Novel Oral Polio Vaccine Type 2 Use for Polio Outbreak Response: A Global Effort for a Global Health Emergency.

A sharp rise in circulating vaccine-derived poliovirus type 2 (cVDPV2) outbreaks in the years following the cessation of routine use of poliovirus type 2-containing oral polio vaccine and the trend of seeding new emergences with suboptimal vaccination response during the same time-period led to the accelerated development of the novel oral polio vaccine type 2 (nOPV2), a vaccine with enhanced genetic stability and lower likelihood of reversion to neuroparalytic variants compared to its Sabin counterpart. In November 2020, nOPV2 became the first vaccine to be granted an Emergency Use Listing (EUL) by the World Health Organization (WHO) Prequalification Team (PQT), allowing close to a billion doses to be used by countries within three years after its first rollout and leading to full licensure and WHO prequalification (PQ) in December 2023. The nOPV2 development process exemplifies how scientific advances and innovative tools can be applied to combat global health emergencies in an urgent and adaptive way, building on a collaborative effort among scientific, regulatory and implementation partners and policymakers across the globe.

Using risk-adjusted cumulative sum to evaluate surgeon, divisional, and institutional outcomes-a feasibility study.

BACKGROUND: Few objective, real-time measurements of surgeon performance exist. The risk-adjusted cumulative sum is a novel method that can track surgeon-level outcomes on a continuous basis. The objective of this study was to demonstrate the feasibility of using risk-adjusted cumulative sum to monitor outcomes after colorectal operations and identify clinically relevant performance variations. METHODS: The National Surgical Quality Improvement Program was queried to obtain patient-level data for 1,603 colorectal operations at a high-volume center from 2011 to 2020. For each case, expected risks of morbidity, mortality, reoperation, readmission, and prolonged length of stay were estimated using the National Surgical Quality Improvement Program risk calculator. Risk-adjusted cumulative sum curves were generated to signal observed-to-expected odds ratios of 1.5 (poor performance) and 0.5 (exceptional performance). Control limits were set based on a false positive rate of 5% (α = 0.05). RESULTS: The cohort included data on 7 surgeons (those with more than 20 cases in the study period). Institutional observed versus expected outcomes were the following: morbidity 12.5% (vs 15.0%), mortality 2.5% (vs 2.0%), prolonged length of stay 19.7% (vs 19.1%), reoperation 11.1% (vs 11.3%), and 30-day readmission 6.1% (vs 4.8%). Risk-adjusted cumulative sum accurately demonstrated within- and between-surgeon performance variations across these metrics and proved effective when considering division-level data. CONCLUSION: Risk-adjusted cumulative sum adjusts for patient-level risk factors to provide real-time data on surgeon-specific outcomes. This approach enables prompt identification of performance outliers and can contribute to quality assurance, root-cause analysis, and incentivization not only at the surgeon level but at divisional and institutional levels as well.

An orally active entry inhibitor of influenza A viruses protects mice and synergizes with oseltamivir and baloxavir marboxil.

Seasonal or pandemic illness caused by influenza A viruses (IAVs) is a major public health concern due to the high morbidity and notable mortality. Although there are several approved drugs targeting different mechanisms, the emergence of drug resistance calls for new drug candidates that can be used alone or in combinations. Small-molecule IAV entry inhibitor, ING-1466, binds to hemagglutinin (HA) and blocks HA-mediated viral infection. Here, we show that this inhibitor demonstrates preventive and therapeutic effects in a mouse model of IAV with substantial improvement in the survival rate. When administered orally it elicits a therapeutic effect in mice, even after the well-established infection. Moreover, the combination of ING-1466 with oseltamivir phosphate or baloxavir marboxil enhances the therapeutic effect in a synergistic manner. Overall, ING-1466 has excellent oral bioavailability and in vitro absorption, distribution, metabolism, excretion, and toxicity profile, suggesting that it can be developed for monotherapy or combination therapy for the treatment of IAV infections.

