Developing Folate-Conjugated miR-34a Therapeutic for Prostate Cancer: Challenges and Promises.

Prostate cancer (PCa) remains a common cancer with high mortality in men due to its heterogeneity and the emergence of drug resistance. A critical factor contributing to its lethality is the presence of prostate cancer stem cells (PCSCs), which can self-renew, long-term propagate tumors, and mediate treatment resistance. MicroRNA-34a (miR-34a) has shown promise as an anti-PCSC therapeutic by targeting critical molecules involved in cancer stem cell (CSC) survival and functions. Despite extensive efforts, the development of miR-34a therapeutics still faces challenges, including non-specific delivery and delivery-associated toxicity. One emerging delivery approach is ligand-mediated conjugation, aiming to achieve specific delivery of miR-34a to cancer cells, thereby enhancing efficacy while minimizing toxicity. Folate-conjugated miR-34a (folate-miR-34a) has demonstrated promising anti-tumor efficacy in breast and lung cancers by targeting folate receptor α (FOLR1). Here, we first show that miR-34a, a TP53 transcriptional target, is reduced in PCa that harbors TP53 loss or mutations and that miR-34a mimic, when transfected into PCa cells, downregulated multiple miR-34a targets and inhibited cell growth. When exploring the therapeutic potential of folate-miR-34a, we found that folate-miR-34a exhibited impressive inhibitory effects on breast, ovarian, and cervical cancer cells but showed minimal effects on and targeted delivery to PCa cells due to a lack of appreciable expression of FOLR1 in PCa cells. Folate-miR-34a also did not display any apparent effect on PCa cells expressing prostate-specific membrane antigen (PMSA) despite the reported folate's binding capability to PSMA. These results highlight challenges in the specific delivery of folate-miR-34a to PCa due to a lack of target (receptor) expression. Our study offers novel insights into the challenges and promises within the field and casts light on the development of ligand-conjugated miR-34a therapeutics for PCa.

Total hip arthroplasty for post-firearm hip arthritis complicated by coloarticular fistula: A case report.

Hip firearm injuries are rare injuries that could lead to serious complications, such as posttraumatic hip arthritis and coloarticular fistula. We report a case of a 25-year-old male who sustained a pelvic injury caused by a single bullet which led to a bilateral acetabular fracture, concomitant with a colon injury treated on an emergency basis by a diverting colostomy; acetabular fractures were treated conservatively by traction. After the patient recovered from the abdominal injury, he was presented with bilateral hip pain and limited motion; plain radiographs showed bilateral hip arthritis with proximal migration of the femoral head and bilateral acetabular defect classified as Paprosky type ⅢA. Reconstruction of the hips was performed using the same technique: impaction bone grafting for acetabular defect reconstruction and a reversed hybrid total hip arthroplasty (THA) 6 months apart. The patient presented with loosening of the left THA acetabular cup 3 years later, which was revised; then he presented with a discharging sinus from the left THA with suspicion of coloarticular fistula, which was confirmed using CT with contrast material. A temporary colostomy and fistula excision were performed, and a cement spacer was applied to the hip. After clearing the infection, a final revision THA for the left hip was performed. Treating post-firearm hip arthritis by THA is challenging, especially in the situation of neglected cases with the presence of an acetabular defect. Concomitant intestinal injury increases the risk of infection with the possibility of coloarticular fistula formation, which could present later. Working with a multidisciplinary team is paramount.

Prediction of leg length change (LLC) after correcting varus and flexion deformity in patients undergoing TKA.

PURPOSE: Patients with varus and fixed flexion deformity (FFD) undergoing TKA may have a significant leg length change (LLC) after surgery. We aimed to determine the correlation between changes in HKA or FFD and leg length in patients undergoing TKA, the combined effect of coronal and sagittal plane deformity correction on LLC, and the possibility of estimating LLC mathematically. MATERIALS AND METHODS: This was a prospective radiographic evaluation of 242 knees, which had undergone primary unilateral TKA for advanced OA with varus and FFD. Full-length standing calibrated anteroposterior radiographs were used to measure the hip-knee-ankle axis (HKA) and functional leg length after adjusting for magnification. Clinical evaluation of FFD was done using a handheld goniometer. RESULTS: 224 knees (92.6%) showed increased limb length after TKA averaging 10.7 mm (SD 9.5 mm, P = .000). There was a significant correlation between the change in HKA and FFD from preoperatively to postoperatively with the amount of LLC (ρ 0.326 and 0.346, respectively, P = .000). FFD improvement from preoperatively to postoperatively was 8.1° to 1° (P = .000), respectively. A linear relationship was established between LLC and changes in HKA and FFD, where 10° improvement in HKA would result in an LLC of nearly 4 mm, and 10° improvement in FFD would result in a LLC of nearly 8 mm. CONCLUSION: LLC may be substantial after correcting varus and FFD with unilateral TKA, it correlates with the change in HKA and FFD and can be mathematically estimated. CLINICAL TRIALS . GOV IDENTIFIER: NCT03502382.

