A critical view on autoantibodies in lupus nephritis: Concrete knowledge based on evidence.

Deposition of autoantibodies in glomeruli is a key factor in the development of lupus nephritis (LN). For a long time, anti-dsDNA and anti-C1q antibodies were thought to be the main cause of the kidney damage. However, recent studies have shown that the list of autoantibidies that have renal tropism and deposit in the kidney in LN is increasing and the link between anti-dsDNA and renal pathology is weak due to potential confounders. Aspecific bindings of dsDNA with cationic antibodies and of anti-dsDNA with several renal antigens such as actinin, laminin, entactin, and annexinA2 raised doubts about the specific target of these antibodies in the kidney. Moreover, the isotype of anti-dsDNA in SLE and LN has never received adequate interest until the recent observation that IgG2 are preponderant over IgG1, IgG3 and IgG4. Based on the above background, recent studies investigated the involvement of anti-dsDNA IgG2 and of other antibodies in LN. It was concluded that circulating anti-dsDNA IgG2 levels do not distinguish between LN versus non-renal SLE, and, in patients with LN, their levels do not change over time. Circulating levels of other antibodies such as anti-ENO1 and anti-H2 IgG2 were, instead, higher in LN vs non-renal SLE at the time of diagnosis and decreased following therapies. Finally, new classes of renal antibodies that potentially modify the anti-inflammatory response in the kidney are emerging as new co-actors in the pathogenetic scenario. They have been defined as 'second wave antibodies' for the link with detoxifying mechanisms limiting the oxidative stress in glomeruli that are classically stimulated in a second phase of inflammation. These findings have important clinical implications that may modify the laboratory approach to LN. Serum levels of anti-ENO1 and anti-H2 IgG2 should be measured in the follow up of patients for designing the length of therapies and identify those patients who respond to treatments. Anti-SOD2 could help to monitor and potentiate the anti-inflammatory response in the kidney.

Reconstruction of Broad Lower Lip Defects Using Karapandzic-Type Flaps.

BACKGROUND: Reconstruction of lower lip defects is challenging because of the functional and aesthetic demands of the lower face. We review the functional and aesthetic outcomes of the Karapandzic-type flaps for reconstructing lower lip defects. METHODS: A retrospective review of patients who underwent repair using Karapandzic-type flaps. RESULTS: Fifty patients with lower lip defects ranging from 20% to 95% (mean 59.2% ± 20%) were included. Eighteen patients (36%) were repaired using a bilateral flap, and 32 (64%) were reconstructed using a unilateral flap design. All patients had preservation of oral competency and a satisfactory aesthetic result. No patient complained of microstomia. A complication rate of 8% was noted (n = 4) with postoperative wound infection and small areas of dehiscence. There was no statistically significant difference in complication rates in patients older than 75 years, in patients with a history of head/neck radiation, or in defects greater than 70% of lower lip breadth. CONCLUSION: Karapandzic-type flaps are versatile and reliable for the reconstruction of a broad range of lower lip defects. This one-stage procedure can produce superior functional and aesthetic results as compared with other local and distant flaps with minimal risk of functional microstomia.

Bluetooth Tactical Headsets Improve The Speed of Accurate Patient Handoffs.

BACKGROUND: The Committee on En Route Combat Casualty Care recently ranked the patient handoff as their fourth research priority. Bluetooth technology has been introduced to the battlefield and has the potential to improve the tactical patient handoff. The purpose of this study is to compare the traditional methods of communication used in tactical medical evacuation by Special Operations medical personnel (radio push-to-talk [PTT] and Tactical Medic Intercom System [TM-ICS]) to Bluetooth communication. METHODS: Twenty-four simulated tactical patient handoffs were performed to compare Bluetooth and traditional methods of communication used in tactical medical evacuation. Patient scenario order and method of communication were randomized. Accuracy and time required to complete the patient handoff were determined. The study took place using a rotary-wing aircraft kept at level 2 to simulate real-world background noise. Preferred method of communication for each study participant was determined. RESULTS: There were no differences in accuracy of the received patient handoffs between groups or patient handoff transmission times at the ramp of the aircraft. However, when comparing patient handoff times to the medical team within the aircraft, Bluetooth communication was significantly faster than both TM-ICS and radio PTT, while Bluetooth PTT and radio PTT were also significantly faster than TM-ICS. Bluetooth communication was ranked as the preferred method of handoff by all study participants. CONCLUSION: The study demonstrated that utilization of Bluetooth technology for patient handover results in faster handoffs compared with traditional methods without sacrificing any accuracy in a scenario with high levels of noise.

