Current Perceptions, Practice Patterns, and Barriers to Adoption of Transperineal Prostate Biopsy under local anesthesia.

OBJECTIVES: To assess perceptions, practice patterns, and barriers to adoption of Transperineal prostate biopsy (TPBx) under local anesthesia. METHODS: Providers from Michigan Urological Surgery Improvement Collaborative (MUSIC) and Pennsylvania Urologic Regional Collaborative (PURC) were administered an online survey to assess beliefs and educational needs regarding TPBx. Providers were divided into those who performed or did not perform TPBx. The MUSIC and PURC registry were queried to assess TPBx utilization. Descriptive analytics and bivariate analysis determined associations between provider/practice demographics and attitudes. RESULTS: Since 2019, TPBx adoption has increased more than 2-fold to 7.0% and 16% across MUSIC and PURC practices, respectively. Of 350 urologists invited to participate in a survey, a total of 91 complete responses were obtained with 21 respondents (23%) reported performing TPBx. Participants estimated the learning curve was <10 procedure for TPBx performers and non-performers. No significant association was observed between learning curve and provider age/practice setting. The major perceived benefits of TPBx were decreased risk of sepsis, improved cancer detection rate and antibiotic stewardship. The most commonly cited challenges to implementation included access to equipment and patient experience. Urologists performing TPBx reported learning curve as an additional barrier, while those not performing TPBx reported duration of procedure. CONCLUSIONS: Access to equipment and patient experience concerns remain substantial barriers to adoption of TPBx. Dissemination of techniques utilizing existing equipment and optimization of local anesthetic protocols for TPBx may help facilitate the continued adoption of TPBx.

Hedgehog pathway inhibitors for locally advanced and metastatic basal cell carcinoma: A real-world single-center retrospective review.

Basal cell carcinoma (BCC) is highly curable by surgical excision or radiation. In rare cases, BCC can be locally destructive or difficult to surgically remove. Hedgehog inhibition (HHI) with vismodegib or sonidegib induces a 50-60% response rate. Long-term toxicity includes muscle spasms and weight loss leading to dose decreases. This retrospective chart review also investigates the impact of CoQ10 and calcium supplementation in patients treated with HHI drugs at a single academic medical center from 2012 to 2022. We reviewed the charts of adult patients diagnosed with locally advanced or metastatic BCC treated with vismodegib or sonidegib primarily for progression-free survival (PFS). Secondary objectives included overall survival, BCC-specific survival, time to and reasons for discontinuation, overall response rate, safety and tolerability, use of CoQ10 and calcium supplements, and insurance coverage. Of 55 patients assessable for outcome, 34 (61.8%) had an overall clinical benefit, with 25 (45.4%) having a complete response and 9 (16.3%) a partial response. Stable disease was seen in 14 (25.4%) and 7 (12.7%) progressed. Of the 34 patients who responded to treatment, 9 recurred. Patients who were rechallenged with HHI could respond again. The median overall BCC-specific survival rate at 5 years is 89%. Dose reductions or discontinuations for vismodegib and sonidegib occurred in 59% versus 24% of cases, or 30% versus 9% of cases, respectively. With CoQ10 and calcium supplementation, only 17% required a dose reduction versus 42% without. HHI is highly effective for treating advanced BCC but may require dosing decreases. Sonidegib was better tolerated than vismodegib. CoQ10 and calcium supplementation can effectively prevent muscle spasms.

FEA-Based Stress-Strain Barometers as Forecasters for Corneal Refractive Power Change in Orthokeratology.