Diagnostic potential of ultrasound in carpal tunnel syndrome with different etiologies: correlation of sonographic median nerve measures with electrodiagnostic severity.

BACKGROUND: Carpal tunnel syndrome (CTS) is the commonest entrapment neuropathy. The aim of this study was to assess the accuracy and validity of high resolution musculoskeletal ultrasound (US) in the diagnosis of CTS in the Saudi population. METHODS: Sixty patients were diagnosed clinically to have CTS involving 89 wrists that were confirmed by neurophysiologic studies. Each affected wrist was characterized as idiopathic or associated with either diabetes mellitus or hypothyroidism and were assigned a severity grade based on results of neurophysiologic studies. Seventy-six healthy wrists from fifty age, sex and BMI matched healthy subjects were included in the control group. High resolution ultrasound (US) was performed to assess median nerve cross sectional area distal (CSAd) at the entry to the carpal tunnel and proximally (CSAp) at the level of pronator quadratus muscle with a further calculation of their difference (ΔCSA) and their mean average or CSAd+CSAp/2 (CSApd). RESULTS: There was a significant difference between both groups regarding mean ± SD of CSAd, CSAp, ∆CSA, and CSApd (p = 0.0001). A positive significant correlation was also found between the CSAd, ∆ CSA and the CSApd measurements with neurophysiologic severity grade of CTS (P = 0.001). A ∆CSA threshold of 2.5 mm2 showed the highest sensitivity and specificity to diagnose CTS in Saudis. CONCLUSION: High resolution ultrasound is a valid and accurate diagnostic modality in carpal tunnel syndrome and correlated to CTS severity. A ∆CSA greater than 2.5 mm2 is considered a valid diagnostic value for CTS in our Saudi population. CTS in our patients with diabetes tend to have greater median nerve US measurement values.

Determination of the dynamics of respiratory diseases using thoracic ultrasonographic examination in preweaned dairy calves.

This study aimed to explore the dynamics of lung consolidation in preweaned calves and the association between ultrasonographic findings and prognosis (defined as the time until first consolidation occurrence during the preweaning period) and average daily gain. Two dairy herds were visited weekly for 9 weeks. The preweaned dairy heifers were: examined for bovine respiratory disease using thoracic ultrasonography and the calf respiratory scoring criteria, weighed, and had blood samples checked for passive immunity transfer status. A total of 57 preweaned dairy calves were examined. Prevalence of lung consolidation increased from the first week of age (12.5%) and peaked (90%) by 10 weeks of age. In a subgroup of 25 calves monitored from birth, lung consolidation appeared as soon as a few hours after birth (1 cm consolidation depth) and by the 17th day of age (3 cm consolidation depth). Lung consolidation can be detected early by routine thoracic ultrasonography in preweaned dairy calves and is therefore valuable for use in farms with a high risk of pneumonia in preweaned calves.

Détermination de la dynamique des maladies respiratoires par examen échographique thoracique chez des veaux laitiers pré-sevrés. L'étude visait à explorer la dynamique de la consolidation pulmonaire par ultrasons chez les veaux pré-sevrés et l'association entre les résultats de l'échographie et le pronostic (défini comme le délai avant la première consolidation pendant la période de pré-sevrage) et le gain quotidien moyen. Deux troupeaux laitiers ont été visités chaque semaine pendant neuf semaines, toutes les génisses pré-sevrées ont été examinées par échographie thoracique. Les scores cliniques respiratoires à des veaux, et des échantillons de sang ont été prélevés pour vérifier leur statut de transfert d'immunité passive. Un total de 57 veaux laitiers pré-sevrés ont été examinés. La prévalence de la consolidation pulmonaire a augmenté dès la première semaine d'âge (12,5 %) jusqu'à son maximum (90 %) à l'âge de 10 semaines. Dans un sous-groupe de 25 veaux suivis depuis la naissance, la consolidation pulmonaire est apparue quelques heures après la naissance (consolidation DEPTH 1 cm) et au 17ème jour (consolidation DEPTH 3 cm). Une détection précoce des lésions pulmonaires peut être réalisée par échographie thoracique systématique ce qui démontre une application potentielle dans les fermes au risque élevé de pneumonie pré-sevrage.(Traduit par les auteurs).

