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The repeat emergence of SARS-CoV-2 variants of concern (VoC) with decreased susceptibility to vaccine-elicited antibodies highlights the need to develop next-generation vaccine candidates that confer broad protection. Here we describe the antibody response induced by the SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine candidate adjuvanted with the Army Liposomal Formulation including QS21 (ALFQ) in non-human primates. By isolating and characterizing several monoclonal antibodies directed against the Spike Receptor Binding Domain (RBD), N-Terminal Domain (NTD), or the S2 Domain, we define the molecular recognition of vaccine-elicited cross-reactive monoclonal antibodies (mAbs) elicited by SpFN. We identify six neutralizing antibodies with broad sarbecovirus cross-reactivity that recapitulate serum polyclonal antibody responses. In particular, RBD mAb WRAIR-5001 binds to the conserved cryptic region with high affinity to sarbecovirus clades 1 and 2, including Omicron variants, while mAb WRAIR-5021 offers complete protection from B.1.617.2 (Delta) in a murine challenge study. Our data further highlight the ability of SpFN vaccination to stimulate cross-reactive B cells targeting conserved regions of the Spike with activity against SARS CoV-1 and SARS-CoV-2 variants., (© 2024. The Author(s).)

Current literature regarding survival and treatment outcome of SBRT in patients with pulmonary oligometastatic head and neck squamous cell carcinoma (HNSCC) is limited. Additionally, most of the published studies include metastatic lesions deriving also from primaries with histologies other than SCC when investigating the outcome of SBRT. The aim of the present retrospective study is to explore local control (LC) of treated metastases, progression-free survival (PFS), and overall survival (OS) of exclusively pulmonary oligometastatic HNSCC-patients treated with SBRT. Between 2006 and 2021, a total of 46 patients were treated with SBRT for a maximum of four pulmonary oligometastases (PM) concurrently (mean PM per patient = 2.0; range 1 to 6 PM, total of 92). Of these, 17 patients (37.0%) developed new pulmonary metastases after their first SBRT. Repeated courses of SBRT were required once in 15 patients (88.2%) and twice in 2 patients (11.8%). Median follow-up was 17 months (range, 0-109 months). One year after completion of SBRT, LC rate, PFS, and OS were 98.7%, 37.9%, and 79.5%, respectively. After two years, LC rate, PFS, and OS were 98.7%, 28.7%, and 54.9%; as well as 98.7%, 16.7%, and 31.0% after five years. Radiochemotherapy (HR 2.72, p < 0.001) or radiotherapy as primary treatment (HR 8.60; p = 0.003), as well as reduced patient performance status (HR 48.30, p = 0.002), were associated with lower PFS. Inferior OS correlated with poor performance status (HR 198.51, p < 0.001) and surgery followed by radiochemotherapy (HR 4.18, p = 0.032) as primary treatment, as well as radiotherapy alone (HR 7.11, p = 0.020). Treatment of more than one PM is an independent predictor of impaired OS (HR 3.30, p = 0.016). SBRT of HNSCC-derived PMs results in excellent LC rates and encouraging OS rates of 54.9% at two years along with good tolerability (no more than grade 2 toxicities). Favourable outcome and low toxicity also apply to repeated courses of SBRT of newly emerging PMs.

Objectives Pelvic vein embolisation is increasing in venous practice for the treatment of conditions associated with pelvic venous reflux. In July 2014, we introduced a local anaesthetic "walk-in walk-out" pelvic vein embolisation service situated in a vein clinic, remote from a hospital. Methods Prospective audit of all patients undergoing pelvic vein embolisation for pelvic venous reflux. All patients had serum urea and electrolytes tested before procedure. Embolisation coils used were interlock embolisation coils (Boston Scientific, USA) as they can be repositioned after deployment and before release. We noted (1) complications during or post-procedure (2) successful abolition of pelvic venous reflux on transvaginal duplex scanning (3) number of veins (territories) treated and number of coils used. Results In 24 months, 121 patients underwent pelvic vein embolisation. Three males were excluded as transvaginal duplex scanning was impossible and six females excluded due to lack of complete data. None of these nine had any complications. Of 112 females analysed, mean age 45 years (24-71), 104 were for leg varices, 48 vulval varices and 20 for pelvic congestion syndrome (some had more than one indication). There were no deaths or serious complications to 30 days. Two procedures were abandoned, one completed subsequently and one was technically successful on review. One more had transient bradycardia and one had a coil removed by snare during the procedure. The mean number of venous territories treated was 2.9 and a mean of 3.3 coils was used per territory. Conclusion Pelvic vein embolisation under local anaesthetic is safe and technically effective in a remote out-patient facility outside of a hospital.