Polyvalent Nanobody Structure Designed for Boosting SARS-CoV-2 Inhibition.

Coronavirus transmission and mutations have brought intensive challenges on pandemic control and disease treatment. Developing robust and versatile antiviral drugs for viral neutralization is highly desired. Here, we created a new polyvalent nanobody (Nb) structure that shows the effective inhibition of SARS-CoV-2 infections. Our polyvalent Nb structure, called "PNS", is achieved by first conjugating single-stranded DNA (ssDNA) and the receptor-binding domain (RBD)-targeting Nb with retained binding ability to SARS-CoV-2 spike protein and then coalescing the ssDNA-Nb conjugates around a gold nanoparticle (AuNP) via DNA hybridization with a desired Nb density that offers spatial pattern-matching with that of the Nb binding sites on the trimeric spike. The surface plasmon resonance (SPR) assays show that the PNS binds the SARS-CoV-2 trimeric spike proteins with a ∼1000-fold improvement in affinity than that of monomeric Nbs. Furthermore, our viral entry inhibition assays using the PNS against SARS-CoV-2 WA/2020 and two recent variants of interest (BQ1.1 and XBB) show an over 400-fold enhancement in viral inhibition compared to free Nbs. Our PNS strategy built on a new DNA-protein conjugation chemistry provides a facile approach to developing robust virus inhibitors by using a corresponding virus-targeting Nb with a desired Nb density.

Effectiveness of poliovirus vaccines against circulating vaccine-derived type 2 poliomyelitis in Nigeria between 2017 and 2022: a case-control study.

BACKGROUND: Between 2018 and 2022, Nigeria experienced continuous transmission of circulating vaccine-derived type 2 poliovirus (cVDPV2), with 526 cases of cVDPV2 poliomyelitis detected in total and approximately 180 million doses of monovalent type 2 oral poliovirus vaccine (mOPV2) and 450 million doses of novel type 2 oral poliovirus vaccine (nOPV2) delivered in outbreak response campaigns. Inactivated poliovirus vaccine (IPV) was introduced into routine immunisation in 2015, with a second dose added in 2021. We aimed to estimate the effectiveness of nOPV2 against cVDPV2 paralysis and compare nOPV2 effectiveness with that of mOPV2 and IPV. METHODS: In this retrospective case-control study, we used acute flaccid paralysis (AFP) surveillance data in Nigeria from Jan 1, 2017, to Dec 31, 2022, using age-matched, onset-matched, and location-matched cVDPV2-negative AFP cases as test-negative controls. We also did a parallel prospective study from March, 2021, using age-matched community controls from the same settlement as the cases. We included children born after May, 2016, younger than 60 months, for whom polio immunisation history (doses of OPV from campaigns and IPV) was reported. We estimated the per-dose effectiveness of nOPV2 against cVDPV2 paralysis using conditional logistic regression and compared nOPV2 effectiveness with that of mOPV2 and IPV. FINDINGS: In the retrospective case-control study, we identified 509 cVDPV2 poliomyelitis cases in Nigeria with case verification and paralysis onset between Jan 1, 2017, and Dec 31, 2022. Of these, 82 children were excluded for not meeting inclusion criteria, and 363 (85%) of 427 eligible cases were matched to 1303 test-negative controls. Cases reported fewer OPV and IPV doses than test-negative controls (mean number of OPV doses 5·9 [SD 4·2] in cases vs 6·7 [4·3] in controls; one or more IPV doses reported in 95 [26%] of 363 cases vs 513 [39%] of 1303 controls). We found low per-dose effectiveness of nOPV2 (12%, 95% CI -2 to 25) and mOPV2 (17%, 3 to 29), but no significant difference between the two vaccines (p=0·67). The estimated effectiveness of one IPV dose was 43% (23 to 58). In the prospective study, 181 (46%) of 392 eligible cases were matched to 1557 community controls. Using community controls, we found a high effectiveness of IPV (89%, 95% CI 83 to 93, for one dose), a low per-dose effectiveness of nOPV2 (-23%, -45 to -5) and mOPV2 (1%, -23 to 20), and no significant difference between the per-dose effectiveness of nOPV2 and mOPV2 (p=0·12). INTERPRETATION: We found no significant difference in estimated effectiveness of the two oral vaccines, supporting the recommendation that the more genetically stable nOPV2 should be preferred in cVDPV2 outbreak response. Our findings highlight the role of IPV and the necessity of strengthening routine immunisation, the primary route through which IPV is delivered. FUNDING: Bill & Melinda Gates Foundation and UK Medical Research Council.