Post-operative hip centre restoration and migration after impaction bone grafting in revision and complex primary hip arthroplasty.

INTRODUCTION/OBJECTIVES: Although impaction grafting proved efficacy in the reconstruction of acetabular defects in primary and revision hip arthroplasty, its role in large segmental defects is still debatable. Our objective is to determine hip centre restoration and last follow-up migration after acetabular reconstruction with impaction grafting in different types of acetabular defects. METHODS: This is a single-centre retrospective radiographic study of (107) total hip arthroplasty (42 primary and 65 revision) in (104) patients using impaction grafting. The available radiographs were examined for normal, preoperative, immediate postoperative, and last follow-up vertical (Y) and horizontal (X) hip centre. Maximum acetabular defect distance (MADD), presence, and size of the mesh were recorded. RESULTS: In type I and II AAOS defects, the post-operative hip centre was not significantly different from the normal hip centre on the contralateral healthy side. In type III defects, there was a significant variation between the normal hip centre and the post-operative hip centre (P value 0.034 and 0.001 for Y and X, respectively). At 44-month follow-up of 36 hips, 31 (86%) hips migrated. The mean migration ± SD was 5.72 ± 3.7, 2, 4.15 ± 1.2, and 11.26 ± 3.9 mm for types I, II, and III, respectively (P value 0.211). Hips with MADD > 15 mm, especially with large mesh sizes migrate significantly more (P value = 0.042, 0.037, and 0.039, respectively). CONCLUSION: Hip centre restoration was better, and migration was less for type I and II AAOS rather than for type III. Other options for reconstruction should be considered.

Developing folate-conjugated miR-34a therapeutic for prostate cancer treatment: Challenges and promises.

Prostate cancer (PCa) remains a common cancer with high mortality in men due to its heterogeneity and the emergence of drug resistance. A critical factor contributing to its lethality is the presence of prostate cancer stem cells (PCSCs), which can self-renew, long-term propagate tumors and mediate treatment resistance. MicroRNA-34a (miR-34a) has shown promise as an anti-PCSC therapeutic by targeting critical molecules involved in cancer stem cell (CSC) survival and functions. Despite extensive efforts, the development of miR-34a therapeutics still faces challenges, including non-specific delivery and delivery-associated toxicity. One emerging delivery approach is ligand-mediated conjugation, aiming to achieve specific delivery of miR-34a to cancer cells, thereby enhancing efficacy while minimizing toxicity. Folate-conjugated miR-34a (folate-miR-34a) has demonstrated promising anti-tumor efficacy in breast and lung cancers by targeting folate receptor α (FOLR1). Here, we first show that miR-34a, a TP53 transcriptional target, is reduced in PCa that harbors TP53 loss or mutations and that miR-34a mimic, when transfected into PCa cells, downregulated multiple miR-34a targets and inhibited cell growth. When exploring the therapeutic potential of folate-miR-34a, we found that folate-miR-34a exhibited impressive inhibitory effects on breast, ovarian and cervical cancer cells but showed minimal effects on and targeted delivery to PCa cells due to a lack of appreciable expression of FOLR1 in PCa cells. Folate-miR-34a also did not display any apparent effect on PCa cells expressing prostate-specific membrane antigen (PMSA) despite the reported folate's binding capability to PSMA. These results highlight challenges in specific delivery of folate-miR-34a to PCa due to lack of target (receptor) expression. Our study offers novel insights on the challenges and promises within the field and cast light on the development of ligand-conjugated miR-34a therapeutics for PCa.

Selective targeting of chemically modified miR-34a to prostate cancer using a small molecule ligand and an endosomal escape agent.