PURPOSE: To improve the effectivity of patient-specific finite element analysis (FEA) to predict refractive power change (RPC) in rigid Ortho-K contact lens fitting. Novel eyelid boundary detection is introduced to the FEA model to better model the effects of the lid on lens performance, and stress and strain outcomes are investigated to identify the most effective FEA components to use in modelling. METHODS: The current study utilises fully anonymised records of 249 eyes, 132 right eyes, and 117 left eyes from subjects aged 14.1 ± 4.0 years on average (range 9 to 38 years), which were selected for secondary analysis processing. A set of custom-built MATLAB codes was built to automate the process from reading Medmont E300 height and distance files to processing and displaying FEA stress and strain outcomes. Measurements from before and after contact lens wear were handled to obtain the corneal surface change in shape and power. Tangential refractive power maps were constructed from which changes in refractive power pre- and post-Ortho-K wear were determined as the refractive power change (RPC). A total of 249 patient-specific FEA with innovative eyelid boundary detection and 3D construction analyses were automatically built and run for every anterior eye and lens combination while the lens was located in its clinically detected position. Maps of four stress components: contact pressure, Mises stress, pressure, and maximum principal stress were created in addition to maximum principal logarithmic strain maps. Stress and strain components were compared to the clinical RPC maps using the two-dimensional (2D) normalised cross-correlation and structural similarity (SSIM) index measure. RESULTS: On the one hand, the maximum principal logarithmic strain recorded the highest moderate 2D cross-correlation area of 8.6 ± 10.3%, and contact pressure recorded the lowest area of 6.6 ± 9%. Mises stress recorded the second highest moderate 2D cross-correlation area with 8.3 ± 10.4%. On the other hand, when the SSIM index was used to compare the areas that were most similar to the clinical RPC, maximum principal stress was the most similar, with an average strong similarity percentage area of 26.5 ± 3.3%, and contact pressure was the least strong similarity area of 10.3 ± 7.3%. Regarding the moderate similarity areas, all components were recorded at around 34.4% similarity area except the contact pressure, which was down to 32.7 ± 5.8%. CONCLUSIONS: FEA is an increasingly effective tool in being able to predict the refractive outcome of Ortho-K treatment. Its accuracy depends on identifying which clinical and modelling metrics contribute to the most accurate prediction of RPC with minimal ocular complications. In terms of clinical metrics, age, Intra-ocular pressure (IOP), central corneal thickness (CCT), surface topography, lens decentration and the 3D eyelid effect are all important for effective modelling. In terms of FEA components, maximum principal stress was found to be the best FEA barometer that can be used to predict the performance of Ortho-K lenses. In contrast, contact pressure provided the worst stress performance. In terms of strain, the maximum principal logarithmic strain was an effective strain barometer.

Human milk oligosaccharides promote intestinal epithelium regeneration independent of the microbiota during necrotizing enterocolitis.

PURPOSE: Necrotizing enterocolitis (NEC) is a severe intestinal disease primarily affecting premature infants, marked by impaired epithelial regeneration. Breastfed infants are less susceptible to NEC than formula-fed ones, and human milk oligosaccharides (HMO) found in breast milk have prebiotic properties that can protect against NEC. However, it is unclear how HMOs influence intestinal epithelium regeneration in relation to the gut microbiota. METHODS: Broad-spectrum antibiotics were administered to pregnant dams to reduce the microbiota in offspring. NEC was induced through administration of hyperosmolar formula, lipopolysaccharide, and hypoxia from postnatal days (p) 5-9. Intestinal epithelial organoids were derived from p9 mice. HMOs were isolated from human donor breast milk and then solubilized in the formula for each feed or culture media for organoids. RESULTS: HMOs did not alter the microbiota profile in the presence of a normal or reduced microbiota. In the reduced microbiota, HMO treatment decreased NEC intestinal injury, and increased proliferation and stem cell activity. Additionally, in the complete absence of the microbiota, HMOs stimulated intestinal organoid growth. CONCLUSION: This study demonstrates that HMOs promoted intestinal epithelial regeneration independent of the gut microbiota. These findings provide further insight into the various benefits HMOs may have in the protection against NEC.

Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase.

