Time-resolved interactome profiling deconvolutes secretory protein quality control dynamics.

Many cellular processes are governed by protein-protein interactions that require tight spatial and temporal regulation. Accordingly, it is necessary to understand the dynamics of these interactions to fully comprehend and elucidate cellular processes and pathological disease states. To map de novo protein-protein interactions with time resolution at an organelle-wide scale, we developed a quantitative mass spectrometry method, time-resolved interactome profiling (TRIP). We apply TRIP to elucidate aberrant protein interaction dynamics that lead to the protein misfolding disease congenital hypothyroidism. We deconvolute altered temporal interactions of the thyroid hormone precursor thyroglobulin with pathways implicated in hypothyroidism pathophysiology, such as Hsp70-/90-assisted folding, disulfide/redox processing, and N-glycosylation. Functional siRNA screening identified VCP and TEX264 as key protein degradation components whose inhibition selectively rescues mutant prohormone secretion. Ultimately, our results provide novel insight into the temporal coordination of protein homeostasis, and our TRIP method should find broad applications in investigating protein-folding diseases and cellular processes.

Dermoscopic Evaluation of Actinic Changes in the Lips of Indigenous Children Living at High Altitude in Ecuador: A Descriptive Study.

BACKGROUND High altitude increases sunlight exposure, resulting in actinic keratosis, which predisposes people to skin cancer. The dermoscopy procedure evaluates keratotic and pigmented skin changes. This study aimed to describe the clinical and dermoscopic actinic changes in the lips of 25 indigenous children living at high altitude in Ecuador. MATERIAL AND METHODS An observational study was conducted in a public school in the Andes region of Ecuador (August-November 2019). Twenty-five children, males and females, age 5-15 years were assessed by complete physical examination, digital dermoscopic photographs, and punch biopsies. Descriptive statistics and Fisher's exact test were used to summarize and analyze the data. RESULTS We included 17 (68%) boys and 8 (32%) girls with a mean age of 9.8±2.0 years. Clinical lips findings reported desquamation [52% Upper Lip (UL); 40% Lower Lip (LL)], fissuring (8% UL; 8% LL), scabs (8% UL; 8% LL), and discoloration (40% UL; 20% LL). Dermoscopic features included a white-yellow lip color (24% UL; p=0.02). The main morphologic pattern of blood vessels was monomorphic (88% UL; p<0.001), polymorphous (60% LL; p<0.001), dotted pattern (64% UL; 28% LL; p=0.02), and linear-irregular (32% UL; 72% LL; p=0.01). Girls had radiating white structures on UL (p=0.025), while boys presented white structureless areas (UL 63.6%; LL 77.8%; p=0.032). No differences in dermoscopic findings were observed according to Fitzpatrick scale score (FSS). Punch biopsies showed no indications of actinic cheilitis. CONCLUSIONS Dermoscopic features in indigenous children living in high altitudes were related to actinic damage, but histopathological findings were negative.

A Refined Minimally Invasive Distal First Metatarsal Osteotomy for Moderate Hallux Valgus Treatment: The BC Procedure.

During the last 2 decades, there was an increasing interest in mini-invasive procedures for hallux valgus correction. In this scenario the Bösch technique appears to be a reproducible distal metatarsal osteotomy (DMO) to achieve a proper correction. Our DMO variant, called BC, was planned to combine the stability and predictability of the chevron osteotomy, with the power of correction, low surgical time and mini-invasive approach of the Bösch-SERI technique. The purpose of this investigation is to describe the surgical technique and report the results of this modified procedure at a minimum 2-year follow-up. Sixty-three patients who underwent the BC technique for mild and moderate hallux valgus were prospectively evaluated. Mean follow-up was 36.5 (range 23.4-59.8) months, the mean American Orthopedic Foot and Ankle Society score improved from a median of 47.4 points preoperatively to a median of 88 points postoperatively (p < .05). First MTPJ ROM did not change from preoperative period (mean 32.5°) to the postoperative period (mean 31.8°) (p > .65). All osteotomies went on to bony healing in the 6-week follow-up visit. Fifty-two (82%) of patients were either very satisfied or satisfied with the procedure (p < .05). With our numbers, BC osteotomy is shown to be a technique that can treat both mild and moderate deformities, achieving correction that is maintained over the follow-up evaluated, with a 24 relatively simple procedure and short operative time.

