not experience analgesia, despite receiving opioid doses up to 20 times greater than those clinically used to treat severe pain among the opioid naïve. Conversely, in two studies, high-potency opioids did produce analgesia, albeit with greater abuse potential. Notably, persons with OUD on OAT remained vulnerable to respiratory depression. CONCLUSIONS: Although persons with OUD on OAT can derive analgesic effects from opioids, high-potency compounds may be required to achieve clinically significant pain relief. Further, persons with OUD on OAT may remain vulnerable to opioid-induced abuse potential and respiratory depression. Together, these finding have clinical, methodological, and mechanistic implications for the treatment of acute pain in the context of OAT.

Influenza Antigens NP and M2 Confer Cross Protection to BALB/c Mice against Lethal Challenge with H1N1, Pandemic H1N1 or H5N1 Influenza A Viruses.

Influenza hemagglutinin (HA) is considered a major protective antigen of seasonal influenza vaccine but antigenic drift of HA necessitates annual immunizations using new circulating HA versions. Low variation found within conserved non-HA influenza virus (INFV) antigens may maintain protection with less frequent immunizations. Conserved antigens of influenza A virus (INFV A) that can generate cross protection against multiple INFV strains were evaluated in BALB/c mice using modified Vaccinia virus Ankara (MVA)-vectored vaccines that expressed INFV A antigens hemagglutinin (HA), matrix protein 1 (M1), nucleoprotein (NP), matrix protein 2 (M2), repeats of the external portion of M2 (M2e) or as tandem repeats (METR), and M2e with transmembrane region and cytoplasmic loop (M2eTML). Protection by combinations of non-HA antigens was equivalent to that of subtype-matched HA. Combinations of NP and forms of M2e generated serum antibody responses and protected mice against lethal INFV A challenge using PR8, pandemic H1N1 A/Mexico/4108/2009 (pH1N1) or H5N1 A/Vietnam/1203/2004 (H5N1) viruses, as demonstrated by reduced lung viral burden and protection against weight loss. The highest levels of protection were obtained with NP and M2e antigens delivered as MVA inserts, resulting in broadly protective immunity in mice and enhancement of previous natural immunity to INFV A.

Tobacco Smoking and Risk of Second Primary Lung Cancer.

INTRODUCTION: Lung cancer survivors are at high risk of developing a second primary lung cancer (SPLC). However, SPLC risk factors have not been established and the impact of tobacco smoking remains controversial. We examined the risk factors for SPLC across multiple epidemiologic cohorts and evaluated the impact of smoking cessation on reducing SPLC risk. METHODS: We analyzed data from 7059 participants in the Multiethnic Cohort (MEC) diagnosed with an initial primary lung cancer (IPLC) between 1993 and 2017. Cause-specific proportional hazards models estimated SPLC risk. We conducted validation studies using the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 3423 IPLC cases) and European Prospective Investigation into Cancer and Nutrition (N = 4731 IPLC cases) cohorts and pooled the SPLC risk estimates using random effects meta-analysis. RESULTS: Overall, 163 MEC cases (2.3%) developed SPLC. Smoking pack-years (hazard ratio [HR] = 1.18 per 10 pack-years, p < 0.001) and smoking intensity (HR = 1.30 per 10 cigarettes per day, p < 0.001) were significantly associated with increased SPLC risk. Individuals who met the 2013 U.S. Preventive Services Task Force's screening criteria at IPLC diagnosis also had an increased SPLC risk (HR = 1.92; p < 0.001). Validation studies with the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and European Prospective Investigation into Cancer and Nutrition revealed consistent results. Meta-analysis yielded pooled HRs of 1.16 per 10 pack-years (pmeta < 0.001), 1.25 per 10 cigarettes per day (pmeta < 0.001), and 1.99 (pmeta < 0.001) for meeting the U.S. Preventive Services Task Force's criteria. In MEC, smoking cessation after IPLC diagnosis was associated with an 83% reduction in SPLC risk (HR = 0.17; p < 0.001). CONCLUSIONS: Tobacco smoking is a risk factor for SPLC. Smoking cessation may reduce the risk of SPLC. Additional strategies for SPLC surveillance and screening are warranted.

Accuracy of Self-reported Colonic Polyps: Results from the Prostate, Lung, Colorectal, and Ovarian Screening Trial Study of Colonoscopy Utilization.

BACKGROUND: Colonoscopy follow-up recommendations depend on the presence or absence of polyps, and if found, their number, size, and histology. Patients may be responsible for conveying results between primary and specialty care or providing medical information to family members; thus, accurate reporting is critical. This analysis assessed the accuracy of self-reported colonoscopy findings. METHODS: 3,986 participants from the Study of Colonoscopy Utilization, an ancillary study nested within the Prostate, Lung, Colorectal, and Ovarian Screening Trial, were included. Self-reports of polyp and adenoma were compared to medical records, and measures of sensitivity and specificity were calculated. Correlates of accurate self-report of polyp were assessed using logistic regression and weighted to account for study sampling. RESULTS: The sensitivity and specificity of self-reported polyp findings were 88% and 85%, respectively, and for adenoma 11% and 99%, respectively. Among participants with a polyp, older age was associated with lower likelihood while polyp severity and non-white race were associated with increased likelihood of accurate recall. Among participants without a polyp, having multiple colonoscopies was associated with lower likelihood while family history of colorectal cancer was associated with increased likelihood of accurate recall. Among both groups, longer time since colonoscopy was associated with lower likelihood of accurate recall. CONCLUSIONS: Participants recalled with reasonable accuracy whether they had a prior polyp; however, recall of histology, specifically adenoma, was much less accurate. IMPACT: Identification of strategies to increase accurate self-report of colonic polyps are needed, particularly for patient-provider communications and patient reporting of results to family members.