Antibody landscape of C57BL/6 mice cured of B78 melanoma via a combined radiation and immunocytokine immunotherapy regimen.

Sera of immune mice that were previously cured of their melanoma through a combined radiation and immunocytokine immunotherapy regimen consisting of 12 Gy of external beam radiation and the intratumoral administration of an immunocytokine (anti-GD2 mAb coupled to IL-2) with long-term immunological memory showed strong antibody-binding against melanoma tumor cell lines via flow cytometric analysis. Using a high-density whole-proteome peptide array (of 6.090.593 unique peptides), we assessed potential protein-targets for antibodies found in immune sera. Sera from 6 of these cured mice were analyzed with this high-density, whole-proteome peptide array to determine specific antibody-binding sites and their linear peptide sequence. We identified thousands of peptides that were targeted by these 6 mice and exhibited strong antibody binding only by immune (after successful cure and rechallenge), not naïve (before tumor implantation) sera and developed a robust method to detect these differentially targeted peptides. Confirmatory studies were done to validate these results using 2 separate systems, a peptide ELISA and a smaller scale peptide array utilizing a slightly different technology. To the best of our knowledge, this is the first study of the full set of germline encoded linear peptide-based proteome epitopes that are recognized by immune sera from mice cured of cancer via radio-immunotherapy. We furthermore found that although the generation of B-cell repertoire in immune development is vastly variable, and numerous epitopes are identified uniquely by immune serum from each of these 6 immune mice evaluated, there are still several epitopes and proteins that are commonly recognized by at least half of the mice studied. This suggests that every mouse has a unique set of antibodies produced in response to the curative therapy, creating an individual "fingerprint." Additionally, certain epitopes and proteins stand out as more immunogenic, as they are recognized by multiple mice in the immune group.

Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s.

Antibody responses to variant surface antigens (VSAs) produced by the malaria parasite Plasmodium falciparum may contribute to age-related natural immunity to severe malaria. One VSA family, P. falciparum erythrocyte membrane protein-1 (PfEMP1), includes a subset of proteins that binds endothelial protein C receptor (EPCR) in human hosts and potentially disrupts the regulation of inflammatory responses, which may lead to the development of severe malaria. We probed peptide microarrays containing segments spanning five PfEMP1 EPCR-binding domain variants with sera from 10 Malian adults and 10 children to determine the differences between adult and pediatric immune responses. We defined serorecognized peptides and amino acid residues as those that elicited a significantly higher antibody response than malaria-naïve controls. We aimed to identify regions consistently serorecognized among adults but not among children across PfEMP1 variants, potentially indicating regions that drive the development of immunity to severe malaria. Adult sera consistently demonstrated broader and more intense serologic responses to constitutive PfEMP1 peptides than pediatric sera, including peptides in EPCR-binding domains. Both adults and children serorecognized a significantly higher proportion of EPCR-binding peptides than peptides that do not directly participate in receptor binding, indicating a preferential development of serologic responses at functional residues. Over the course of a single malaria transmission season, pediatric serological responses increased between the start and the peak of the season, but waned as the transmission season ended. IMPORTANCE Severe malaria and death related to malaria disproportionately affect sub-Saharan children under 5 years of age, commonly manifesting as cerebral malaria and/or severe malarial anemia. In contrast, adults in malaria-endemic regions tend to experience asymptomatic or mild disease. Our findings indicate that natural immunity to malaria targets specific regions within the EPCR-binding domain, particularly peptides containing EPCR-binding residues. Epitopes containing these residues may be promising targets for vaccines or therapeutics directed against severe malaria. Our approach provides insight into the development of natural immunity to a binding target linked to severe malaria by characterizing an "adult-like" response as recognizing a proportion of epitopes within the PfEMP1 protein, particularly regions that mediate EPCR binding. This "adult-like" response likely requires multiple years of malaria exposure, as increases in pediatric serologic response over a single malaria transmission season do not appear significant.

Identifying and Addressing Barriers to Implementing Core Electronic Health Record Use Metrics for Ambulatory Care: Virtual Consensus Conference Proceedings.