Early Implementation of Robotic Training in Surgical and Surgical Subspecialty Residency.

BACKGROUND: Robotic surgery has emerged as an operative tool for many elective and urgent surgical procedures. The purpose of this study was to evaluate early surgical trainees' experiences and opinions of robotic surgery. METHODS: An introductory robotic training course consisting of online da Vinci Xi/X training and in-person, hands on training was implemented for residents and medical students across surgical subspecialties at a single institution. A voluntary survey evaluating perceptions of and interest in robotic surgery and prior robotic surgery experience, as well as a basics of robotics quiz, was distributed to participants prior to the start of the in-person session. Descriptive statistics were used to evaluate the cohort. RESULTS: 85 trainees participated in the course between 2020 and 2023, including 58 first- and second-year surgical residents (general surgery, urology, OB/GYN, and thoracic surgery) and 27 fourth-year medical students. 9.4% of participants reported any formal robotic surgery training prior to the session, with only 19% of participants reporting robotic operative experience. 52% of the participants knew of and/or had completed the da Vinci online course modules prior to the scheduled training session. Participants unanimously (100%) agreed that robotic surgery should be implemented into surgical training. CONCLUSIONS: There is rising enthusiasm for robotic surgery, yet early exposure and training remain infrequent and inconsistent amongst medical students and new surgical residents. A standardized introduction of multi-disciplinary robotic surgery training should be incorporated into medical school and/or early residency education to ensure surgical residents receive appropriate exposure and training to achieve competency.

Physiotherapy-led, community-based airway clearance services for people with chronic lung conditions: a retrospective descriptive evaluation of an existing model of care.

OBJECTIVES: Airway clearance interventions are recommended for people with chronic lung conditions and mucus hypersecretion, but there are few published models of care or descriptions of airway clearance service provision. This evaluation describes a dedicated, physiotherapy-led, community-based airway clearance service in a metropolitan local health network. DESIGN: Retrospective evaluation using existing airway clearance service administrative database. PARTICIPANTS: All first referrals to the airway clearance service in a 5-year period (1/1/2017 to 31/12/2021). MAIN OUTCOME MEASURES: Available service data grouped into four domains: participant demographics, referral demographics, service provision and outcomes. RESULTS: Of the 1335 first referrals eligible for inclusion, 1157 (87%) people attended. Bronchiectasis was the commonest condition (n = 649/1135, 49%). A total of 2996 occasions of service (face to face clinic n = 2108, 70%, phone n = 736, 25%, telehealth n = 99, 3%, home visit n = 53, 2%) were delivered. Airway clearance devices frequently prescribed were the Aerobika (525/1157, 45%), bubble-positive expiratory pressure (263/1157, 23%) and the Acapella (127/1157, 11%). On average, initial appointment with the airway clearance service occurred within 36 days of referral and people attended the service three times. Individuals voluntarily completed both pre/post service questionnaires around a third of the time. At least half of responders reported an improvement in respiratory symptom outcome measures consistent with the minimum clinically important difference. CONCLUSIONS: This evaluation describes an airway clearance service as it exists, providing an example from which airway clearance services can be planned, implemented and improved.

The Role of Artificial Intelligence in Surgery: What do General Surgery Residents Think?