Two-step Testing for Clostridioides Difficile is Inadequate in Differentiating Infection From Colonization in Children.

OBJECTIVES: Recent Infectious Disease Society of America guidelines recommend multistep testing algorithms to diagnose Clostridioides difficile infection (CDI), including a combination of nucleic acid amplification-based testing (NAAT) and toxin enzyme immunoassay (EIA). The use of these algorithms in children, including the ability to differentiate between C. difficile colonization and CDI, however, has not been evaluated. METHODS: We prospectively enrolled asymptomatic pediatric patients with cancer, cystic fibrosis (CF), or inflammatory bowel disease (IBD) and obtained a stool sample for NAAT testing. If positive by NAAT (colonized), EIA was performed. In addition, children with symptomatic CDI who tested positive by NAAT via the clinical laboratory were enrolled, and EIA was performed on residual stool. A functional cell cytotoxicity neutralization assay (CCNA) was also applied to stool samples from both the colonized and symptomatic cohorts. RESULTS: Of the 225 asymptomatic children enrolled in the study, 47 (21%) were colonized with C. difficile including 9/59 (15.5%) with cancer, 30/92 (32.6%) with CF, and 8/74 (10.8%) with IBD. An additional 41 children with symptomatic CDI were enrolled. When symptomatic and colonized children were compared, neither EIA positivity (44% vs 26%, P = 0.07) nor CCNA positivity (49% vs 45%, P = 0.70) differed significantly or were able to predict disease severity in the symptomatic cohort. CONCLUSIONS: Use of a multistep testing algorithm with NAAT followed by EIA failed to differentiate symptomatic CDI from asymptomatic colonization in our pediatric cohort. As multistep algorithms are moved into clinical care, the pediatric provider will need to be aware of their limitations.

Correction Power of Percutaneous Adductor Tendon Release (PATR) for the Treatment of Hallux Valgus: A Cadaveric Study.

Osteotomies are commonly used in order to correct hallux valgus deformity. However, soft tissue structures also play an essential role in the etiology, progression, and treatment of hallux valgus (HV). The purpose of the present study was to analyze the correcting power (varus), reduction strength (sesamoid) and rotation of metatarsal and proximal phalanx after percutaneous adductor tendon release (PATR). To date, no study addresses this issue. Eleven cadaveric fresh-frozen below-the-knee cadaveric lower limbs with associated hallux valgus deformity were used. These specimens were subjected to a constant abduction force after PATR. HV and intermetatarsal angles showed statistically significant differences when comparing the preoperative and postoperative periods. PATR showed to be a reliable technique as the adductor tendon was completely released in 9 cases, and 75% released in the remaining 2 feet. The study supports that PATR provides powerful and quantifiable correction of HV deformity and can be accurately performed percutaneously.

Youngswick osteotomy for treatment of moderate hallux rigidus: Thirteen years without arthrodesis.

PURPOSE: The purpose of this study was to evaluate the need for first metatarsophalangeal joint (MTPJ) arthrodesis as a measure of the Youngswick osteotomy survival, or any other secondary procedures in the long term follow up in patients with stage II and III hallux rigidus. METHODS: We retrospectively evaluated 61 patients with stage II and III hallux rigidus who had undergone Youngswick osteotomy and analyzed their outcomes in the long term using first metatarsophalangeal arthrodesis as an end point. The candidates for inclusion underwent clinical and radiographic evaluation, including the Foot and Ankle Outcome Score (FAOS). RESULTS: Mean follow-up time was 54.8 months. All patients had improved their FAOS, with all achieving postoperative scores >75 points at the final follow up (P<0.05). Although 49 % (P<0.05) of the patients depicted worsening of the radiological aspect of the MTPJ, over the long time, no patient needed a first MTPJ arthrodesis. CONCLUSION: Our results show satisfying long-term outcomes with regard to function, pain relief, and patient satisfaction of the Youngswick osteotomy in grade II as well as grade III hallux rigidus that sustained over the follow up period; even in patients followed up for over 13 years. LEVEL OF EVIDENCE: III.

