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Supplementary Figures S1-S6. Supplementary Figure S1. Liquid chromatography electrospray ionization tandem mass spectrometry analysis; Supplementary Figure S2. TM4SF1 expression in human breast and colon cancers; Supplementary Figure S3A. Clearance of anti-TM4SF1 antibody from HUVEC surface; Supplementary Figure S3B. Uptake of anti-TM4SF1 antibody in HUVEC; Supplementary Figure S4A. NSCLC killing by anti-TM4SF1 ADC; Supplementary Figure S4B. Tumor cell killing by anti-TM4SF1 ADC; Supplementary Figure S5. Expression level of TM4SF1 and other endothelial cell markers in tumor xenografts; Supplementary Figure S6. Clearance of anti-TM4SF1 ADCs; tolerance in mice.

Supplementary Data from First-in-Class Anti-immunoglobulin–like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors

Purpose:In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.Patients and Methods:Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated.Results:Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti–PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.Conclusions:This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti–PD-1/PD-L1 agent.

Purpose:In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.Patients and Methods:Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated.Results:Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti–PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.Conclusions:This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti–PD-1/PD-L1 agent.

Objectives Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting. Design The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting. Methods Eligible adults initiated DTG/3TC 14 days or less after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance less than 30 ml/min per 1.73 m2, participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA less than 50 copies/ml at Week 24, regardless of antiretroviral regimen, among all participants (intention-to-treat exposed) and those with available HIV-1 RNA data (observed). Results Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in eight participants [five with HBV co-infection, one with baseline M184V, one for adverse event (rash), one participant decision]. At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA less than 50 copies/ml. Incidence of drug-related adverse events was low (7%); no drug-related serious adverse events occurred. Conclusion These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed [ClinicalTrials.gov, NCT03945981; see Supplemental Digital Content 1, video abstract (Video abstract summarizing the STAT study design and results), http://links.lww.com/QAD/C189].

Supplemental Digital Content is Available in the Text., Background: With the highest rates of HIV/AIDS in the United States, Black Americans are still underrepresented in HIV medical research. Setting: BRAAVE (NCT03631732) is a randomized, phase 3b, multicenter, open-label US study. Methods: Adults identifying as Black or African American and virologically suppressed on 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus third agent were randomized (2:1) to switch to open-label bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) once daily or stay on baseline regimen (SBR) for 24 weeks, after which SBR had delayed switch to B/F/TAF. Resistance to non-NRTIs, protease inhibitors, and/or NRTIs was permitted; integrase strand transfer inhibitor resistance was exclusionary. Primary endpoint was proportion of participants with HIV-1 RNA ≥50 copies/mL at week 24 (snapshot algorithm; noninferiority margin of 6%). Results: Of 558 screened, 495 were randomized/treated (B/F/TAF n = 330; SBR n = 165). Overall, 32% were ciswomen, 2% transwomen, and 10% had an M184V/I mutation. At week 24, 0.6% on B/F/TAF vs 1.8% on SBR had HIV-1 RNA ≥50 copies/mL (difference −1.2%; 95% confidence interval −4.8% to 0.9%), demonstrating noninferiority of B/F/TAF vs SBR. Proportions with HIV-1 RNA

Despite numerous publications emphasizing the value of dose finding, drug development in oncology is dominated by the mindset that higher dose provides higher efficacy. Examples of dose finding implemented by biopharmaceutical firms can change this mindset. The purpose of this article is to outline a pragmatic dose selection strategy for immuno-oncology (IO) and other targeted monoclonal antibodies (mAbs). The approach was implemented for pembrolizumab. Selecting a recommended phase II dose (RP2D) with a novel mechanism of action is often challenging due to uncertain relationships between pharmacodynamics measurements and clinical end points. Additionally, phase I efficacy and safety data are generally inadequate for RP2D selection for IO mAbs. Here, the RP2D was estimated based on phase I (clinical study KN001 A and A2) pharmacokinetics data as the dose required for target saturation, which represents a surrogate for maximal pharmacological effect for antagonist mAbs. Due to limitations associated with collecting and analyzing tumor biopsies, characterizing intratumoral target engagement (TE) is challenging. To overcome this gap, a physiologically-based pharmacokinetic model was implemented to predict intratumoral TE. As tumors are spatially heterogeneous, TE was predicted in well-vascularized and poorly vascularized tumor regions. Additionally, impact of differences in target expression, for example, due to interindividual variability and cancer type, was simulated. Simulations showed that 200 mg every 3 weeks can achieve ≥ 90% TE in clinically relevant scenarios, resulting in the recommendation of 200 mg every 3 weeks as the RP2D. Randomized dose comparison studies (KN001 B2 and D) showing similar efficacy over a fivefold dose/exposure range confirmed the RP2D as the pivotal dose.