Use of tumor-suppressive microRNAs (miRNAs) as anti-cancer agents is hindered by the lack of effective delivery vehicles, entrapment of the miRNA within endocytic compartments, and rapid degradation of miRNA by nucleases. To address these issues, we developed a miRNA delivery strategy that includes (1) a targeting ligand, (2) an endosomal escape agent, nigericin and (3) a chemically modified miRNA. The delivery ligand, DUPA (2-[3-(1,3-dicarboxy propyl) ureido] pentanedioic acid), was selected based on its specificity for prostate-specific membrane antigen (PSMA), a receptor routinely upregulated in prostate cancer-one of the leading causes of cancer death among men. DUPA was conjugated to the tumor suppressive miRNA, miR-34a (DUPA-miR-34a) based on the ability of miR-34a to inhibit prostate cancer cell proliferation. To mediate endosomal escape, nigericin was incorporated into the complex, resulting in DUPA-nigericin-miR-34a. Both DUPA-miR-34a and DUPA-nigericin-miR-34a specifically bound to, and were taken up by, PSMA-expressing cells in vitro and in vivo. And while both DUPA-miR-34a and DUPA-nigericin-miR-34a downregulated miR-34a target genes, only DUPA-nigericin-miR-34a decreased cell proliferation in vitro and delayed tumor growth in vivo. Tumor growth was further reduced using a fully modified version of miR-34a that has significantly increased stability.

Total knee arthroplasty post-high tibial osteotomy, results of an early experience from a North African arthroplasty unit, and a comprehensive review of the literature.

PURPOSE: To report an early experience after converting HTO to TKA by reporting the incidence of functional, radiological, and complications in a single surgeon case series from a North African specialized arthroplasty unit. METHODS: Between 2010 and 2020, 33 knees in 31 patients (two bilateral) were operated upon, 24 females and seven males, had a mean age of 65 ± 4.5 years; 17 (51.5%) knees had medial wedge opening (WMO), while 16 (48.5%) had lateral wedge closure (LWC) osteotomies. The mean time from HTO to TKA was 8.1 ± 3.3 years. A posterior stabilized (PS) implant was used in 31 (93.9%), while in 2 (6.1%), a varus-valgus constrained (VVC) implant was used. A tibial stem was needed in 13 (39.4%) knees. The functional assessment was performed according to the Knee Society Scoring System (KSS). The radiographic assessment included the anatomical femorotibial angle (aFTA) for alignment, the medial proximal tibial angle (MPTA), and the tibial slope (TS). RESULTS: After a mean follow-up of 4.3 ± 1.1 years, the KSS knee and function sub-scores improved from a preoperative mean of 41 ± 8.9 (26 to 57) and 37.7 ± 9.2 (25 to 55) points to 91.3 ± 3.8 (81 to 94) and 85.5 ± 5 (80 to 95) points at the last follow-up, respectively (P < 0.05). The preoperative knee flexion improved from a mean of 84.5° ± 15.9 (55 to 110) to 110.6° ± 9.3 (95 to 125) (P < 0.05). The aFTA improved from a preoperative mean of 182.2° ± 10.3 (164 to 205) to a postoperative mean of 186° ± 2.6 (179 to 190) (P < 0.05). The MPTA changed from a preoperative mean of 88.4° ± 6.7 (77 to 102) to a postoperative (tibial component alignment) mean of 90° ± 1.7 (85 to 94) (P < 0.05). The mean preoperative TS changed from 80.9° ± 7.3 (68 to 96) to a mean postoperative of 86.9° ± 1.3 (83 to 89) (P < 0.05). Non-progressive radiolucent lines were detected at the tibial component in four (12%) knees. Complications were reported in seven (21.2%) knees; no revision was needed in any knee. CONCLUSIONS: The authors' early experience showed improved functional and radiological outcomes; however, the complication incidence was relatively high, but no knees required revision. A longer follow-up is mandatory to prove the consistency of the results.

Cyclic Esotropia Managed With Botulinum A Toxin Injections: A Report of Four Cases and Literature Review.