Influence of Age, Sex, and Body Mass Index on the Depth of the Superficial Fascia in the Face and Neck.

BACKGROUND: Nonsurgical skin-tightening procedures are increasing in popularity, as patients seek aesthetic interventions that are safe with minimal downtime. OBJECTIVE: This study was designed to provide precise data on the depth of the superficial fascia-the structure of action-of the face and neck. METHODS: One hundred fifty Caucasian individuals (75 men and 75 women) were investigated with a balanced distribution of age (n = 30 per decade: 20-29, 30-39, 40-49, 50-59, and 60-69 years) and body mass index (BMI) (n = 50 per group: BMI ≤ 24.9 kg/m, BMI between 25.0 and 29.9 kg/m, and BMI ≥ 30 kg/m). The distance between skin surface and the superficial fascia was measured through ultrasound in the buccal region, premasseteric region, and lateral neck. RESULTS: The mean distance between skin surface and superficial fascia was for the buccal region 4.82 ± 0.9 mm, range (2.60-6.90); for the premasseteric region 4.25 ± 0.6 mm, range (2.60-5.80); and for the lateral neck 3.71 ± 0.5 mm, range (2.0-5.0). The depth of the superficial fascia increased with increasing BMI, whereas it decreased with advanced age. CONCLUSION: Knowing the precise depth of the superficial fascia for nonsurgical skin-tightening procedures will guide practitioners toward safer and more effective outcomes.

Joint Preserving Procedure for Moderate Hallux Rigidus: Does the Metatarsal Index Really Matter?

Surgical treatment of moderate hallux rigidus remains controversial and the optimal surgical technique has yet to be defined. Decompressive metatarsal osteotomy is one of the procedures available; however, one of the potential drawbacks is the effect of the metatarsal shortening. We evaluated the global effect of the decompressive metatarsal osteotomy, accounting for the metatarsal index. We retrospectively evaluated 78 patients with stage II and III hallux rigidus who had undergone Youngswick osteotomy and analyzed their outcomes according to the metatarsal index. The candidates for inclusion underwent clinical and radiographic evaluation, including the visual analog scale foot and ankle score, first metatarsophalangeal joint range of motion, and first metatarsal protrusion distance to define the metatarsal index. Also, shortening of the first metatarsal was measured postoperatively, and the occurrence of metatarsalgia was considered a postoperative complication. The mean follow-up period was 53 ± 17 months. The groups stratified according to the metatarsal index (index plus, index plus minus, and index minus) presented with similar results (p > .05). The average preoperative visual analog scale foot and ankle score of 56.4 ± 13.8 points improved significantly to 84.1 ± 5.5 points postoperatively (p < .0001). Also, the mean preoperative dorsiflexion of 20.4° ± 1.5° improved to 37.3° ± 1.6° postoperatively (p < .0001). Of the 78 patients, 97% would recommend the procedure to a family member or friend. Four patients (6%) experienced postoperative metatarsal pain. We found consistent results with this procedure. The reported functional score and dorsiflexion improvement provide evidence that good outcomes and high levels of patient satisfaction can be achieved, regardless of the metatarsal length.

Cholinesterases in Gambusia yucatana: Biochemical Characterization and its Relationship with Sex and Total Length.