Objectives: Endovenous thermal ablation (EVTA) of varicose veins was introduced in the late 1990s with radiofrequency ablation (RFA) using the VNUS Closure device. The results of the original VNUS Closure device for the abolition of truncal venous reflux at 15 years are reported., Methods: A prospective audit of a group of patients treated with VNUS Closure 15 years previously was carried out, using clinical assessment and duplex ultrasound. A total of 189 patients were treated with VNUS Closure between March 1999 and December 2001 and were invited for clinical assessment (subjective and objective) and duplex ultrasonography (DUS) to assess treatment outcome and de novo disease progression. DUS outcome of the treated vein was graded: 1, complete success (complete atrophy); 2, partial success (> 1 patent section; none giving rise to recurrent varicose veins); 3, partial failure (≥ 1 patent sections giving rise to recurrent varicose veins); 4, complete failure., Results: Fifty-eight patients (91 legs, 101 truncal veins) returned for follow-up DUS, giving a 31.5% response rate (many patients had moved or had died in the 15 years). Two truncal veins had been excluded following treatment elsewhere presumably for partial or complete failure. At a mean of 15.4 years post-procedure, 51 (56%) reported no varicose veins, 58 (100%) that they were pleased that they had the procedure and 57 (98%) that they would recommend the procedure. DUS showed 88% of patients achieved success with no clinical recurrence in the originally treated veins. De novo reflux was identified in 47 of 91 legs (51.6%), showing disease progression in veins that were originally competent., Conclusions: RFA with VNUS Closure achieved excellent long-term technical success in treating venous reflux in truncal veins 15 years post-procedure, demonstrated by DUS. This bodes well for the increased use of EVTA in treating truncal vein reflux., (Copyright © 2017 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective/background: Traditionally, sclerotherapy has been thought to work by the cytotoxic effect of the sclerosant upon the endothelium alone. However, studies have shown that sclerotherapy is more successful in smaller veins than in larger veins. This could be explained by the penetration of the sclerosant, or its effect, into the media. This study aimed to investigate intimal and medial damage profiles after sclerosant treatment., Methods: Fresh human varicose veins were treated ex vivo with either 1% or 3% sodium tetradecyl sulphate (STS) for 1 or 10 minutes. The effect of the sclerosant on the vein wall was investigated by immunofluorescent labelling of transverse vein sections using markers for endothelium (CD31), smooth muscle (α-actin), apoptosis (p53) and inflammation (intercellular adhesion molecule-1 [ICAM-1]). Polidocanol (POL; 3%) treatment at 10 minutes was similarly investigated., Results: Endothelial cell death was concentration- and time-dependent for STS but incomplete for both sclerosants. Time, but not concentration, significantly affected cell death (p > .001). A 40% and 30% maximum reduction was observed for STS and POL, respectively. Destruction of 20-30% of smooth muscle cells was found up to 250 μm from the lumen after 3% STS treatment for 10 minutes. POL treatment for 10 minutes showed inferior destruction of medial cells. Following STS treatment and 24-hour tissue culture, p53 and ICAM-1 were upregulated to a depth of around 300 μm. This effect was not observed with POL., Conclusion: Inflammatory and apoptotic markers show the same distribution as medial cell death, implying that sclerotherapy with STS works by inducing apoptosis in the vein wall rather than having an effect restricted to the endothelium. Incomplete loss of endothelial cells and penetration of the sclerosant effect up to 250 μm into the media suggest that medial damage is crucial to the success of sclerotherapy and may explain why it is less effective in larger veins., (Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective: The objective of this study was to report a phenomenon in patients with primary varicose veins that resembles neovascular tissue in postsurgical recurrences-primary avalvular varicose anomalies (PAVA)., Methods: Between March 2012 and July 2013, 756 patients (122 men, 634 women) with primary varicose veins (mean age, 53 years; range, 18-89 years) underwent duplex ultrasonography with retrospective analysis of their reflux patterns. We diagnose PAVA as small, refluxing vessels in legs with primary varicose veins and no history of surgery, trauma, or infection in the area that show one or more of three patterns of distribution: lymph node pattern-PAVA arising directly from groin lymph nodes; peritruncal pattern-PAVA wrapping around the great, small, or anterior accessory saphenous veins; and atypical pattern. PAVA are predominantly found within the saphenous fascia, but components have been found to emerge into the superficial and deep venous compartments., Results: We analyzed results from 1398 legs (756 patients). Sixty-four legs (4.6%) in 58 patients exhibited PAVA, bilateral in six patients and unilateral in 52 patients. Lymph node involvement and peritruncal PAVA were seen in 23.4% and 70.3% of legs, respectively. The small saphenous vein was the most common truncal vein to be involved (48.9% of peritruncal cases). More than one pattern of PAVA could be observed in seven legs. Of the 48 women with PAVA, 42% had concurrent pelvic vein reflux., Conclusions: Neovascularization has been identified as a major cause of clinically recurrent varicose veins. Neovascular tissue has been described after endovenous thermoablation. We suggest that this might represent PAVA undetected preoperatively in some cases. PAVA are thin-walled, serpiginous, incompetent vessels that resemble neovascular tissue. We conclude that neovascularization should be diagnosed as a source of recurrence after endovenous surgery only if PAVA had been actively looked for, and excluded, in the preoperative diagnostic duplex ultrasound examination., (Copyright © 2014 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