Myeloid-derived suppressor cell (MDSC) levels are elevated in patients with cancer and contribute to reduced efficacy of immune checkpoint therapy. MDSC express Bruton's tyrosine kinase (BTK) and BTK inhibition with ibrutinib, an FDA-approved irreversible inhibitor of BTK, leads to reduced MDSC expansion/function in mice and significantly improves the antitumor activity of anti-PD-1 antibody treatments. Single-cell RNA sequencing (scRNA-seq) was used to characterize the effect of ibrutinib on gene expression of fluorescence-activated cell sorting-enriched MDSC from patients with different cancer types [breast, melanoma, head and neck squamous cell cancer (HNSCC)]. Melanoma patient MDSC were treated in vitro for 4 hours with 5 µmol/L ibrutinib or DMSO, processed for scRNA-seq using the Chromium 10× Genomics platform, and analyzed via the Seurat v4 standard integrative workflow. Baseline gene expression of MDSC from patients with breast, melanoma, and HNSCC cancer revealed similarities among the top expressed genes. In vitro ibrutinib treatment of MDSC from patients with melanoma resulted in significant changes in gene expression. GBP1, IL-1ß, and CXCL8 were among the top downregulated genes whereas RGS2 and ABHD5 were among the top upregulated genes (P < 0.001). Double positive CD14+CD15+ MDSC and PMN-MDSC responded similarly to BTK inhibition and exhibited more pronounced gene changes compared with early MDSC and M-MDSC. Pathway analysis revealed significantly downregulated pathways including TREM1, nitric oxide signaling, and IL-6 signaling (P < 0.004). IMPLICATIONS: scRNA-seq revealed characteristic gene expression patterns for MDSC from different patients with cancer and BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration.

Uncovering the Potential of CD40 Agonism to Enhance Immune Checkpoint Blockade.

In this CCR Translations, we discuss the therapeutic potential of CD40 agonism, which stimulates antigen-presenting cells (APC) to activate effector T and NK cells. CD40 agonism may lead to development of an interferon-activated, T cell-inflamed tumor microenvironment and has the potential to facilitate long-term response with immune checkpoint blockade. See related article by Weiss et al., p. 74.

Acral lentiginous melanoma with multiple bone metastasis: case report.

Acral lentiginous melanoma (ALM) is a type of melanoma that is traditionally seen on the soles of the feet, palms of the hand, and under the fingernails or toenails. It is the least frequently diagnosed melanoma among the four histologic subtypes of cutaneous melanoma, accounting for less than 5% of all cases. ALM is frequently diagnosed at late stages and has higher incidences in non-white populations in relation to the other forms of cutaneous malignant melanoma. The most common sites of metastases in melanoma are the skin and subcutaneous tissue followed by lung, liver, brain, and bone. Bone metastases from malignant melanoma usually occur in patients who already have widespread metastases. We present this paper as a unique case study of ALM lesion in an 84-year-old African American male presenting originally in the base of right fifth toe plantar aspect then found multiple bone metastases without any other organ involved.

Association between Prostate Carcinoma and Multiple Myeloma.

Synchronous or sequential development of multiple myeloma and prostate carcinoma is rare. It is not sure whether these two occur independently or if one influences the development of the other. We reviewed the cases published in the English literature; eight cases of myeloma developing after diagnosis and treatment for prostate carcinoma, five cases of simultaneous occurrence of myeloma and prostate carcinoma, and five cases where the patient with multiple myeloma later developed prostate carcinoma were found. This short review attempts to analyze the occurrence of these two diseases in the same patient and dissect whether there is a close association or it is just a mere coincidence.

A cost-effective transperineal prostate biopsy method utilizes the original transrectal setting.

PURPOSE: Transperineal prostate biopsy (TPB) offers an alternative to transrectal prostate biopsy (TRB) for prostate cancer diagnosis. However, TPB may result in additional disposable and capital equipment costs, which can limit implementation within urology practice. Herein, we report the initial experience of a novel TPB technique within a tertiary referral center in Taiwan. MATERIALS AND METHODS: A retrospective review of all men undergoing prostate biopsy January to October in 2021 was performed. Both biopsy techniques were performed with the same setting using the convex-convex array ultrasound probe under local anesthesia alone or with the addition of sedation using double free-hand technique. Complications within 30 days and cancer detection rate (CDR) were compared between the groups. RESULTS: A total of 118 biopsies were included for final analysis. Eleven patients received systematic biopsy with additional MRI-targeted biopsy (TB) cores with all performed via a transperineal approach. The TPB group (n = 47) and TRB group (n = 58) had similar CDR after excluding TB cores (46.8% vs. 44.8%, p = 0.675). General complication rates for TPB were significantly lower than in the TRB group (27.7% vs. 46.6%, p = 0.047). No patients undergoing TPB had infectious complications, where five episodes were recorded in the TRB group (p = 0.114). CONCLUSIONS: TPB performed with convex-convex ultrasound probe and double free-hand technique is safe, feasible, cost-effective, and demonstrates equivalent CDR to TRB. Its use may eliminate infectious hospitalizations while minimizing the need for additional capital in the adoption of TPB.