Since several reports have indicated that cholinesterases (ChE) type and distribution is species specific and that in some species there is a relationship among gender, size and ChE activities, characterization has been suggested. The aim of the present study was to characterize the ChE present in head and muscle of Gambusia yucatana (using selective substrates and inhibitors) and to find its relationship with total length or gender. Results indicated that the ChE present in G. yucatana is an acetylcholinesterase (AChE) with high sensitivity to BW284C51 and an atypical smaller Km with butyrylthiocholine. Scatterplots indicated that there is no linearity between total length and AChE in male or female wild mosquitofish. There were no sex differences in AChE activities. Results indicated significant differences between a single collection site in the Yucatan peninsula and depurated organisms. This study emphasized the importance of characterizing ChE before usage in biomonitoring.

A Novel Uni- and Biplanar External Fixator for Initial and Definitive Complex Foot Trauma.

Background: Evidence concerning the complex foot trauma, especially its definitive management, is scarce. Soft tissue envelope sequalae are the primary parameters that delay or make internal fixation implausible. Stability conferred by external fixators makes them a reasonable initial treatment choice. Although AO or circular fixators can be applied around the foot, this can involve a learning curve and substantial costs, especially for the circular fixator. There is little evidence as to how well external fixators work as a definite method of fixation in patients where progression to internal fixation cannot be made. Methods: We prospectively evaluated 10 adult patients with severe and complex foot trauma who were consecutively treated at our clinic. Initial reduction and stabilization were performed with an external fixator that was initially conceived for distal radius fractures, applied during the initial procedure and mantained throughout the treatment. Results: Fracture healing was obtained in all 10 cases, and both internal and external column length was restored. One of the patients developed chronic osteomyelitis. At the 1-year follow-up visit, these patients averaged 45.6 points in the physical and 44.8 points on the mental status sections of the 12-Item Short Form Health Survey (SF-12). The Foot Function Index findings for pain, disability, and daily activities limitations were 33.3, 39, and 41.5, respectively, which suggest moderate residual impairment. Conclusion: In this relatively small case series of complex foot trauma, we found that the use of simple external fixation as definitive treatment worked reasonably well. Level of Evidence: Level III, prospective cohort study.

Training of Field-Workers for Rapid Assessment of Scabies Prevalence: A Diagnostic Accuracy Study in Mozambique.

Scabies is endemic in many resource-poor tropical areas, causing significant morbidity. However, our understanding of the true burden of scabies in Africa is limited, partly owing to limited capacity and challenges accessing the currently recommended diagnostic tools. The primary objective of this study was to assess the diagnostic accuracy of scabies assessments made by minimally trained field-workers. We trained field-workers with a minimum of secondary school education in the diagnosis of scabies. After the training, we assessed the diagnostic accuracy of assessments made by nine field-workers compared with the reference standard. In all, 193 individuals were assessed for scabies. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated, as well as agreement (κ coefficients) between medical doctors and between field-workers. Of the 193 participants, 26% had scabies according to the reference standard. The sensitivity of field-worker diagnosis compared with the reference standard was 94% (95% CI: 90-99%), and the specificity was 96% (95% CI: 90-97%). The determination of severity by field-workers was less accurate; the sensitivity for severe scabies was 61% (95% CI: 48-74%), and the mean specificity was 97% (95% CI: 93-100%). This study demonstrated that field-workers without medical qualifications were capable of diagnosing scabies to a similar level of accuracy as experienced medical doctors after a short period of focal training. This may facilitate rapid assessments of scabies prevalence for public health purposes and decisions about mass drug administration implementation in similar settings.

Research about eye health and eye health services in Pacific Island Countries and Territories: a scoping review.

Background: We aimed to summarise the extent and nature of published research about eye health and eye health services in Pacific Island Countries and Territories since 1980. Methods: We searched Medline, EMBASE, Global Health and Cochrane Library to identify publications about eye health and eye health services in 22 Pacific Island Countries and Territories from 1 January 1980 to 26 January 2024. Study selection and data extraction were conducted by two reviewers independently. Findings: Of the 1610 publications identified, 180 were included. This research was most commonly conducted in Papua New Guinea (n = 52) or Fiji (n = 33) and focused on diabetic retinopathy (n = 29) or trachoma (n = 18), with few focused on cataract or refractive error. While eye health services research was common in the past, recent research focused on trachoma. The included research was largely undertaken and funded by people and organisations from Australia, Aotearoa New Zealand and the USA, though authors with Pacific affiliations is increasing. Interpretation: Few countries have up-to-date estimates of the prevalence of vision impairment or service coverage to enable evidence-informed planning. Increased effort is required to strengthen research capability to ensure research priorities in eye health are set by Pacific Peoples. Funding: The Fred Hollows Foundation New Zealand.

