Outcomes of surgically managed adult traumatic brachial plexus injuries in an upper-middle-income country.

Background: Traumatic brachial plexus injuries (TBPIs) are debilitating and complex to treat. The last five decades have seen advances in surgical management, and consequently improved functional outcomes in patients with these injuries. There is limited data available describing the outcomes of surgically managed TBPIs within the South African context. This study aimed to identify the common causes of injury, injury characteristics, and functional outcomes of surgically managed patients with TBPIs. Methods: We conducted a retrospective chart review of all adult patients that underwent surgery for TBPIs over a period of ten years at a specialised hand unit in South Africa. The minimum follow-up period was one year. Patient demographic details, injury characteristics and functional outcomes were collected. Statistical analysis was performed to determine factors associated with functional outcomes. A good functional outcome for recovery was defined as a Medical Research Council (MRC) grade of three or more for the affected elements of the plexus at the most recent follow-up. Results: Forty-seven patients of median age 32 years were included in the final analysis. Most patients were male (87.2 %). The majority of patients were injured in motor vehicle accidents (MVAs) or from penetrating stab wounds (48.9 % and 38.3 % respectively). The median pre-operative MRC grade of the affected elements of the brachial plexus was 0.0, and post-operatively was 2.0. Fourteen patients (14 of 47, 29.8 %) had a good outcome and 33 had a poor outcome (33 of 47, 70.2 %). There was no difference in outcome comparing penetrating injury mechanisms to closed traction or blunt injuries, (p = 0.386, OR 1.75, 95 % CI 0.49-6.20). All patients with pan-plexal injuries had a poor outcome (15 of 33, 46 %). All patients who received intercostal (6 of 33, 18 %) or phrenic nerve transfers (3 of 33, 9 %) had a poor outcome. Conclusion: Adult traumatic BPIs in this South African sample typically presented more than two months after injury and were comprised of a high proportion of penetrating injuries. Just under a third of surgically managed patients had a good outcome. Pan plexal injuries have uniformly poor outcomes. We recommend early referral for all TBPIs to a unit that manages BPI to improve outcomes.

Nevus Spilus With Dermatoheliosis: A Histologic Mimicker of Melanoma in Situ at Melanoma Excision Margins.

ABSTRACT: Nevus spilus, or speckled lentiginous nevus, is a relatively common lesion that presents at birth or in early childhood. It consists of a background tan patch, which appears similar to a café au lait macule or lentigo simplex on histology, studded with various types of nevi. Rarely, these nevi can undergo malignant transformation to melanoma. When melanoma develops within a heavily photodamaged nevus spilus, evaluating excision margins may be challenging because the combined histologic features of nevus spilus and severe dermatoheliosis can mimic melanoma in situ. We report a case of an elderly man with extensive sun damage who developed malignant melanoma within an occult nevus spilus, resulting in multiple excisions with false-positive margins.

Operating in the margins: Women's lived experience of training and working in orthopaedic surgery in South Africa.

Medicine in South Africa (SA), as in other parts of the world, is becoming an increasingly gender diverse profession, yet orthopaedic surgery continues to be dominated by men, with women constituting approximately 5% of the profession in SA. The aim of this descriptive qualitative study was to explore women's experiences of training and working as orthopaedic surgeons in SA and identify structures, practices, attitudes, and ideologies that may promote or impede the inclusion of women. Data were collected via focus group discussions with women orthopaedic surgeons (n=16). Grounded in phenomenology, data were analysed using thematic analysis following a data-driven inductive approach to making sense of participants' experiences. Five main themes emerged: i) dynamic working environments and the work of transformation; ii) negotiating competing roles of mother and surgeon; iii) belonging, exclusion and internalised sexism; iv) gaslighting and silencing; and v) acts of resistance - agency and pushing back. The findings highlight the dynamic process in which both men and women contribute to co-creating, re-producing, and challenging practices that make medicine more inclusive.

Evaluation of the immunogenicity and efficacy of an rVSV vaccine against Zika virus infection in macaca nemestrina.