Precise, reliable, valid metrics that are cost-effective and require reasonable implementation time and effort are needed to drive electronic health record (EHR) improvements and decrease EHR burden. Differences exist between research and vendor definitions of metrics. PROCESS: We convened three stakeholder groups (health system informatics leaders, EHR vendor representatives, and researchers) in a virtual workshop series to achieve consensus on barriers, solutions, and next steps to implementing the core EHR use metrics in ambulatory care. CONCLUSION: Actionable solutions identified to address core categories of EHR metric implementation challenges include: (1) maintaining broad stakeholder engagement, (2) reaching agreement on standardized measure definitions across vendors, (3) integrating clinician perspectives, and (4) addressing cognitive and EHR burden. Building upon the momentum of this workshop's outputs offers promise for overcoming barriers to implementing EHR use metrics.

Prosthetic Aortic Valve Obstruction With Pannus Formation, an Approach for Diagnosis and Management: A Case Report.

Mechanical valve obstructions are critical medical and surgical emergencies that require immediate attention when patients present with new complaints and exhibit signs such as the onset of murmurs or the disappearance of mechanical valve clicks. Obstructions can arise from various causes, including pannus formation, thrombus, vegetations, or subvalvular tissue growth. While pannus formations have been previously reported for the mitral valve, they are less commonly observed in the aortic valve, and several hypotheses have been proposed to understand pannus formation. Accurate diagnosis relies on imaging techniques such as echocardiography and fluoroscopy, and surgical intervention is considered the optimal treatment approach. Here, we present the case of a 69-year-old female who had previously undergone aortic valve replacement and subsequently developed progressive dyspnea, fatigue, and a new onset murmur. Imaging modalities revealed a closed leaflet and a high transvalvular gradient over the valve. The patient underwent a prosthetic redo valve replacement, and post-surgery, she was discharged home without complications.

The Use of a Dehydrated Complete Human Placental Membrane Allograft for Mohs Surgical Defects of the Nose.

BACKGROUND: Repair options for Mohs surgical defects include primary closure, flap or graft, or healing by second intention. These options may not be optimal in all cases. A dehydrated complete human placental membrane (dCHPM) allograft may serve as an alternative repair option. OBJECTIVE: To assess the aesthetic and functional outcomes of an alternative repair technique for Mohs surgical defects of the nose. METHODS: Twenty patients with Mohs surgical defects of the nose repaired with a dCHPM allograft were retrospectively identified. Photographs were used to demonstrate surgical technique and outcomes. Two blinded observers evaluated final outcomes using the Patient and Observer Scar Assessment Scale. RESULTS: Observers rated the scar outcome a combined mean score of 8.4 ± 3.2 (scale 5-50). Patients rated their outcomes a mean of 12.6 ± 7.4 (scale 6-60). The mean "Overall Opinion score" was 2.5 ± 1.8 by patients and 1.9 ± 1.3 by observers (scale 1-10). LIMITATIONS: This was a single institution study with a small sample size. CONCLUSION: Our study demonstrates that dCHPM allografts are a viable alternative repair option for Mohs surgical defects of the nose.

Role of short-dwell daily ethanol-lock therapy in the management of hemodialysis tunneled cuffed catheter-related bloodstream infection.

BACKGROUND: Catheter-Related Blood Stream Infection (CRBSI) is the major limitation of using Tunneled cuffed catheter (TCC) for long-term Hemodialysis. The standard therapy of CRBSI involves systemic antibiotics with catheter replacement/removal. As antibiotic alone is rarely effective therapy for CRBSI, biofilm eradication using antimicrobial locking solutions is a promising modality for CRBSI treatment, hence catheter salvage. The present study evaluated the efficacy and safety of Ethanol-lock therapy (ELT) in combination with systemic antibiotics for the management of CRBSI associated with hemodialysis TCC. METHOD: 56 patients with CRBSI were treated with 70% ELT (1 h daily for 5 days) along with systemic antibiotics. Seventeen patients with CRBSI who didn't consent to ELT were treated with antibiotics alone. The effect of ELT was evaluated as clinical cure (fever resolution and negative surveillance cultures), infection-free TCC survival duration and adverse events of ELT among patients with CRBSI. The parameters were compared with 17 patients treated with antibiotics alone. RESULTS: ELT was successful in 50 out of 56 patients (89.28%); compared to 41.17% (seven out of 17) with antibiotics alone (p < 0.001). Mean TCC survival was also significantly higher with ELT combined with systemic antibiotics (126.23 ± 18.67 days) compared to antibiotics alone (38.76 ± 9.91) (p = 0.006). No systemic adverse effects were noted with ELT; two patients receiving ELT had catheter breakage during the study period. CONCLUSION: We conclude that short-dwell daily ELT with systemic antibiotics is an effective therapy for CRBSI in hemodialysis patients with TCC.