Background Telemedicine use has expanded rapidly since the COVID-19 pandemic in order to adhere to social distancing protocols and has been met with much enthusiasm. However, less is known about the use of telemedicine in sports and exercise medicine (teleSEM) and its utility to treat emergent craniofacial injuries. Given how common facial trauma is among athletes and its possible complications, incorporation of telemedicine in sports-related injuries may prove to be quintessential for athletes and coaches. Methods A comprehensive literature search of the MEDLINE, PubMed, Google Scholar, EMBASE, and Cochrane Central Register of Controlled Trials was conducted for studies published through December 2020 with multiple search terms related to telemedicine in sports and trauma care. Results Overall, teleSEM is appreciated by both patients and physicians alike. Studies show that the satisfaction rate among patients and physicians are high. Sports-related telemedicine visits can help improve resource utilization and total costs. Facial trauma studies also reveal that the level of concurrency of treatment options between telemedicine visits and in-person consultations is almost perfect. Further, there are many additional ways that teleSEM can be implemented in treating injured athletes, including possible collaboration between athletic coaches and physicians as well as mobile device applications. Telemedicine may be particularly useful in treating acute injuries in low-resourced areas with limited equipment and training. Conclusion Telemedicine has been widely employed for sports-related injuries and in traumatic care. Patients and providers alike have noted its utility over other methods of communication with physicians. Our findings suggest that telemedicine has a significant potential in treating sports-related injuries and improving the efficiency of diagnoses and treatments. It may enhance outcomes for participants in athletic events. This may become a key aspect of determining whether a player can return to immediate competition.

Ankle arthrodesis (AA) provides reliable pain relief, good patient satisfaction scores, and improved overall function. However, this procedure has been associated with numerous complications and sequelae, such as pseudoarthrosis, malunion, gait abnormalities, increased demand on surrounding joints, and a long period of convalescence. Conversion to total ankle arthroplasty (TAA) is a potential option in the management of these complex and challenging situations. The purpose of this study is to investigate the outcomes of AA conversion to TAA. A systematic review of electronic databases was performed. Six studies involving 172 ankles met inclusion criteria. The weighted mean preoperative Visual Analogue Scale (VAS) score at the time of TAA conversion was 7.8 and the weighted mean postoperative VAS score at the time of final follow-up was 2.5. The weighted mean preoperative AOFAS score at the time of TAA conversion was 32 and the weighted mean postoperative AOFAS score at the time of final follow-up was 72.4. The rate of salvage tibiotalocalcaneal arthrodesis was 2.3% and rate of transtibial amputation was also 2.3% after attempted conversion from initial AA to TAA. Conversion of AA to TAA appears to be a viable option to improve patient outcomes and prevent extensive hindfoot arthrodesis and transtibial amputation. More prospective studies with consistent reporting of outcomes, complications, and revision rates with long-term follow-up are needed.

Total ankle replacement has become a viable alternative to ankle arthrodesis in the surgical management of advanced ankle arthritis. Total ankle replacement has generally been reserved for patients who are older and for those who will have a lower demand on the replacement. The purpose of the current study is to review patient outcomes, complications, and implant survival in patients younger than 55 years who underwent total ankle replacement at a single institution. A single-center chart and radiographic review was performed of consecutive patients who underwent total ankle replacement for treatment of end-stage ankle arthritis. All surgeries were performed by 1 of 5 fellowship-trained foot and ankle surgeons at a single institution. A total of 51 patients met inclusion criteria with a mean follow-up of 31.2 months (SD = 16.2). Implant survival was 94%, There were 7 major complications (13%) requiring an unplanned return to the operating room and 8 minor complications (15%) that resolved with conservative care. The results of this study show that total ankle replacement is a viable treatment option for patients younger than 55 years. Levels of Evidence: A retrospective case series

Brain infections are a major public health problem in India and other parts of the world, causing both mortality and lifelong disability. Even after a thorough investigation, many cases remain without an etiological diagnosis. Primate erythroparvovirus 1 (B19V) has been identified as a pathogen associated with undiagnosed meningoencephalitis in other settings, including the United Kingdom, France, and Latvia. Here, we reported 13/403 (3.2%) B19V PCR positive cases of meningoencephalitis in West Bengal, India. The positive samples were mostly from children (10/13, 76.92%) and presented as a spectrum consisting of acute encephalitis (7/13), acute meningoencephalitis (3/13), and meningitis (3/13). Of the 13 cases, 8/13 (61.5%) had no known etiology and 5/13 (38.5%) had a previous etiological diagnosis. The cases did not cluster in time or by location, suggesting sporadic occurrence rather than outbreaks. We were able to retrieve the complete B19V genomes from cerebrospinal fluid (CSF) in 12/13 cases. The sequences clustered into genotype 3b with complete genomes from Brazil, Ghana, and France, and partial genomes from India and Kyrgyzstan. This is the first report of B19V in cases of neurological infections from India. It highlights the need to evaluate the causal relationship between B19V with meningoencephalitis in the country. These were also the first complete genomes of genotype 3b from CSF and will be critical in the evaluation of the relationship between genotypes and disease.