The family Bunyaviridae contains over 350 named isolates, classified into five genera: Orthobunyavirus, Hantavirus, Nairovirus, Phlebovirus and Tospovirus. The Orthobunyavirus genus contains some 170 isolates that are mainly transmitted by mosquitoes and are responsible for a range of disease syndromes in humans including self-limiting febrile illness, encephalitis and haemorrhagic fever. The viruses have a tripartite, negative-sense RNA genome. Analyses of viruses in four serogroups (Bunyamwera, California, Group C and Simbu) showed that the smallest (S) RNA segment encodes the nucleocapsid protein (N) and a non-structural protein called (NSs). The NSs protein of Bunyamwera virus (BUNV) has been shown to play a role in shut-off of host cell protein synthesis in mammalian cells, but no protein shut-off is observed in BUNVinfected mosquito cells (Aedes albopictus C6/36 cells). Protein shut-off in infected mammalian cells is achieved by global inhibition of RNA polymerase II-mediated transcription and enables the virus to overcome the host innate immune response. As innate defence mechanisms constitute a significant barrier to virus infection of different hosts, NSs would appear to play a key role in determining the zoonotic capacity of orthobunyaviruses.

The NSs protein of Bunyamwera virus (Bunyaviridae) is an antiapoptotic interferon antagonist involved in silencing host protein expression by interfering with mRNA synthesis. Here, we show that the ability to inhibit both host transcription and the interferon response is linked to interaction of NSs with the MED8 component of Mediator, a protein complex necessary for mRNA production. The interacting domain on NSs was mapped to the C-terminal region, which contains amino acids conserved among orthobunyavirus NSs proteins. A recombinant virus in which the interacting domain in NSs was deleted had strongly reduced ability to inhibit host protein expression and was unable to inhibit the interferon response. This study provides further information on the mechanisms by which bunyavirus nonstructural proteins are involved in pathogenesis.

Artificial minigenomes are powerful tools for studying the replication and transcription of negative-strand RNA viruses. Bunyamwera virus (BUN; genus Orthobunyavirus, family Bunyaviridae) is an arbovirus that shows fundamental biological differences when replicating in mammalian versus mosquito cells. To study BUN RNA synthesis in mosquito cells, we developed a bacteriophage T7 RNA polymerase-based minireplicon system similar to that described previously for mammalian cells. An Aedes albopictus C6/36-derived mosquito cell line stably expressing T7 RNA polymerase was established. Viral proteins and artificial minigenomes (containing Renilla luciferase as a reporter) were transcribed and expressed in these cells from transfected T7 promoter-containing plasmids. Transcription of the minigenome required two viral proteins, the nucleocapsid protein N and the RNA-dependent RNA polymerase L, a situation similar to that in mammalian cells. However, unlike the situation in mammalian cells, the viral polymerase was not inhibited by the viral nonstructural protein NSs. We also report that promoter strength is different for vertebrate versus invertebrate cells. The development of this system opens the way for a detailed comparison of bunyavirus replication in cells of disparate phylogeny.

The authors present a retrospective study of the opening base wedge osteotomy with first metatarsophalangeal joint implant arthroplasty, for the correction of long-standing hallux abducto valgus deformity. Twenty cases involving 23 feet were performed, and the results are discussed. The indications and procedure are described, as well as an in-depth discussion.

Recently, the approach in management of diabetic foot disorders has undergone critical re-evaluation. Major foot infections, such as plantar space infections and osteomyelitis do not automatically result in Syme's or below-the-knee amputations. When indicated, midfoot amputations should be attempted because of the functional and psychologic advantages compared with more proximal amputation levels of the lower extremity. In Part III of this series of articles concerning diabetic foot amputations, the authors present case studies along with midfoot amputations and muscle-balancing procedures.