Tales From VA Anesthesiology.

A 99-year-old veteran, his family, and an anesthesiologist practice shared decision making to ensure patient-centered care before a procedure.

Patient-Centered Perioperative Care for a Victim of Military Sexual Trauma.

INTRODUCTION: The patient population seen in our nation's Veterans Affairs Healthcare system is increasingly female and an alarming percentage of our veterans, male and female alike, report a history of military sexual trauma (MST), which is associated with an increased burden of morbidities including post-traumatic stress disorder (PTSD) and substance abuse. The experience of surgery can produce symptoms of PTSD in a clinically significant percentage of patients. This article describes the challenges of achieving a patient-centered perioperative care plan in the case of a female veteran who suffers from PTSD as a result of MST. METHODS: We provide a brief background on the changing demographics of our nation's veterans, a review of MST and patient-centered care, and a description of the interdisciplinary care plan created and implemented for our patient. We note how this care model employs key elements of the Perioperative Surgical Home Model as developed by the American Society of Anesthesiologists. Finally, we propose an agenda for improving perioperative care for this group of veterans. No institutional review board was required for this case report-based discussion. RESULTS: The patient-centered care plan developed and implemented by an interdisciplinary team was well received by the patient and enabled her to comply with her postsurgical physical therapy. This recent interdisciplinary experience was in stark contrast to her experience of former surgical procedures, and produced much higher patient satisfaction. CONCLUSION: Improvements are needed in patient-centered perioperative care for victims of MST, both within the Veterans Affairs system and in the larger health care system. We suggest an agenda to improve care for these patients including: (1) increasing provider awareness and education about MST and about the potential psychological trauma of surgery per se, (2) employing elements of the Perioperative Surgical Home to encourage patient-centered care involving collaboration within an interdisciplinary team, (3) and measurement of patient centered outcomes. Perioperative care for the victim of MST is heretofore not addressed in the literature. We hope this case report and review will stimulate further research into optimizing care for these vulnerable patients.

An Agenda for Improving Perioperative Code Status Discussion.

Code status discussions (CSDs) clarify patient preferences for cardiopulmonary resuscitation in the event of cardiac or respiratory arrest. CSDs are a key component of perioperative care, particularly at the end of life, and must be both patient-centered and shared. Physicians at all levels of training are insufficiently trained in and inappropriately perform CSD; this may be particularly true of perioperative physicians. In this article, we describe the difficulty of achieving a patient-centered, shared perioperative CSD in the case of a medical professional with a do-not-resuscitate order. We provide a brief background in cardiopulmonary resuscitation, do-not-resuscitate, and CSD before proposing an agenda for improving perioperative CSD.

Occurrence of Distal Colorectal Neoplasia Among Whites and Blacks Following Negative Flexible Sigmoidoscopy: An Analysis of PLCO Trial.

BACKGROUND: It is unclear whether the higher rate of colorectal cancer (CRC) among non-Hispanic blacks (blacks) is due to lower rates of CRC screening or greater biologic risk. OBJECTIVE: We aimed to evaluate whether blacks are more likely than non-Hispanic whites (whites) to develop distal colon neoplasia (adenoma and/or cancer) after negative flexible sigmoidoscopy (FSG). DESIGN: We analyzed data of participants with negative FSGs at baseline in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial who underwent repeat FSGs 3 or 5 years later. Subjects with polyps or masses were referred to their physicians for diagnostic colonoscopy. We collected and reviewed the records of diagnostic evaluations. PARTICIPANTS: Our analytic cohort consisted of 21,550 whites and 975 blacks. MAIN MEASURES: We did a comparison by race (whites vs. blacks) in the findings of polyps or masses at repeat FSG, the follow-up of abnormal test results and the detection of colorectal neoplasia at diagnostic colonoscopy. KEY RESULTS: At the follow-up FSG examination, 304 blacks (31.2 %) and 4183 whites (19.4 %) had abnormal FSG, [adjusted relative risk (RR) = 1.00; 95 % confidence interval (CI), 0.90-1.10]. However, blacks were less likely to undergo diagnostic colonoscopy (76.6 % vs. 83.1 %; RR = 0.90; 95 % CI, 0.84-0.96). Among all included patients, blacks had similar risk of any distal adenoma (RR = 0.86; 95 % CI, 0.65-1.14) and distal advanced adenoma (RR = 1.01; 95 % CI, 0.60-1.68). Similar results were obtained when we restricted our analysis to compliant subjects who underwent diagnostic colonoscopy (RR = 1.01; 95 % CI, 0.80-1.29) for any distal adenoma and (RR = 1.18; 95 % CI, 0.73-1.92) for distal advanced adenoma. CONCLUSIONS: We did not find any differences between blacks and whites in the risk of distal colorectal adenoma 3-5 years after negative FSG. However, follow-up evaluations were lower among blacks.