BACKGROUND: Artificial intelligence (AI) holds significant potential in medical education and patient care, but its rapid emergence presents ethical and practical challenges. This study explored the perspectives of surgical residents on AI's role in medicine. METHODS: We performed a cross-sectional study surveying general surgery residents at a university-affiliated teaching hospital about their views on AI in medicine and surgical training. The survey covered demographics, residents' understanding of AI, its integration into medical practice, and use of AI tools like ChatGPT. The survey design was inspired by a recent national survey and underwent pretesting before deployment. RESULTS: Of the 31 participants surveyed, 24% identified diagnostics as AI's top application, 12% favored its use in identifying anatomical structures in surgeries, and 20% endorsed AI integration into EMRs for predictive models. Attitudes toward AI varied based on its intended application: 77.41% expressed concern about AI making life decisions and 70.97% felt excited about its application for repetitive tasks. A significant 67.74% believed AI could enhance the understanding of medical knowledge. Perception of AI integration varied with AI familiarity (P = .01), with more knowledgeable respondents expressing more positivity. Moreover, familiarity influenced the perceived academic use of ChatGPT (P = .039) and attitudes toward AI in operating rooms (P = .032). Conclusion: This study provides insights into surgery residents' perceptions of AI in medical practice and training. These findings can inform future research, shape policy decisions, and guide AI development, promoting a harmonious collaboration between AI and surgeons to improve both training and patient care.

Analysis of 10 years of open, laparoscopic, and robotic rectal surgeries in the community setting.

Background: Colorectal cancer is the fourth most common cancer in the US. Many of these patients will require operations. Although there is significant data in the literature that supports minimally invasive colorectal operations in the academic setting, few studies have examined their performance in community hospitals. Methods: Data was collected from a high-volume, university-affiliated, community center. Our Cancer Registry Database was queried to include any patients that had rectal surgery at our institution from 2010 to 2020. One hundred-twenty-two patients were identified and reviewed retrospectively. Main outcome measures include estimated blood loss (EBL), blood transfusion, time to first bowel movement, oncologic resection, length of stay (LOS), survival, and cost analysis. Results: Both robotic and laparoscopic operations resulted in lower average EBL, less blood transfusions, and less time to first bowel movement (p = 0.003, 0.006, 0.003, respectively). There was no significant difference in ability to achieve R0 resection, adequate lymph node retrieval, and adequate total mesorectal excision (TME, p = 0.856, 0.489, 0.500, respectively). LOS was significantly shorter for minimally invasive operations, 4.35 vs 8.48 days, and average survival was longest for laparoscopic operations at 7.19 years as compared to 5.55 years for open operations (p < 0.001, 0.026, respectively). Cost was lowest for robotic operations (0.003). Conclusions: Minimally invasive rectal operations, especially robotic, lead to better short- and long-term outcomes, equivalent oncologic resection, and are more cost-effective as compared to open operations even in the community setting, supporting continued performance and growth of robotic colorectal operations in the community setting. Key message: Although there is significant data in the literature that supports minimally invasive colorectal operations in the academic setting, few studies have examined their performance in community hospitals as this study does. This study found that minimally invasive rectal operations, especially robotic, lead to better short- and long-term outcomes, equivalent oncologic resection, and are more cost-effective as compared to open operations even in the community setting, supporting continued performance and growth of robotic colorectal operations in the community setting.

Use of inactivated poliovirus vaccine for poliovirus outbreak response.