Cyclic strabismus is a rare entity and is unique in that patients follow variable but reliable time cycles where they alternate between orthotropia or "straight" eyes and strabismus, most commonly in the form of esotropia. Despite many theories on the underlying etiology and unique features of this diagnosis, none have been proven and its pathophysiology remains unknown. Four cases of cyclic esotropia diagnosed by pediatric ophthalmologists have been included in this report. The ages of the patients ranged from 10 months to eight years. The time duration from the onset of deviation to presentation to an ophthalmologist ranged from 1-52 weeks with three of the four patients presenting in the cyclic phase and the fourth presenting with a constant esotropia after a clear history and photographically documented cyclic esotropia for the preceding two months. All four patients were followed for periods ranging from one to four months to confirm their diagnosis or obtain multiple readings of the maximal deviation on the strabismic days before any intervention. The angle of esotropia when present ranged from 25 to 35 prism diopters and the cycle duration was 48 hours for all four cases (24 hours of esotropia followed by 24 hours of orthotropia). All patients were treated with botulinum toxin A injections to both medial recti, which resulted in an end to their cyclic deviation with excellent alignment obtained during follow-up periods ranging from 12-36 months for all cases. Cyclic esotropia is an elusive diagnosis that can be easily overlooked. When identified, classical treatment is usually extraocular muscle surgery targeting the largest angle of deviation. Many non-surgical treatments have been tried to no avail. However, in recent times, botulinum toxin A has been seen as a viable alternative.

A first-in-class fully modified version of miR-34a with outstanding stability, activity, and anti-tumor efficacy.

Altered by defects in p53, epigenetic silencing, and genomic loss, the microRNA miR-34a represents one of the most clinically relevant tumor-suppressive microRNAs. Without question, a striking number of patients with cancer would benefit from miR-34a replacement, if poor miR-34a stability, non-specific delivery, and delivery-associated toxicity could be overcome. Here, we highlight a fully modified version of miR-34a (FM-miR-34a) that overcomes these hurdles when conjugated to a synthetically simplistic ligand. FM-miR-34a is orders of magnitude more stable than a partially modified version, without compromising its activity, leading to stronger repression of a greater number of miR-34a targets. FM-miR-34a potently inhibited proliferation and invasion, and induced sustained downregulation of endogenous target genes for >120 h following in vivo delivery. In vivo targeting was achieved through conjugating FM-miR-34a to folate (FM-FolamiR-34a), which inhibited tumor growth leading to complete cures in some mice. These results have the ability to revitalize miR-34a as an anti-cancer agent, providing a strong rationale for clinical testing.

The Association between Prepartum Rumination Time, Activity and Dry Matter Intake and Subclinical Hypocalcemia and Hypomagnesemia in the First 3 Days Postpartum in Holstein Dairy Cows.

Changes in prepartum behaviors such as total daily rumination (TDR), total daily activity (TDA) and dry matter intake (DMI) have the potential to be used as early indicators for cows at risk for subclinical hypocalcemia (SCH) or hypomagnesemia (HYM) after calving. Our objective was to investigate associations between average daily rate of change in total daily rumination (ΔTDR), total daily activity (ΔTDA) and dry matter intake (ΔDMI) from -3 days prepartum to calving with SCH and HYM at D0 or D3 relative to calving. Prepartum TDR, TDA and DMI were measured in 64 Holstein dairy cows. Blood samples were taken at D0 and D3 post-calving for the measurement of total plasma Ca and Mg concentration. Linear regression models were used to analyze the association between ΔTDR, ΔTDA and ΔDMI and SCH and HYM at D0 and D3 relative to calving. Potential confounding variables were offered to the models and backwards selection was used to determine which covariates to retain. No significant differences in prepartum ΔTDR, ΔTDA or ΔDMI were found between cows with or without SCH and HYM at D0 and D3. Our results suggest that the change in TDR, TDA and DMI in the last 3 days prepartum are not effective predictors for cows that will have SCH or HYM in the first 3 days postpartum.

Nonsurgical management of atraumatic early distal femoral periprosthetic insufficiency fracture after primary total knee arthroplasty, a report of two cases.

Periprosthetic distal femoral fractures after primary total knee arthroplasty (TKA) are considered rare; however, they pose a challenge for the treating surgeon, and the management options are mostly surgical (open reduction and internal fixation or revision surgery). We present two female patients who developed atraumatic lateral femoral condyle fractures three weeks after primary TKA; both were treated nonsurgically with acceptable outcomes and patient satisfaction. We believe that nonsurgical management of periprosthetic distal femoral fractures could be an economical solution in selected cases; it also could help maintain the distal femoral bone stock till a revision surgery is performed.

Smartphone Application Helps Improve the Accuracy of Cup Placement by Young, Less-Experienced Surgeons during Primary Total Hip Arthroplasty.