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes an acute febrile illness. ZIKV can be transmitted between sexual partners and from mother to fetus. Infection is strongly associated with neurologic complications in adults, including Guillain-Barré syndrome and myelitis, and congenital ZIKV infection can result in fetal injury and congenital Zika syndrome (CZS). Development of an effective vaccine is imperative to protect against ZIKV vertical transmission and CZS. Recombinant Vesicular Stomatitis virus (rVSV) is a highly effective and safe vector for the delivery of foreign immunogens for vaccine purposes. Here, we evaluate an rVSV vaccine expressing the full length pre-membrane (prM) and ZIKV envelope (E) proteins (VSV-ZprME), shown to be immunogenic in murine models of ZIKV infection, for its capacity to induce immune responses in nonhuman primates. Moreover, we assess the efficacy of the rVSVΔM-ZprME vaccine in the protection of pigtail macaques against ZIKV infection. Administration of the rVSVΔM-ZprME vaccine was safe, but it did not induce robust anti-ZIKV T-cell responses, IgM or IgG antibodies, or neutralizing antibodies in most animals. Post ZIKV challenge, animals that received the rVSVΔM control vaccine lacking ZIKV antigen had higher levels of plasma viremia compared to animals that received the rVSVΔM-ZprME vaccine. Anti-ZIKV neutralizing Ab titers were detected in a single animal that received the rVSVΔM-ZprME vaccine that was associated with reduced plasma viremia. The overall suboptimal ZIKV-specific cellular and humoral responses post-immunization indicates the rVSVΔM-ZprME vaccine did not elicit an immune response in this pilot study. However, recall antibody response to the rVSVΔM-ZprME vaccine indicates it may be immunogenic and further developments to the vaccine construct could enhance its potential as a vaccine candidate in a nonhuman primate pre-clinical model.

A replicon RNA vaccine can induce durable protective immunity from SARS-CoV-2 in nonhuman primates after neutralizing antibodies have waned.

The global SARS-CoV-2 pandemic prompted rapid development of COVID-19 vaccines. Although several vaccines have received emergency approval through various public health agencies, the SARS-CoV-2 pandemic continues. Emergent variants of concern, waning immunity in the vaccinated, evidence that vaccines may not prevent transmission and inequity in vaccine distribution have driven continued development of vaccines against SARS-CoV-2 to address these public health needs. In this report, we evaluated a novel self-amplifying replicon RNA vaccine against SARS-CoV-2 in a pigtail macaque model of COVID-19 disease. We found that this vaccine elicited strong binding and neutralizing antibody responses against homologous virus. We also observed broad binding antibody against heterologous contemporary and ancestral strains, but neutralizing antibody responses were primarily targeted to the vaccine-homologous strain. While binding antibody responses were sustained, neutralizing antibody waned to undetectable levels in some animals after six months but were rapidly recalled and conferred protection from disease when the animals were challenged 7 months after vaccination as evident by reduced viral replication and pathology in the lower respiratory tract, reduced viral shedding in the nasal cavity and lower concentrations of pro-inflammatory cytokines in the lung. Cumulatively, our data demonstrate in pigtail macaques that a self-amplifying replicon RNA vaccine can elicit durable and protective immunity to SARS-CoV-2 infection. Furthermore, these data provide evidence that this vaccine can provide durable protective efficacy and reduce viral shedding even after neutralizing antibody responses have waned to undetectable levels.

Reducing risk and building agency for vulnerable asylum seekers.

Asylum seekers are inherently vulnerable. Certain populations who were vulnerable before becoming asylum seekers, such as females, lesbian, gay, bisexual, transgender, queer, and other sexual identities (LGBTQ+) persons, and unaccompanied minors (UAMs) become increasingly vulnerable when seeking asylum. This study conducted a focused literature review of these three groups that led to a series of recommendations. Findings reveal that female, LGBTQ+, and UAM asylum seekers are three of the most underserved groups in the humanitarian social vulnerability context. Ongoing barriers to supporting programs include bureaucratic shortfalls, lack of funding, turnover of support staff, and lack of national or local support. This research produced three main recommendation categories. The first, overarching, recommendation is the building of agency within these populations through dialogue. This recommendation is explored in the most detail. The final two recommendations include enforcing protection of these groups and providing access to physical and mental healthcare. Female, LGBTQ+, and UAM asylum seekers struggle to survive the prevalent violence, sexual assault, and health issues associated with their circumstance. Related programing can more effectively address all these threats if they are tailored to the specific needs of these groups.

Relapsing Helicobacter cinaedi Cellulitis without Bacteremia in a Patient with X-linked Agammaglobulinemia after 1 Year of Antibiotic Prophylaxis.