Review of Merkel cell carcinoma with solitary pancreatic metastases mimicking primary neuroendocrine tumor of the pancreas.

OBJECTIVE/BACKGROUND: Merkel cell carcinoma (MCC) but metastases to the pancreas are very rare. There are only a few cases of isolated metastases of MCC to the pancreas. Because of this rarity, it can be wrongly diagnosed as a neuroendocrine tumor of the pancreas(pNET), especially the poorly differentiated neuroendocrine carcinoma (PNEC) subtype, in which the treatment is vastly different than that of MCC with isolated metastases of the pancreas. METHODS: An electronic search of the PubMed and google scholar databases was performed to obtain the literature on MCC with pancreatic metastases, using the following search terms: Merkel cell carcinoma, pancreas, and metastases. Results are limited to the following available article types: case reports and case series. We identified 45 cases of MCC with pancreatic metastases from the PubMed and Google Scholar database search and examined their potential relevance. Only 22 cases with isolated pancreatic metastases were taken for review including one case that we encountered. RESULTS: The results from our review of cases of isolated pancreatic metastases of MCC were compared to the characteristics of the poorly differentiated pancreatic neuroendocrine tumor (PNEC). We found the following: (a) MCC with isolated pancreatic metastases occurred at an older age than PNEC and with male gender predominance (b) Most of the metastases occurred within 2 years of initial diagnosis of MCC (c) Resection of pancreatic mass was the first line treatment in case of resectable PNECs whereas resection of metastases was infrequently performed in MCC with pancreatic metastases.

Chemotherapy and Immune Checkpoint Inhibitors in a Case of SMARCA4-dUT: A Case Report and Review of Literature.

SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) are infrequently occurring aggressive neoplasms found predominantly in young male smokers. These tumors are distinguished by the loss of expression of Brahma-related gene 1 (BRG1) due to a deactivating mutation of SMARCA4. Immunophenotype can be variable but characteristically lack the expression of BRG1. SMARCA4-dUT has a poor prognosis and generally progresses or recurs. The median survival is around 6 months. Here, we report a case of a 36-year-old male smoker who presents with multiple right-sided lung masses. The patient was found to have a loss of SMARAC4 and SMARCA2 along with the absence of markers of vascular, melanocytic, lymphoid, keratin, or myogenic origin. Tumor size was reduced significantly after 3 cycles of carboplatin and 1 cycle of pembrolizumab. From reviewing the literature and the clinical course in our case, we suggest combination chemotherapy plus immune checkpoint inhibitor (ICI) therapy to be the first choice of therapy for treating SMARCA4-dUT of lungs. Further research and studies are needed to evaluate the response to ICI therapy alone or combination therapy (chemotherapy plus ICI).

Longitudinal Analysis of Caregiver Burden in Head and Neck Cancer.