Background: Dislocation after total hip arthroplasty (THA) partly under the surgeon's control, by appropriate placement of the components. We aimed in this study to determine the accuracy of using intra-operative smartphone applications (Apps) to place the acetabular cup within the safe abduction angle by less experienced surgeons during THA surgery when compared to the conventional freehand technique for cup placement. Methods: Sixty primary THAs were performed, 30 using the conventional freehand technique (control group) and 30 using the smartphone app technique (study group) to determine the acetabular cup abduction angle by the same young surgeon with less than one year of experience. Postoperative mean cup abduction angle, mean cup anteversion angle, and the percentage of cups within the safe abduction zone as measured on radiographs were compared between the two groups. Results: In the study group, the mean cup abduction angle was significantly lower (P=0.0008), and the acetabular cup was placed within the safe zone in a significantly higher (P<0.001) percentage of patients (93% vs 63%) when compared to the control group. However, there was no significant difference (P=0.40) between the two groups when the mean cup anteversion angle was compared. Conclusion: The smartphone app technique may help achieve an accurate acetabular cup abduction angle and a higher percentage of cups placed within the safe zone of abduction by a less experienced surgeon when compared to the conventional freehand technique. Using tools such as the smartphone app to measure the acetabular cup position can reduce intraoperative errors by young and less experienced surgeons during THA surgery.

The Outcome of Posterior-Stabilized, Rotating Platform Total Knee Arthroplasty at a Minimum Ten-Year Follow-Up, a Middle East Institution Experience.

Posterior-stabilized, rotating platform knee prosthesis design was aimed to decrease polyethylene wear for the sake of improving implant survivorship. The purpose of the present prospective study was to evaluate the long-term clinical and radiographic results as well as the survival rate after using a rotating platform, posterior-stabilized knee prosthesis at a minimum of 10 years at a Middle East institution. We compared the results with reports in the literature on western populations. From January 2002 to June 2008, 96 patients (106 knees) underwent total knee arthroplasty (TKA) using a cemented rotating platform posterior-stabilized knee prosthesis. At a mean of 11.5 ± 1.3 years, 85 patients (95 TKAs) were available for clinical, radiographic, and implant survival analysis. At the final follow-up, 78.9% of the patients had excellent Knee Society Scoring system score, the average knee flexion was 110 ± 17 degrees, the average anatomical knee coronal alignment was 186 ± 2 degrees and 187 ± 3 degrees for varus and valgus knees, respectively. Five (5.2%) knees were revised of these: two for bearing dislocation, two for aseptic loosening, and one for infection. The Kaplan-Meier survival rate was 94.7% for all revisions and 97.8% when only revision for aseptic loosening considered as the end point. At a long-term follow-up, reasonable clinical and radiographic outcomes had been achieved after using a rotating platform, posterior-stabilized knee prosthesis in our population with acceptable survival rate reaching up to 95%, which is comparable to reports from the western population.

Normative Values for Corneal Tomography and Comparison of Both Eyes in Young Saudi Males with 20/20 Vision Using Pentacam-HR Scheimpflug Imaging.

Purpose: Anterior segment evaluation using Scheimpflug imaging with the Pentacam scanner allows the acquisition of a plethora of information. It aids in screening and diagnosing corneal pathologies and determining suitability for keratorefractive procedures. This research has significant benefits in terms of establishing normative tomographic values, which is crucial in countries where Keratoconus (KC) is more prevalent, especially among young age group, along with aiding future research in the field of refractive surgery by providing relevant normative data. Methods: A retrospective review of digital corneal tomography images for a group of medically and ophthalmologically free males aged between 18 and 21 years with 20/20 unaided distant visual acuity was performed. Results: A total of 1272 subjects (2544 eyes) were included. Findings revealed a mean maximal corneal curvature (Kmax) of 42.91 ± 1.40D (range 36.90-47.80D). The mean flat keratometry (K1) was 41.87 ± 1.31D (range 36.00-46.40D). The mean steep keratometry (K2) was 42.66 ± 1.35D (range 36.70-47.60D). The mean corneal astigmatism (CA) was 0.79 ± 0.37D (range 0.00D-2.30D). The mean central corneal thickness (CCT) was 558.53 ± 33.84 µm (range 421-677 µm). The mean thinnest corneal location thickness (TCLT) was 551.64 ± 34.08 µm (range 417-669µm). The mean corneal diameter (CD) and anterior chamber depth (ACD) were 12.13 ± 0.39 mm (range 10.50-13.60 mm) and 3.12 ± 0.29 mm (range 2.08-4.08 mm), respectively. The median differences between both eyes of the same subject were as follows: kmax difference of 0.20D (IQR 0.1-0.4); K1, K2 and CA difference of 0.20D (IQR 0.1-0.3) for all 3 parameters; CCT and TCLT difference of 5.00 µm (IQR 3.0-9.0) and 6.00 µm (IQR 3.0-10.0), respectively; CD difference of 0.10 mm (IQR 0.0-0.1); and ACD difference of 0.04 (IQR 0.02-0.06). Conclusion: We believe our data can aid in establishing normative tomographic values and acceptable differences between both eyes. Our data may also help detect subtle corneal pathology and be useful for researchers and innovators in the field of ophthalmology.