A 23-year-old man with Bruton's X-linked agammaglobulinemia (XLA), who required intravenous immunoglobulin G (IgG) every 3 weeks, presented with an erythematous scaly eruption adjacent to the chest port for antibiotic therapy (Figures 1A,B). His past medical history included Helicobacter cinaedi cellulitis in 2015 that was treated with intravenous vancomycin and ertapenem with no improvement after several months. The therapy was switched to ertapenem and amikacin, which was also unsuccessful after 1 year. Subsequently, on switching to oral doxycycline for 6 months, he had a 2-year period without skin lesions. He presented to Mount Sinai Hospital in 2019 with 2-day fever and newly appearing skin lesions. (SKINmed. 2022;20:457-459).

Distinct sensitivities to SARS-CoV-2 variants in vaccinated humans and mice.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has led to the development of a large number of vaccines, several of which are now approved for use in humans. Understanding vaccine-elicited antibody responses against emerging SARS-CoV-2 variants of concern (VOCs) in real time is key to inform public health policies. Serum neutralizing antibody titers are the current best correlate of protection from SARS-CoV-2 challenge in non-human primates and a key metric to understand immune evasion of VOCs. We report that vaccinated BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses elicited by various vaccine platforms against VOCs, compared with non-human primates or humans, suggesting caution should be exercised when interpreting data obtained with this animal model.

Systematic Improvement in the Patient Transfer Process to a Tertiary Care Children's Hospital.

OBJECTIVE: Interfacility transfer of pediatric patients to a children's hospital is a complex process that can be time consuming and dissatisfying for referring providers. We aimed to improve the efficiency of communication and acceptance for interfacility transfers to our hospital. METHODS: We implemented iterative improvements to the process in 2 phases from 2013 to 2016 (pediatric medicine) and 2019 to 2022 (pediatric critical care and surgery). Key interventions included creation of a hospitalist position to manage transfers with broad ability to accept patients and transition to direct phone access for transfer requests to streamline connection. Effective initiatives from Phase 1 were adapted and spread to the other services in Phase 2. Data were manually extracted monthly from call transcripts and monitored by using statistical process control (SPC) charts. Primary outcome measures were time from call to connection to a provider and number of providers added to the call before making a disposition decision. RESULTS: Average time from call initiation to provider connection for pediatric medicine calls decreased from 11 minutes to 5 minutes. The average number of internal physicians on each call before acceptance decreased from 2.1 to 1.3. In Phase 2, time to provider connection decreased from 11 to 4 minutes for pediatric critical care calls and 16 to 5 minutes for pediatric surgery calls. CONCLUSIONS: We streamlined the process of accepting incoming transfer requests throughout our children's hospital. Prioritizing direct communication led to efficient disposition decisions and progression toward transfer and was effective for multiple service lines.

STING Is Required in Conventional Dendritic Cells for DNA Vaccine Induction of Type I T Helper Cell- Dependent Antibody Responses.

DNA vaccines elicit antibody, T helper cell responses and CD8+ T cell responses. Currently, little is known about the mechanism that DNA vaccines employ to induce adaptive immune responses. Prior studies have demonstrated that stimulator of interferon genes (STING) and conventional dendritic cells (cDCs) play critical roles in DNA vaccine induced antibody and T cell responses. STING activation by double stranded (dsDNA) sensing proteins initiate the production of type I interferon (IFN),but the DC-intrinsic effect of STING signaling is still unclear. Here, we investigated the role of STING within cDCs on DNA vaccine induction of antibody and T cell responses. STING knockout (STING-/- ) and conditional knockout mice that lack STING in cDCs (cDC STING cKO), were immunized intramuscularly with a DNA vaccine that expressed influenza A nucleoprotein (pNP). Both STING-/- and cDC STING cKO mice had significantly lower type I T helper (Th1) type antibody (anti-NP IgG2C) responses and lower frequencies of Th1 associated T cells (NP-specific IFN-γ+CD4+ T cells) post-immunization than wild type (WT) and cDC STING littermate control mice. In contrast, all mice had similar Th2-type NP-specific (IgG1) antibody titers. STING-/- mice developed significantly lower polyfunctional CD8+ T cells than WT, cDC STING cKO and cDC STING littermate control mice. These findings suggest that STING within cDCs mediates DNA vaccine induction of type I T helper responses including IFN-γ+CD4+ T cells, and Th1-type IgG2C antibody responses. The induction of CD8+ effector cell responses also require STING, but not within cDCs. These findings are the first to show that STING is required within cDCs to mediate DNA vaccine induced Th1 immune responses and provide new insight into the mechanism whereby DNA vaccines induce Th1 responses.

Opioid use during pregnancy: An analysis of comment data from the 2016 Pregnancy Risk Assessment Monitoring System survey.