Importance: Despite the critical role of caregivers in head and neck cancer (HNC), there is limited literature on caregiver burden (CGB) and its evolution over treatment. Research is needed to address evidence gaps that exist in understanding the causal pathways between caregiving and treatment outcomes. Objective: To evaluate the prevalence of and identify risk factors for CGB in HNC survivorship. Design, Setting, and Participants: This longitudinal prospective cohort study took place at the University of Pittsburgh Medical Center. Dyads of treatment-naive patients with HNC and their caregivers were recruited between October 2019 and December 2020. Eligible patient-caregiver dyads were 18 years or older and fluent in English. Patients undergoing definitive treatment identified a caregiver as the primary, nonprofessional, nonpaid person who provided the most assistance to them. Among 100 eligible dyadic participants, 2 caregivers declined participation, resulting in 96 enrolled participants. Data were analyzed from September 2021 through October 2022. Main Outcomes and Measures: Participants were surveyed at diagnosis, 3 months postdiagnosis, and 6 months postdiagnosis. Caregiver burden was evaluated with the 19-item Social Support Survey (scored 0-100, with higher scores indicating more support), Caregiver Reaction Assessment (CRA; scored 0-5, with higher scores on 4 subscales [disrupted schedule, financial problems, lack of family support, and health problems] indicating negative reactions, and higher scores on the fifth subscale [self-esteem] indicating favorable influence); and 3-item Loneliness Scale (scored 3-9, with higher scores indicating greater loneliness). Patient health-related quality of life was assessed using the University of Washington Quality of Life scale (UW-QOL; scored 0-100, with higher scores indicating better QOL). Results: Of the 96 enrolled participants, half were women (48 [50%]), and a majority were White (92 [96%]), married or living with a partner (81 [84%]), and working (51 [53%]). Of these participants, 60 (63%) completed surveys at diagnosis and at least 1 follow-up. Of the 30 caregivers, most were women (24 [80%]), White (29 [97%]), married or living with a partner (28 [93%]), and working (22 [73%]). Caregivers of nonworking patients reported higher scores on the CRA subscale for health problems than caregivers of working patients (mean difference, 0.41; 95% CI, 0.18-0.64). Caregivers of patients with UW-QOL social/emotional (S/E) subscale scores of 62 or lower at diagnosis reported increased scores on the CRA subscale for health problems (UW-QOL-S/E score of 22: CRA score mean difference, 1.12; 95% CI, 0.48-1.77; UW-QOL-S/E score of 42: CRA score mean difference, 0.74; 95% CI, 0.34-1.15; and UW-QOL-S/E score of 62: CRA score mean difference, 0.36; 95% CI, 0.14-0.59). Woman caregivers had statistically significant worsening scores on the Social Support Survey (mean difference, -9.18; 95% CI, -17.14 to -1.22). The proportion of lonely caregivers increased over treatment. Conclusions and Relevance: This cohort study highlights patient- and caregiver-specific factors that are associated with increased CGB. Results further demonstrate the potential implications for negative health outcomes for caregivers of patients who are not working and have lower health-related quality of life.

Recurrence of T-Cell Prolymphocytic Leukemia With a Rare Presentation as Diffuse Generalized Skin Lesion.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm that originates from mature post-thymic T-cells. Cutaneous manifestations are a common presentation in T-PLL but rarely are a presentation in the recurrent setting. Here, we describe the case of a 75-year-old female with a history of T-PLL-who at the time of initial diagnosis did not exhibit any rash-presenting with diffuse rash, facial swelling, sore throat, and dysphagia 7 months later and was found to have recurrent T-PLL. She had diffuse lymphadenopathy and diffuse skin lesions. Biopsy of the skin lesions also confirmed infiltration with T-PLL cells. After review of the literature, no previously reported cases of recurrent T-PLL presented as diffuse skin lesions. This case demonstrates that recurrent T-PLL may present with diffuse rash, respiratory distress, and anasarca. It is important to stay vigilant in patients with history of T-PLL to recognize signs of recurrent disease to allow prompt diagnosis and treatment.

Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

The Regulatory Role of Nuclear Respiratory Factor 1 in Bladder Cancer Cells.

BACKGROUND/AIM: Nuclear respiratory factor 1 (NRF1) is a key mediator of genes involved in mitochondrial biogenesis and the respiratory chain; however, its role in bladder cancer remains unknown. Transitional cell carcinoma, also known as urothelial cell carcinoma, is the most common type of bladder cancer resistant to chemotherapy. An established high-grade and invasive transitional cell carcinoma line from patients with urinary bladder cancer, known as T24, has been extensively used in cancer research. In this study, we aimed to investigate the mechanisms through which NRF1 regulates proliferation and cell migration of bladder cancer cells using the T24 cell line. MATERIALS AND METHODS: Cells were transfected with plasmid cloning DNA for NRF1 to evaluate the effect of NRF1 overexpression on bladder cancer cells. Western blot was used to examine epithelial and mesenchymal markers (E-cadherin and α-smooth muscle actin), transcriptional regulators for epithelial-mesenchymal transition (snail family transcriptional repressors), components of transforming growth factor-ß1/SMADs signaling, high-mobility group box 1 (HMGB1), and receptor for advanced glycation end-products (RAGE). The in situ expression of E-cadherin, α-smooth muscle actin and SMAD7 was determined using immunofluorescence staining. Cell migration capacity was assessed by wound-healing assay. RESULTS: Transfection with NRF1 expression vector repressed the migration capacity of bladder cancer cells, diminishing HMGB1/RAGE expression and reducing transforming growth factor ß-associated epithelial-mesenchymal transition in T24 cells. CONCLUSION: Therapeutic avenues that increase NRF1 expression may serve as an adjunct to conventional treatments for bladder cancer.