With continued wild poliovirus transmission in Afghanistan and Pakistan and circulating vaccine-derived poliovirus in certain countries, there exists an ongoing risk of importation of polioviruses into other countries, including those that have been polio-free for decades. Diversifying the poliovirus outbreak response toolkit is essential to account for different public health and epidemiological contexts. In this Personal View, we discuss data on intestinal and pharyngeal mucosal immunity induced by inactivated poliovirus vaccine (IPV), previous programmatic experience of poliovirus outbreak response with IPV, and outbreak response guidelines in countries that exclusively use IPV. With recent reports of poliovirus detection in polio-free countries such as the USA and the UK, it is important to assess the interplay of virus transmission dynamics, vaccine impact on preventing paralysis and virus spread, and regulatory complexities of using oral poliovirus vaccine (OPV) and IPV options for outbreak response. As the global eradication programme navigates through cessation of routine OPV use with replacement by IPV and stockpiling of novel OPVs, clarity on the impact of IPV use will be important for informed decision making by global, regional, and national policy makers.

SARS-CoV-2 Bottlenecks and Tissue-Specific Adaptation in the Central Nervous System.

Severe COVID-19 and post-acute sequelae of SARS-CoV-2 infection are associated with neurological complications that may be linked to direct infection of the central nervous system (CNS), but the selective pressures ruling neuroinvasion are poorly defined. Here, we assessed SARS-CoV-2 evolution in the lung versus CNS of infected mice. Higher levels of viral diversity were observed in the CNS than the lung after intranasal challenge with a high frequency of mutations in the Spike furin cleavage site (FCS). Deletion of the FCS significantly attenuated virulence after intranasal challenge, with lower viral titers and decreased morbidity compared to the wild-type virus. Intracranial inoculation of the FCS-deleted virus, however, was sufficient to restore virulence. After intracranial inoculation, both viruses established infection in the lung, but this required reversion of the FCS deletion. Cumulatively, these data suggest a critical role for the FCS in determining SARS-CoV-2 tropism and compartmentalization with possible implications for the treatment of neuroinvasive COVID-19.

Topical Synthetic Platelets Loaded With Gentamicin Decrease Bacteria in Deep Partial-Thickness Burns.

INTRODUCTION: Prolonged inflammation and infection in burns may cause inadequate healing. Platelet granules contain anti-inflammatory mediators that impact wound healing. Synthetic platelets (SPs) avoid portability and storage difficulties of natural platelets and can be loaded with bioactive agents. We evaluated wound healing outcomes in deep partial-thickness (DPT) burns treated topically with SP loaded with antibiotics. MATERIALS AND METHODS: Thirty DPT burns were created on the dorsum of two Red Duroc hybrid pigs. Six wounds were randomized into five groups: SP alone, SP loaded with gentamicin vesicles, SP with gentamicin mixture, vehicle control (saline), or dry gauze. Wounds were assessed from postburn days 3-90. Primary outcome was re-epithelialization percentage at postburn day 28. Secondary outcomes included wound contraction percentage, superficial blood flow relative to normal skin controls, and bacterial load score. RESULTS: Results showed that re-epithelialization with the standard of care (SOC) was 98%, SP alone measured 100%, SP loaded with gentamicin vesicles was 100%, and SP with gentamicin mixture was 100%. Wound contraction was 5.7% in the SOC and was ∼10% in both the SP loaded with gentamicin vesicles and SP with gentamicin mixture groups. Superficial blood flow in the SOC was 102.5%, SP alone was 170%, the SP loaded was 155%, and gentamicin mixture 162.5%. Bacterial load score in the SOC was 2.2/5.0 and was significantly less at 0.8/5.0 in SP loaded with gentamicin vesicles (P > 0.05). SP and gentamicin mixture scored 2.7 and 2.3/5.0. CONCLUSIONS: Topical SP treatment did not significantly improve outcomes. However, SP loaded with gentamicin-infused vesicles decreased bacterial load.

Full-thickness skin columns: A method to reduce healing time and donor site morbidity in deep partial-thickness burns.