ABTSTRACTBackground: Opioid misuse during pregnancy has been associated with adverse infant outcomes including preterm birth, stillbirth, and neonatal opioid withdrawal syndrome. The Pregnancy Risk Assessment Monitoring System (PRAMS) is an on-going state-based surveillance system of maternal behaviors, attitudes, and experiences prior to, during, and after pregnancy. Methods: We analyzed qualitative comments related to opioid use during pregnancy collected in 2016 from an open-ended prompt at the end of the PRAMS survey in 35 states (N = 40,408). Key word searches were conducted on the open-ended responses (n = 9,549) to identify opioid-related content with an automated function using Microsoft Excel. All responses from the initial screening (n = 1,035) were manually reviewed, and 69 responses were confirmed to relate to the respondent's personal experience with opioid use during pregnancy. Content analysis was conducted by 3 independent coders; key themes were compiled, discussed, and finalized by the coding team. Results: Five key themes related to opioid use during pregnancy were identified: (1) gratitude for treatment, recovery, and healthy infants; (2) pregnancy as motivation to seek treatment; (3) difficulty finding prenatal care providers with training in substance use disorders; (4) concern about the effects of treatment on the infant; and (5) experiences of discrimination and stigma in the hospital around the time of delivery. Conclusions: Women may be aware of the potential impact of opioid use during pregnancy on the health of their infants and motivated to seek treatment. Findings may help inform new and ongoing initiatives designed to improve care and reduce stigma for women needing or seeking treatment.

Technologies Enabling Situational Awareness During Disaster Response: A Systematic Review.

Situational awareness (SA) is critical to mobilizing a rapid, efficient, and effective response to disasters. Limited by time and resources, response agencies must make decisions about rapidly evolving situations, which requires the collection, analysis, and sharing of actionable information across a complex landscape. Emerging technologies, if appropriately applied, can enhance SA and enable responders to make quicker, more accurate decisions. The aim of this systematic review is to identify technologies that can improve SA and assist decision-making across the United States Government and the domestic and international agencies they support during disaster response operations. A total of 1459 articles and 36 after-action reports were identified during literature searches. Following the removal of duplicates and application of inclusion/exclusion criteria, 302 articles and after-action reports were included in the review. Our findings suggest SA is constrained primarily due to unreliable and significantly delayed communications, time-intensive data analysis and visualization, and a lack of interoperable sensor networks and other capabilities providing data to shared platforms. Many of these challenges could be addressed by existing technologies. Bridging the divide between research and development efforts and the operational needs of response agencies should be prioritized.

Macaque-human differences in SARS-CoV-2 Spike antibody response elicited by vaccination or infection.

Macaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses recapitulate, and thus appropriately model, the response in humans. To answer this question, we employed a phage-based deep mutational scanning approach (Phage-DMS) to compare which linear epitopes are targeted on the SARS-CoV-2 Spike protein in humans and macaques following either vaccination or infection. We also used Phage-DMS to determine antibody escape pathways within each epitope, enabling a granular comparison of antibody binding specificities at the locus level. Overall, we identified some common epitope targets in both macaques and humans, including in the fusion peptide (FP) and stem helix-heptad repeat 2 (SH-H) regions. Differences between groups included a response to epitopes in the N-terminal domain (NTD) and C-terminal domain (CTD) in vaccinated humans but not vaccinated macaques, as well as recognition of a CTD epitope and epitopes flanking the FP in convalescent macaques but not convalescent humans. There was also considerable variability in the escape pathways among individuals within each group. Sera from convalescent macaques showed the least variability in escape overall and converged on a common response with vaccinated humans in the SH-H epitope region, suggesting highly similar antibodies were elicited. Collectively, these findings suggest that the antibody response to SARS-CoV-2 in macaques shares many features with humans, but with substantial differences in the recognition of certain epitopes and considerable individual variability in antibody escape profiles, suggesting a diverse repertoire of antibodies that can respond to major epitopes in both humans and macaques.

Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines.

Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.

A Gut Reaction to SIV and SHIV Infection: Lower Dysregulation of Mucosal T Cells during Acute Infection Is Associated with Greater Viral Suppression during cART.