Surgery Alone (Without Adjuvant Radiation) Adequately Treats Histologic Perineural Basal Cell Carcinomas: A Systematic Review With Meta-Analysis.

BACKGROUND: Histologic perineural invasion (PNI) in basal cell carcinomas (BCC) lacks evidence-based treatment guidelines. OBJECTIVE: Systematically review and analyze treatment outcomes of BCC with histologic PNI (PNBCC). MATERIALS AND METHODS: PubMed, Embase, and Cochrane Reviews were searched through June 25, 2021. Thirteen eligible cohort studies were meta-analyzed. RESULTS: 502 of 713 PNBCC were treated with Mohs Surgery (MMS), wide local excision (WLE), or surgery (MMS or WLE) with adjuvant radiation (Surg + RT). Overall 5-year local control (LC) was 97.2% and cancer-specific survival (CSS) was 99.6%. Surg and Surg + RT did not differ in recurrence (2.1% vs 4.7%; p-value 0.56; RR 1.51 [0.37, 6.20]), LC (97.9% vs 96.2%; p-value 0.19; RR 0.98 [0.96, 1.01]) or CSS (100% vs 99.1%; p-value 0.40; RR 0.99 [0.95, 1.02]). LIMITATIONS: No randomized controlled trials were found. Outcome data were often lacking. CONCLUSION: Overall LC and CSS were high at median 5-year follow-up for surgery alone and Surg + RT. Surgery alone and Surg + RT demonstrated statistically equivalent outcomes. We do not recommend adjuvant radiation therapy for solely histologic PNBCC if clear margins are achieved.

Gorlin-Goltz Syndrome: Report of a Rare Case with an Update on the Review of the Literature.

Keratocyst is a developmental odontogenic cyst arising from remnants/rests of the dental lamina with biologic behavior similar to benign neoplasm. The presence of multiple odontogenic keratocysts is rare and seen in Gorlin-Goltz syndrome (GGS). GGS syndrome presents with multisystem involvement and the classical triad of multiple basocellular epitheliomas, keratocysts in the jaws, and bifid ribs; that characterize the diagnosis of this syndrome. Multiple odontogenic keratocyst are the most consistent features of the syndrome in 65%-100% of affected individuals and are generally diagnosed at a very early age. Early diagnosis and proper counseling of the parent and patient might help to reduce the morbidity, encourage follow-up for timely treatment, and help in avoiding ionizing radiation that would lead to the development of malignancies.

Valproic Acid Overdose: Case Report and Literature Review.

BACKGROUND: Valproic acid (VPA) is a common antiepileptic drug that is also used routinely for various psychiatric disorders. VPA toxicity typically manifests as central nervous system depression, while hyperammonemic encephalopathy and hepatotoxicity are potentially life-threatening complications. CASE REPORT: We describe the case of a 56-year-old man who presented to the emergency department after an intentional VPA overdose, was found to have hyperammonemia, and was treated with L-carnitine exclusively. He was subsequently admitted to the hospital for monitoring and serial laboratory testing. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although VPA toxicity has conventionally been managed by gastric decontamination, L-carnitine, and, in severe and refractory cases, extracorporeal removal, recent literature supports the use of carbapenem antibiotics, particularly meropenem. Thus, we report the details of current treatment modalities for VPA toxicity by reviewing current literature.

Utility of serum lactate on differential diagnosis of seizure-like activity: A systematic review and meta-analysis.