Determining Gaps in Current Physiatric Tele-Physical Assessments via a Needs Assessment Survey.

OBJECTIVES: Physical examinations are essential for in-person patient visits but remain difficult to replicate during virtual encounters. This work aims to identify gaps in the current state of telemedicine-based physical assessments by surveying physical medicine and rehabilitation physicians who perform physical examinations. DESIGN: A survey of 29 Likert-scale questions and five open-ended questions was distributed to practicing physical medicine and rehabilitation physicians. The Likert-scale questions covered remote physical assessment, access, perception/engagement, implementation/effectiveness, and administrative concerns. RESULTS: Fifty-three participants completed the survey. More than 80% of respondents suggested that while telemedicine was universally well accepted, they could not effectively perform telemedicine-based physical assessments, especially the musculoskeletal and neurological components. Remote assessment of upper and lower limb strength, reflexes, and sensation were examples of key unmet needs. Responses to open-ended questions suggested that telemedicine-based physical assessments can reduce the burden of travel and increase adherence to follow-up visits, but complex technology setup can pose difficulty for older patients and patients with cognitive deficits. CONCLUSIONS: These findings suggest that current telemedicine technology is insufficient to meet physical medicine and rehabilitation physicians' telemedicine-based physical assessments needs. Despite high levels of provider and patient engagement with telemedicine, numerous deficits remain in performing musculoskeletal and neurological examinations. These results can inform future technology developments that address these identified telemedicine-based physical assessments gaps.

Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial.

BACKGROUND: Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the antimalarial monoclonal antibody CIS43LS conferred high protection against parasitaemia at doses of 20 mg/kg or 40 mg/kg administered intravenously followed by controlled human malaria infection. The ability of CIS43LS to confer protection at lower doses or by the subcutaneous route is unknown. We aimed to provide data on the safety and optimisation of dose and route for the human antimalaria monoclonal antibody CIS43LS. METHODS: VRC 612 Part C was the third part of a three-part, first-in-human, phase 1, adaptive trial, conducted at the University of Maryland, Baltimore Center for Vaccine Development and Global Health, Baltimore, MD, USA. We enrolled adults aged 18-50 years with no previous malaria vaccinations or infections, in a sequential, dose-escalating manner. Eligible participants received the monoclonal antibody CIS43LS in a single, open-label dose of 1 mg/kg, 5 mg/kg, or 10 mg/kg intravenously, or 5 mg/kg or 10 mg/kg subcutaneously. Participants underwent controlled human malaria infection by the bites of five mosquitoes infected with Plasmodium falciparum 3D7 strain approximately 8 weeks after their monoclonal antibody inoculation. Six additional control participants who did not receive CIS43LS underwent controlled human malaria infection simultaneously. Participants were followed-up daily on days 7-18 and day 21, with qualitative PCR used for P falciparum detection. Participants who tested positive for P falciparum were treated with atovaquone-proguanil and those who remained negative were treated at day 21. Participants were followed-up until 24 weeks after dosing. The primary outcome was safety and tolerability of CIS43LS at each dose level, assessed in the as-treated population. Secondary outcomes included protective efficacy of CIS43LS after controlled human malaria infection. This trial is now complete and is registered with ClinicalTrials.gov, NCT04206332. FINDINGS: Between Sept 1, 2021, and Oct 29, 2021, 47 people were assessed for eligibility and 31 were enrolled (one subsequently withdrew and was replaced) and assigned to receive doses of 1 mg/kg (n=7), 5 mg/kg (n=4), and 10 mg/kg (n=3) intravenously and 5 mg/kg (n=4) and 10 mg/kg (n=4) subcutaneously, or to the control group (n=8). CIS43LS administration was safe and well tolerated; no serious adverse events occurred. CIS43LS protected 18 (82%) of 22 participants who received a dose. No participants developed parasitaemia following dosing at 5 mg/kg intravenously or subcutaneously, or at 10 mg/kg intravenously or subcutaneously. All six control participants and four of seven participants dosed at 1 mg/kg intravenously developed parasitaemia after controlled human malaria infection. INTERPRETATION: CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Visual Performance and Binocular/Accommodative Function of S.T.O.P. Contact Lenses Compared With MiSight.