Republication of "How Accurate Is Clinical Evaluation in Hindfoot Coronal Alignment?"

Background: Hindfoot coronal alignment is an important factor in the assessment of patients with many different foot and ankle complaints. A number of clinical and radiographic techniques have been described to measure hindfoot coronal alignment, but none of them are widely accepted. The purpose of the present study was to assess the correlation between clinical and radiographic hindfoot alignment measures and to evaluate the reproducibility of each. Methods: We evaluated 85 patients with foot and/or ankle symptoms. Hindfoot clinical alignment was measured from photographs. Each patient was placed at a distance of 1 m from the observer, with both feet placed parallel. Four photographs were taken, at a height of 40 cm: a posterior view of both lower limbs including knees, a posterior view focalized on the studied hindfoot, an anterior view of the foot, and the last view of the medial aspect of the foot. Radiographic alignment was quantified on long axial view radiographs. Patients were lying over the film cassette with a focus distance of 1 m and the beam pointed to the ankle joint. The inclination angle of the beam was 45 degrees to the floor. Measurements were independently made by 2 observers, who were asked to classify pictures into 3 categories: varus, neutral, and valgus. Radiographic measurements were made using the angle measurement tool on the radiograph viewer. The intraclass correlation coefficients (ICCs) and the 95% confidence interval (CI) of the ICC were used to quantify the inter- and intraobserver reliability for clinical assessment. Radiographic parameters were correlated by calculating the Pearson correlation coefficient (r). Results: The intraobserver ICC for clinical analysis was good for both observers, while the interobserver ICC was moderate for both measurements. Regarding radiographic assessment, there was significant intra- and interobserver reliability. The correlation between both methods was weak for both observers. Conclusions: We found only weak intra- and interobserver correlations between the clinical and radiographic assessment of hindfoot coronal alignment. It is therefore necessary to complement the clinical evaluation of hindfoot alignment with an objective measurement method such as a long axial view radiograph. Further studies comparing different measurement methods need to be performed to establish the most objective evaluation. Level of Evidence: Level III, diagnostic study.

Comparison of Visual Field Test Measurements With a Novel Approach on a Wearable Headset to Standard Automated Perimetry.

PRCIS: This study of inter-test comparability of a novel visual field application installed on an augmented-reality portable headset and Humphrey field analyzer Swedish interactive thresholding algorithm (SITA) Standard visual field test demonstrates the excellent correlation of mean deviation (MD) and mean sensitivity (MS). PURPOSE: To determine the correlation between visual field testing with novel software on a wearable headset versus standard automated perimetry. PATIENTS AND METHODS: Patients with and without visual field defects attributable to glaucoma had visual field testing in one eye of each patient with 2 methods: re:Imagine Strategy (Heru, Inc.) and the Humphrey field analyzer (Carl Zeiss Meditec, Inc.) SITA Standard 24-2 program. Main outcome measures included MS and MD, which were evaluated by linear regression, intraclass correlation coefficient (ICC), and Bland Altman analysis for assessment of the mean difference and limits of agreement. RESULTS: Measurements from 89 eyes of 89 patients (18 normal and 71 glaucomas) were compared with both instruments. Linear regression analysis demonstrated an excellent Pearson correlation coefficient of r = 0.94 for MS and r = 0.95 for MD. ICC analysis demonstrated high levels of concordance (ICC = 0.95, P < 0.001 for MS and ICC = 0.94, P < 0.001 for MD). Bland-Altman analysis determined a small mean difference between the two devices (Heru minus Humphrey) of 1.15 dB for MS and 1.06 dB for MD. CONCLUSIONS: The Heru visual field test correlated well with SITA Standard in a population of normal eyes and eyes with glaucoma.