Selection of a pre-clinical non-human primate (NHP) model is essential when evaluating therapeutic vaccine and treatment strategies for HIV. SIV and SHIV-infected NHPs exhibit a range of viral burdens, pathologies, and responses to combinatorial antiretroviral therapy (cART) regimens and the choice of the NHP model for AIDS could influence outcomes in studies investigating interventions. Previously, in rhesus macaques (RMs) we showed that maintenance of mucosal Th17/Treg homeostasis during SIV infection correlated with a better virological response to cART. Here, in RMs we compared viral kinetics and dysregulation of gut homeostasis, defined by T cell subset disruption, during highly pathogenic SIVΔB670 compared to SHIV-1157ipd3N4 infection. SHIV infection resulted in lower acute viremia and less disruption to gut CD4 T-cell homeostasis. Additionally, 24/24 SHIV-infected versus 10/19 SIV-infected animals had sustained viral suppression <100 copies/mL of plasma after 5 months of cART. Significantly, the more profound viral suppression during cART in a subset of SIV and all SHIV-infected RMs corresponded with less gut immune dysregulation during acute SIV/SHIV infection, defined by maintenance of the Th17/Treg ratio. These results highlight significant differences in viral control during cART and gut dysregulation in NHP AIDS models and suggest that selection of a model may impact the evaluation of candidate therapeutic interventions for HIV treatment and cure strategies.

Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs.

A therapeutic vaccine that induces lasting control of HIV infection could eliminate the need for lifelong adherence to antiretroviral therapy. This study investigated a therapeutic DNA vaccine delivered with a single adjuvant or a novel combination of adjuvants to augment T cell immunity in the blood and gut-associated lymphoid tissue in SIV-infected rhesus macaques. Animals that received DNA vaccines expressing SIV proteins, combined with plasmids expressing adjuvants designed to increase peripheral and mucosal T cell responses, including the catalytic subunit of the E. coli heat-labile enterotoxin, IL-12, IL-33, retinaldehyde dehydrogenase 2, soluble PD-1 and soluble CD80, were compared to mock-vaccinated controls. Following treatment interruption, macaques exhibited variable levels of viral rebound, with four animals from the vaccinated groups and one animal from the control group controlling virus at median levels of 103 RNA copies/ml or lower (controllers) and nine animals, among all groups, exhibiting immediate viral rebound and median viral loads greater than 103 RNA copies/ml (non-controllers). Although there was no significant difference between the vaccinated and control groups in protection from viral rebound, the variable virological outcomes during treatment interruption enabled an examination of immune correlates of viral replication in controllers versus non-controllers regardless of vaccination status. Lower viral burden in controllers correlated with increased polyfunctional SIV-specific CD8+ T cells in mesenteric lymph nodes and blood prior to and during treatment interruption. Notably, higher frequencies of colonic CD4+ T cells and lower Th17/Treg ratios prior to infection in controllers correlated with improved responses to ART and control of viral rebound. These results indicate that mucosal immune responses, present prior to infection, can influence efficacy of antiretroviral therapy and the outcome of immunotherapeutic vaccination, suggesting that therapies capable of modulating host mucosal responses may be needed to achieve HIV cure.

Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines.

Understanding the ability of SARS-CoV-2 vaccine-elicited antibodies to neutralize and protect against emerging variants of concern and other sarbecoviruses is key for guiding vaccine development decisions and public health policies. We show that a clinical stage multivalent SARS-CoV-2 receptor-binding domain nanoparticle vaccine (SARS-CoV-2 RBD-NP) protects mice from SARS-CoV-2-induced disease after a single shot, indicating that the vaccine could allow dose-sparing. SARS-CoV-2 RBD-NP elicits high antibody titers in two non-human primate (NHP) models against multiple distinct RBD antigenic sites known to be recognized by neutralizing antibodies. We benchmarked NHP serum neutralizing activity elicited by RBD-NP against a lead prefusion-stabilized SARS-CoV-2 spike immunogen using a panel of single-residue spike mutants detected in clinical isolates as well as the B.1.1.7 and B.1.351 variants of concern. Polyclonal antibodies elicited by both vaccines are resilient to most RBD mutations tested, but the E484K substitution has similar negative consequences for neutralization, and exhibit modest but comparable neutralization breadth against distantly related sarbecoviruses. We demonstrate that mosaic and cocktail sarbecovirus RBD-NPs elicit broad sarbecovirus neutralizing activity, including against the SARS-CoV-2 B.1.351 variant, and protect mice against severe SARS-CoV challenge even in the absence of the SARS-CoV RBD in the vaccine. This study provides proof of principle that sarbecovirus RBD-NPs induce heterotypic protection and enables advancement of broadly protective sarbecovirus vaccines to the clinic.