Ultrasonographic diagnosis of clinical and subclinical bovine respiratory disease in Holstein calves.

Background and Aim: Bovine respiratory disease (BRD) is the main cause of death in calves, and early BRD diagnosis saves lives. This study aimed to diagnose clinical and subclinical BRD in calves by assessing some biochemical alterations and ultrasonography (USG). Materials and Methods: Fifty-four Holstein dairy calves in Al-Sharqiyah Province, Egypt, were used in the study. They were divided into three groups. The first control group consisted of 10 clinically healthy calves. The second group consisted of 34 calves suffering from clinical lower respiratory tract disorders. The third group consisted of 10 subclinical BRD-affected calves. Ultrasonographic examinations of chest and thoracic ultrasound scoring were performed once per 2 weeks for each calf. Blood samples were collected for serum separation to measure albumin (ALB), total protein (TP), ALB, globulin, and haptoglobin (HP). Results: The USG revealed small consolidation areas within an aerated lung lobe, a hypoechoic parenchyma of the entire distal lung lobe, and a hypoechoic-circumscribed structure surrounded by an echogenic wall appeared within the lung tissue in calves that suffered from lobular pneumonia, lobar pneumonia, and lung abscess, respectively. However, subclinical cases showed a small consolidation area in the cranial aspects of the right cranial lung lobe. The ultrasound lung score (ULS) was greater in clinical than in subclinical cases. The BRD-affected calves recorded significant increases in serum TP, globulin, and HP. Meanwhile, serum ALB decreased significantly. Conclusion: Thoracic ultrasound had a reliable tool in the BRD diagnosis, especially in the early prediction of subclinical cases in newborn calves. In addition, the ULS appeared to be a better classifier than the clinical respiratory score (CRS) for BRD diagnosis. On the other side, it was found that regression models were very useful in assessing the prediction of biochemical blood parameters based on the ULS and CRS in diseased cases.

Ligand-mediated delivery of RNAi-based therapeutics for the treatment of oncological diseases.

RNA interference (RNAi)-based therapeutics (miRNAs, siRNAs) have great potential for treating various human diseases through their ability to downregulate proteins associated with disease progression. However, the development of RNAi-based therapeutics is limited by lack of safe and specific delivery strategies. A great effort has been made to overcome some of these challenges resulting in development of N-acetylgalactosamine (GalNAc) ligands that are being used for delivery of siRNAs for the treatment of diseases that affect the liver. The successes achieved using GalNAc-siRNAs have paved the way for developing RNAi-based delivery strategies that can target extrahepatic diseases including cancer. This includes targeting survival signals directly in the cancer cells and indirectly through targeting cancer-associated immunosuppressive cells. To achieve targeting specificity, RNAi molecules are being directly conjugated to a targeting ligand or being packaged into a delivery vehicle engineered to overexpress a targeting ligand on its surface. In both cases, the ligand binds to a cell surface receptor that is highly upregulated by the target cells, while not expressed, or expressed at low levels on normal cells. In this review, we summarize the most recent RNAi delivery strategies, including extracellular vesicles, that use a ligand-mediated approach for targeting various oncological diseases.

Indications of Keratoplasty and Outcomes of Deep Anterior Lamellar Keratoplasty Compared to Penetrating Keratoplasty.