OBJECTIVES: The objective of this study was to compare the visual performance and binocular/accommodative function of two novel S.T.O.P. design (F2 and DT) contact lenses against MiSight when worn by myopic, young adults. METHOD: This was a prospective, randomized, cross-over, single-masked study. Each lens was worn daily wear with overnight peroxide disinfection for approximately 7 days. Visual performance was assessed with subjective ratings (0-100): clarity of vision and lack of ghosting (far away, intermediate, and near), vision when driving, overall vision satisfaction, and with monocular high-contrast and low-contrast visual acuity (HCVA/LCVA) at 6 m, binocular HCVA (6 m, 70 cm, 50 cm, and 40 cm), binocular LCVA (6 m and 70 cm). Binocular function was assessed with heterophorias (3 m and 40 cm). Accommodative function was assessed with monocular accommodative facility (AF: 40 cm) and dynamic monocular accommodative response (AR: 6 m, 70 cm, and 40 cm). RESULTS: F2 was rated higher than MiSight for clarity of vision (near and intermediate) and lack-of-ghosting ( P <0.001), while MiSight was rated higher than DT for clarity of vision (near, P <0.001). MiSight was better than F2 and DT for monocular HCVA (6 m) and binocular HCVA (6 m and 40 cm, P ≤0.02), but the maximum difference was ≤2 letters. There were no differences between designs for heterophoria ( P =0.61) nor were there any differences between DT and MiSight for any accommodative measure ( P >0.1). F2 was higher for monocular-AF ( P =0.007) and lower for AR (70 cm and 40 cm; P ≤0.007) compared with MiSight. CONCLUSIONS: The visual performance and binocular/accommodative function of S.T.O.P. designs F2 and DT were comparable with MiSight. F2 outperformed MiSight in some aspects of subjective visual performance and monocular accommodative function.

Comparison of in-person and synchronous remote musculoskeletal exam using augmented reality and haptics: A pilot study.

INTRODUCTION: Utilization of telemedicine for health care delivery increased rapidly during the coronavirus disease 2019 (COVID-19) pandemic. However, physical examination during telehealth visits remains limited. A novel telerehabilitation system-The Augmented Reality-based Telerehabilitation System with Haptics (ARTESH)-shows promise for performing synchronous, remote musculoskeletal examination. OBJECTIVE: To assess the potential of ARTESH in remotely examining upper extremity passive range of motion (PROM) and maximum isometric strength (MIS). DESIGN: In this cross-sectional pilot study, we compared the in-person (reference standard) and remote evaluations (ARTESH) of participants' upper extremity PROM and MIS in 10 shoulder and arm movements. The evaluators were blinded to each other's results. SETTING: Participants underwent in-person evaluations at a Veterans Affairs hospital's outpatient Physical Medicine and Rehabilitation (PM&R) clinic, and underwent remote examination using ARTESH with the evaluator located at a research lab 30 miles away, connected via a high-speed network. PATIENTS: Fifteen participants with upper extremity pain and/or weakness. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Inter-rater agreement between in-person and remote evaluations on 10 PROM and MIS movements and presence/absence of pain with movement was calculated. RESULTS: The highest inter-rater agreements were noted in shoulder abduction and protraction PROM (kappa (κ) = 0.44, confidence interval (CI): -0.1 to 1.0), and in elbow flexion, shoulder abduction, and shoulder protraction MIS (κ = 0.63, CI: 0 to 1.0). CONCLUSIONS: This pilot study suggests that synchronous tele-physical examination using the ARTESH system with augmented reality and haptics has the potential to provide enhanced value to existing telemedicine platforms. With the additional technological and procedural improvements and with an adequately powered study, the accuracy of ARTESH-enabled remote tele-physical examinations can be better evaluated.