Part II of this series of articles on diabetic foot amputation represents case studies, along with appropriate metatarsal amputation procedures. Misdiagnosis or delayed treatment of these patients can lead to loss of limb and, in some cases, can be life threatening. Diabetic feet have varying degrees of neurovascular compromise, but this should not result in traditional below-the-knee or above-the-knee amputations.

The authors review the basic principles of tendon healing and repair as they apply to a ruptured Achilles tendon, and discuss its diagnosis and treatment. The treatment, either surgical or conservative, is a controversial subject. Both forms have their problems. The authors conclude that while surgical repair is the treatment of choice in most cases, conservative management should be considered an effective alternative.

The authors present a case report of iatrogenic metatarsal coalition, a postoperative complication of adjacent V-osteotomies. The paper also includes a discussion of surgical considerations of multiple adjacent osteotomies contributing to such a sequela, including adequate irrigation, instrumentation, anatomy, and the use of corticosteroids.

In our study we examined Bernstein's hypothesis that practice alters the motor coordination among the muscular and passive joint moments. In particular, we conducted dynamical analyses of a human multisegmental movement during the practice of a task involving the upper extremity. Seven male human volunteers performed maximal-speed, unrestrained vertical arm movements whose upward and downward trajectories between two target endpoints required the hand to round a barrier, resulting in complex shoulder, elbow, and wrist joint movements. These movements were recorded by high-speed ciné film, and myopotentials from selected upper-extremity muscles were recorded. The arm was modeled as interconnected rigid bodies, so that dynamical interactions among the upper arm, forearm, and hand could be calculated. With practice, subjects achieved significantly shorter movement times. As movement times decreased, all joint-moment components (except gravity) increased, and the moment-time and EMG profiles were changed significantly. Particularly during reversals in movement direction, the changes in moment-time and EMG profiles were consistent with Bernstein's hypothesis relating practice effects and intralimb coordination: with practice, motor coordination was altered so that individuals employed reactive phenomena in such a way as to use muscular moments to counterbalance passive-interactive moments created by segment movements.

Thermodilatometric, dynamic thermomechanical, and light-microscopic analyses were done on the anterior and posterior regions of the rat knee menisci to correlate regional differences in morphology and extracellular matrix composition with regional mechanical behavior. Following the administration of a general anesthetic, menisci were excised from 12 young female Sprague-Dawley rats. During thermodilatometric and thermomechanical testing, tissue temperature was increased at a constant rate of 3.5 degrees C/min from 30 to 100 degrees C. Light microscopy revealed regional differences in cell density and proteoglycan content. The anterior horn was significantly heavier (greater than 87%) and thicker (greater than 60%) than the posterior region. During thermal analyses, both the anterior and posterior horns decreased in tissue thickness as the temperature increased from 30 to 73 degrees C. After 73 degrees C, however, the posterior horn expanded significantly, whereas the anterior remained in a comparatively contracted state. The rates of linear contraction and expansion of the posterior horn were seven times those of the anterior horn, and the stiffness of the anterior horn was significantly greater than the posterior horn.

The authors present a perspective study using bleomycin sulfate in the treatment of plantar verrucae. Also, they review the literature concerning this modality. Although the effective cure rate obtained in this study was less than that reported previously, the authors found bleomycin to be particularly effective in the treatment of mosaic verrucae.

Clinical manifestations of von Recklinghausen's disease on the plantar aspect are very rare. Most of the neurofibromas involving the skin are asymptomatic, but when they occupy an unusual position or attain a large size, they lead to significant disability. A case report and the surgical treatment of a 39-year-old female with the pathognomonic clinical characteristics, along with a symptomatic plantar neurofibroma, are presented. The pathogenesis, clinical manifestations, diagnosis, complications, and treatment of this progressive disease are described in this report.

The differentiation between diabetic osteoarthropathy and osteomyelitis is a very difficult one to make, even in the presence of a pedal ulceration. However, considering present medical costs, the incorrect diagnosis of osteomyelitis can be a costly one, not only for the hospital, but also for the patient. In light of a normal white blood cell count, a benign 67Ga-citrate scan, and two noncontiguous areas of bone destruction, the diagnosis of diabetic osteoarthropathy can be made without the necessity of a bone biopsy.

The authors report the case of a deep plantar abscess in a diabetic patient. The pathophysiology of diabetic foot lesions as well as classification is discussed. The philosophy of local radical debridement involving ray resection, as well as postdebridement management is discussed in detail.