Background Corneal diseases are a significant cause of visual impairment and blindness. Despite the treatable nature of many corneal diseases before visual demise, many cases of advanced disease necessitating keratoplasty for visual rehabilitation are encountered. A mismatch between the number of corneal donors and potential recipients also exists worldwide, with underutilization of certain types of keratoplasty techniques that may allow more efficient use of this limited resource. Methodology A retrospective cohort study of all cases of optical corneal transplantations performed from January 1, 2015 to October 31, 2020 was performed. Indications for keratoplasty, type of keratoplasty, complications, intraocular pressure elevation, and best corrected visual acuity (BCVA) by category and range at different time intervals were collected and analyzed. Findings were compared between penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) for all indications, specifically for keratoconus (KCN). Results A total of 58 corneal transplants meeting our criteria were performed during the study period. PK was performed for 29 eyes, DALK for 28 eyes, and endothelial keratoplasty for one eye. The most frequently encountered indication was KCN (62.1%). The number of eyes with BCVA of 20/100 or better increased from preoperative BCVA, 37/58 eyes had BCVA worse than 20/100 before keratoplasty (63.8%), while at the time of last follow-up 45/58 eyes had BCVA of 20/100 or better (77.6%). At the time of last follow-up 16/58 had BCVA in the range of 20/20 to 20/40 (27.6%) and 29/58 eyes had BCVA in the range of 20/50 to 20/100 (50%). Comparison of all cases of PK to DALK for all indications showed significantly better BCVA by category at one year, at last follow-up, and BCVA range at last follow-up (p = 0.032, 0.001, and 0.014, respectively). Although better visual acuity results by category and range at one year and last follow-up, respectively, were observed in more patients undergoing DALK than PK, for KCN the results were not statistically significant (p = 1.00, 1.00, 0.417, and 0.374, respectively). Overall, 70% of recorded complications, intraocular pressure (IOP) elevations, and graft rejections were seen in eyes that underwent PK; however, these findings were not statistically significant (p = 0.297). Graft failures occurred more frequently with PK than deep anterior keratoplasty when analyzed for all indications of keratoplasty (p = 0.010). Conclusions Despite advancement and improvements in surgical techniques, statistics continue to show underutilization of the invaluable resource of donor corneas, with PK still being performed more than DALK for diseases that do not affect the endothelium. Our study found superior visual acuity outcomes of DALK as well as the advantages of less frequent complications, IOP elevations, graft rejections, and graft failures. We encourage ophthalmologists to utilize DALK in appropriate candidates to more fully utilize the scarce and potentially vision-restoring resource of donor corneal tissue.

Prevalence of gastrointestinal nematodes, parasite control practices and anthelmintic resistance patterns in a working horse population in Egypt.

BACKGROUND: Anthelmintic resistance is commonly reported in horse populations in developed countries, but evidence in some working horse populations is either lacking or inconclusive. OBJECTIVES: To estimate prevalence of GI nematode infections in working horses in Egypt and to evaluate strongyle resistance to ivermectin, doramectin and fenbendazole. STUDY DESIGN: Cross-sectional study. METHODS: Faecal egg count was performed on 644 working horses from 2 provinces in Egypt. A short questionnaire about horse signalment and worming history was completed for each horse. Horses identified with ≥50 strongyle type egg/g (n = 146) underwent faecal egg count reduction testing (FECRT) following treatment with ivermectin (n = 33), doramectin (n = 33) or fenbendazole (n = 30). Risk factors for strongyle (≥200 egg/g) and Parascaris equorum (>0 egg/g) infection were investigated using multivariable logistic regression analyses. RESULTS: The prevalence of low (0-199 epg), medium (200-500 epg) and high (>500 epg) strongyle infection was 88.4%, 5.9% and 5.8%, respectively. P. equorum eggs were detected in 5.1% (n = 33) of horses. Strongyle FECR was 100%, 99.97% and 100% following treatment with ivermectin, doramectin and fenbendazole respectively. Anthelmintic treatment in the 12 months preceding examination was associated with reduced likelihood of strongyle infection (odds ratio [OR] = 0.26, 95% confidence interval [CI] = 0.14, 0.47, P < .001). The likelihood of P. equorum infection was significantly associated with horses' age (OR = 0.78, 95% CI = 0.69, 0.90; P < .001). Male horses were more likely to have P. equorum infection (OR = 2.86, 95% CI = 1.37, 5.93, P = .005). MAIN LIMITATIONS: Nonrandomised selection of study areas and larval cultures was unsuccessful for some samples. CONCLUSIONS: There were low prevalence of strongyle and P. equorum infection and no evidence of macrocyclic lactones or benzimidazole resistance in strongyles in the studied working horse population.