The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis.

Collagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl 4 ) administration or by high fat diet. Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), which is known to be critical for collagen maturation, as a major IRE1-induced gene. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states.

Metatarsalgia: Assessment Algorithm and Decision Making.

Historically, metatarsalgia was approached as a forefoot condition, most often associated with hallux valgus. Consequently, surgical treatments were limited to that anatomic zone, disregarding more proximal structures. In order to assess this entity properly, it is necessary to consider anatomic and biomechanical factors, as well as general and local conditions of the affected patients. A thorough understanding of the multiple potential causal factors is essential to ensure selection of the optimal treatment.

Mini thigthrope® fixation of unstable bony avulsion of the extensor hallucis longus tendon.

Reports of isolated avulsion fracture of the distal phalanx of the hallux that comprise the functionality of the extensor hallucis longus tendon (EHL) are scarce and treatment for such injury has only been described in isolated single case reports. Two patients with an unstable avulsion fracture of the distal phalanx treated with reinsertion of the EHL with a Mini ThigthRope® system are presented in this paper. Two patients whom suffered an extreme plantarflexion mechanism sought attention in our clinic. Plain x-rays depicted a displaced and angulated bony avulsion fracture of the base of the distal phalanx of the hallux. The interphalangeal joint was in a slightly plantarflexed position and the patient was not able to perform active extension upon request. Surgical fixation performed with Mini ThigthRope® system without transarticular immobilization of the interphalangeal joint. In the two patients the Mini ThigthRope® system provided adequate reduction of the displaced articular fragment, restored the extensor function and allowed early postoperative mobilization of the IP joint. Removal of the implants was not necessary and patients were able to resume their previous activity levels. Level of Evidence: IV.

What Metrics Can Be Used to Determine the Optimal Timing of Reimplantation in Patients Who Have Undergone Resection Arthroplasty as Part of a Two-Stage Exchange for Infected Total Ankle Arthroplasty (TAA)?

RECOMMENDATION: There is no conclusive data regarding what metrics can be used in order to determine the optimal timing of reimplantation for an infected TAA. We recommend that reimplantation is performed when there are clinical signs of resolution of infection (well-healed wound, lack of erythema, etc), and the serologic markers have substantially declined (>40%) from baseline (measured at the time of diagnosis of infection). LEVEL OF EVIDENCE: Consensus. DELEGATE VOTE: Agree: 100%, Disagree: 0%, Abstain: 0% (Unanimous, Strongest Consensus).

Should Routine Methicillin-Resistant Staphylococcus aureus (S. aureus), or MRSA, Screening Be in Place Prior to Total Ankle Arthroplasty (TAA)?

RECOMMENDATION: Unknown. The role of screening for methicillin-resistant Staphylococcus aureus (MRSA) and decolonization prior to total ankle arthroplasty (TAA) remains unclear. Further data are needed to support this practice in TAA, which can be costly and logistically difficult to implement. LEVEL OF EVIDENCE: Consensus. DELEGATE VOTE: Agree: 100%, Disagree: 0%, Abstain: 0% (Unanimous, Strongest Consensus).

What Are the Benefits and Risks Associated With the Use of Vancomycin Powder in the Wound During Total Ankle Arthroplasty (TAA) or Other Foot and Ankle Procedures?

RECOMMENDATION: Though one study supporting topically applied vancomycin has shown it to reduce the rate of deep infection in diabetic patients undergoing foot and ankle surgery, there is insufficient evidence to show benefits or to show any risks associated with the use of vancomycin powder during total ankle arthroplasty (TAA) or other foot and ankle procedures in a general population. LEVEL OF EVIDENCE: Consensus. DELEGATE VOTE: Agree: 100%, Disagree: 0%, Abstain: 0% (Unanimous, Strongest Consensus).