INTRODUCTION: Differentiating epileptic seizures from other causes of Transient Loss of Consciousness (TLOC) remains a challenge in the Emergency Department (ED), where it may lead to erroneous administration of anti-epileptic drugs. Although video electroencephalography (EEG) is the gold standard for diagnosing epileptic seizures, it is not widely available in ED settings. Therefore, simple and quick diagnostic techniques for patients with TLOC in ED are needed. We performed a meta-analysis to review relevant literature and determine the efficacy of serum lactate in differentiating epileptic seizures from other causes of TLOC in the ED setting. METHODS: We performed a literature search of PubMed and Scopus from inception up to April 2022. Randomized trials and observational (prospective or retrospective) studies reporting lactate levels in adults ≤ 3 h after a TLOC episode were included. The primary outcome of interest was the serum lactate level difference between patients with a generalized tonic-clonic seizures (GTCS) and those with other forms of TLOC. Other outcomes were the differences in serum lactate levels among patients with other types of TLOC, such as psychogenic nonepileptic seizures (PNES), syncope, and non-GTCS. Random-effects meta-analysis was performed to compare the mean difference in serum lactate levels among different types of TLOC. The PROSPERO registration is CRD42022316163. RESULTS: We included eight studies (1348 patients) in our analysis. Serum lactate levels from patients who had GTCS were significantly higher than those from patients who had TLOC from any other cause (mean difference 5.27 mmol/L, 95% CI 1.73, 8.81, P = 0.004). Similarly, there was statistically a significant difference in serum lactate between patients with GTCS and non-GTCS (2.96 mmol/L, 95% CI 1.68, 4.24, P = 0.001), and patients with GTCS and syncope (4.29 mmol/L, 95% CI 2.48, 6.10, P = 0.001). However, there was no difference in mean lactate between syncope and PNES, and between syncope and non-GTCS, demonstrating that the serum lactate levels between other forms of TLOC other than GTCS were similar. A serum lactate concentration of 2.4 mmol/L provided a good capability to differentiate between GTCS and non-GTCS, with AUROC ranging from 0.94 - 0.97. CONCLUSION: Serum lactate can be a valuable tool to differentiate GTCS from other forms of TLOC, but it is not valuable in distinguishing non-GTCS types of TLOC from each other. However, lactate level should not be used as an absolute diagnostic tool and should be interpreted along with proper clinical context.

Correlation of the Position of the Anal Dimple with the Caudal Termination of the Striated Muscle Complex in Patients with Anorectal Malformations.

Background: In children with anorectal malformations (ARM), the vertical fibres of the striated muscle complex (SMC) are believed to be located within the limits of the anal dimple (AD). Methods: Forty five cases of ARM underwent posterior sagittal anorectoplasty (PSARP), median age 8.5 months. During PSARP the anterior, posterior limits and midpoint of the AD and SMC were marked. The location of AD was correlated with SMC. Results: A 'well developed' AD and SMC was seen in 80 % and 86.7 % patients respectively. The mean width of the AD and SMC was more in females than in males (20.96 vs. 18.98 mm and 14.24mm vs. 13.45mm respectively). In 36 cases (80 %), across the spectrum of ARM, the SMC was posterior in relation to the AD. In 7 cases (15.5 %) it correlated in position with the AD and in 2 cases (4.44 %), it was anterior to the AD. Conclusions: In the majority of cases AD and SMC were 'well developed' and the location of the SMC does not correlate with that of the AD. This has significant practical value in the important step of optimizing the placement of the rectum through the center of the SMC during repair.

Discovery of anti-Formin-like 1 protein (FMNL1) antibodies in membranous nephropathy and other glomerular diseases.

Evidence has shown that podocyte-directed autoantibodies can cause membranous nephropathy (MN). In the present work we investigated sera of MN patients using a high-density peptide array covering the whole coding sequences of the human genome encompassing 7,499,126 tiled peptides. A panel of 21 proteins reactive to MN sera were identified. We focused our attention on Formin-like 1 (FMNL1), a protein expressed by macrophages in MN patients tissues. High levels of anti-FMNL1 IgG4 were demonstrated in sera of MN patients with an orthogonal methodology (ELISA) contemporary demonstrating FMNL1 positive cells in kidney co-staining with CD68 in glomeruli. High levels of circulating anti-FMNL1 IgG4 were associated with lack of remission of proteinuria, potentially indicating that autoantibodies directed against cells other than podocytes, involved in tissue repair, might play a role in MN disease progression. High serum levels of anti-FMNL1 IgGs were also observed in other non-autoimmune glomerolonephrites, i.e. idiopathic and genetic FSGS, IgAGN. These findings are suggestive of a broader role of those autoantibodies in other glomerular disease conditions.