The current standard of care for the coverage of large wounds often involves split thickness skin grafts (STSGs) which have numerous limitations. One promising technique that has gained traction is fractional autologous skin grafting using full-thickness skin columns (FTSC). Harvesting occurs orthogonally by taking numerous individual skin columns containing the epidermis down through the dermis and transferring them to the wound bed. The purpose of this porcine study was to investigate the efficacy of implanting FTSCs directly into deep partial-thickness burn wounds, as well as examining donor site healing at the maximal harvest density. It was hypothesised that by utilising FTSCs, the rate of healing in deep partial thickness burns can be improved without incurring the donor morbidity seen in other methods of skin grafting. Deep partial-thickness burns were created on the dorsum of female red duroc swine, debrided 3 days later and FTSCs were implanted at varying expansion ratios directly into the burn wounds. At day 14, 1:50 expansion ratio showed significantly faster re-epithelialisation compared to the debrided burn control and 1:200. Donor sites (at 7%-10% harvest density) were 100% re-epithelialised by day 7. Additionally, the maximal harvest density was determined to be 28% in an ex vivo model, which then five donor sites were harvested at 28% density on a red duroc swine and compared to five STSG donor sites. At maximal harvest density, FTSC donor sites were significantly less hypopigmented compared to STSGs, but no significant differences were observed in re-epithelialisation, contraction, blood flow or dermal thickness. In conclusion, implantation directly into deep partial-thickness burns is a viable option for the application of FTSCs, favouring lower expansion ratios like 1:50 or lower. Little difference in donor site morbidity was observed between FTSC at a maximal harvest density of 28% and STSGs, exceeding the optimal harvest density.

Designer DNA NanoGripper.

DNA has shown great biocompatibility, programmable mechanical properties, and structural addressability at the nanometer scale, making it a versatile material for building high precision nanorobotics for biomedical applications. Herein, we present design principle, synthesis, and characterization of a DNA nanorobotic hand, called the "NanoGripper", that contains a palm and four bendable fingers as inspired by human hands, bird claws, and bacteriophages evolved in nature. Each NanoGripper finger has three phalanges connected by two flexible and rotatable joints that are bendable in response to binding to other entities. Functions of the NanoGripper have been enabled and driven by the interactions between moieties attached to the fingers and their binding partners. We showcase that the NanoGripper can be engineered to interact with and capture various objects with different dimensions, including gold nanoparticles, gold NanoUrchins, and SARS-CoV-2 virions. When carrying multiple DNA aptamer nanoswitches programmed to generate fluorescent signal enhanced on a photonic crystal platform, the NanoGripper functions as a sensitive viral biosensor that detects intact SARS-CoV-2 virions in human saliva with a limit of detection of ~ 100 copies/mL, providing RT-PCR equivalent sensitivity. Additionally, we use confocal microscopy to visualize how the NanoGripper-aptamer complex can effectively block viral entry into the host cells, indicating the viral inhibition. In summary, we report the design, synthesis, and characterization of a complex nanomachine that can be readily tailored for specific applications. The study highlights a path toward novel, feasible, and efficient solutions for the diagnosis and therapy of other diseases such as HIV and influenza.

Cecal-Colon Intussusception due to Appendiceal Mucinous Adenocarcinoma.

Intussusception is a rare presentation in adults and describes when one portion of the intestine telescopes into another portion. Intussusception is associated with malignancies serving as the lead point in adults. Appendiceal mucinous neoplasms are uncommon tumors often incidentally discovered during appendectomy procedures to manage acute appendicitis. Here we present a case report of an instance of mucinous adenocarcinoma of the appendix that manifested as a large bowel obstruction with intussusception limited to the colon, underscoring the possibility of concurrent intussusception and mucinous neoplasms. The case highlights the importance of meticulous diagnostic evaluation and management, particularly without well-defined treatment protocols. Appropriate diagnostic workup and management, including surgical intervention, are critical for patient outcomes and overall prognosis. The study recommends that patients diagnosed with confirmed or suspected appendiceal neoplasms undergo upfront oncologic resection where aggressive malignancy is a concern. Colonoscopy should be performed postoperatively for all patients to identify synchronous lesions.