Joint arthroplasty of the first metatarsophalangeal (MTP) joint is an accepted surgical option for patients with hallux rigidus. However, this procedure has been reported to have a high complication rate and unpredictable survivorship. Implant arthroplasty failure is a devastating complication that results in significant osseous defect with altered biomechanics of the foot. Commonly, salvage options are limited to arthrodesis with bone grafting. However, outcomes are rarely reported. The purpose of this study is to investigate the fusion rates of first metatarsophalangeal joint arthrodesis after conversion from failed implant arthroplasty. A systematic review of electronic databases to find reports of conversion arthrodesis after failed implant arthroplasty was performed. Six studies involving a total of 76 patients with a weighted mean age of 54.9 met the inclusion criteria. Out of the 6 included articles, the nonunion rate was 16.5% at a weighted mean follow-up of 48.1 months. The nonunion rate in the current report is higher than reported nonunion rates of primary arthrodesis. More prospective studies with consistent and standard outcome measures are needed to further determine the success rate of this salvage procedure. Levels of Evidence: 4, Systematic Review of Level 4 Studies

Objectives Burden of illnesses has been described in the literature using the health-related quality of life (HRQoL) in people with chronic conditions. However, the studies reporting trends of burden are sparse. The aim of this study was to explore the trends of burden of chronic illness from the perspective of HRQoL. Study design This was a secondary analysis of administrative database. Methods Seven data sets of the Canadian Community Health Survey from 2001 to 2014 were obtained for the analysis. Multiple linear and logistic regression models were used on each data set to assess the burden of illness on the Health Utilities Index Mark III (HUI3), life satisfaction (LS), and perceived health (PH). Results People with the effect of stroke constantly had low scores on the HUI3, LS, and PH. Regression analyses revealed that arthritis, back problem, and mood disorder have greater impact on the HUI3 score. Effect of stroke, mood disorder, and anxiety disorder stably had the largest negative impact on LS, while chronic obstructive pulmonary disease (COPD), effect of stroke, and cancer had the largest effect on PH. Conclusion This study identified that arthritis, back pain, mood disorder, effect of stroke, and COPD constantly have high burden on health outcomes compared with other chronic condition over the past decade.

Co3C magnetic nanoparticles have been synthesized using supercritical conditions of ethanol. The phase structure of the samples has shown two phases of orthorhombic Co3C and Co structures. The morphology of the prepared nanoparticles reveals a spherical-like shape. Tailoring the synthesis parameters has led to controlling the magnetic properties depending on the ratio of Co3C:Co in the samples. The magnetic properties of the samples have been measured, revealing ferromagnetic behavior. The data yield coercivity (HC) was of 600–950 Oe and saturation magnetization (MS) of 20–38 emu/g. The results present alternative approach to nucleate Co3C magnetic nanoparticles. The synthesis method will be optimized in the future to produce a pure Co3C phase structure.

Naviculocuneiform (NC) joint arthrodesis is an effective procedure to treat pain and provide stability to the medial column. Various forms of fixation have been described for NC arthrodesis. Despite this, the available literature is scant and questions remain regarding nonunion rate and contributory factors. A systematic review of the literature was undertaken to determine the rate of nonunion for NC joint arthrodesis. Seven studies involving 139 NC joint arthrodeses met inclusion criteria. The nonunion rate was 6.5% at a weighted mean follow-up of 73.2 months. There is insufficient evidence to provide a practice guideline based on the current literature. Adequately powered prospective clinical trials comparing well-matched patient groups with long-term follow-up are required to limit systematic error and enhance external validity. Specific outcomes measures should include union, functional assessment, complications, and cost-benefit analysis.

Social distancing protocols during the COVID-19 pandemic have resulted in a rapid expansion of telemedicine. It has allowed patients to save time and money on clinic visits, and physicians to communicate with patients who live remotely. Telemedicine has also been valuable in plastic surgery during initial consultations, transfers, and follow up visits. However, given the often-sensitive nature of plastic surgery, the professionalism and expectations of telemedicine have to be reviewed. A comprehensive literature search of the MEDLINE, PubMed, Google Scholar, EMBASE, and Cochrane Central Register of Controlled Trials was conducted for studies published through October 2020 with multiple search terms related to telemedicine and its use in plastic surgery. Data on the effectiveness, challenges, and professionalism of telemedicine were collected. Our review suggests that telemedicine can be an effective mode of communication in many realms of plastic surgery, including cleft care and craniofacial deformities. However, many plastic surgeons are unfamiliar with the existing platforms, and there are no clear guidelines on the most optimal platforms. Physicians have to recognize that patients might have low digital health literacy or may not even possess digital device for telemedicine. There also needs to be an overall improvement in patient education. Given that telemedicine use will continue to increase after the COVID-19 pandemic, regulations on Health Insurance Portability and Accountability Act-compliant platforms and specific guidelines on telemedicine visits, such as undressing, chaperones, privacy matters, need to be established while maintaining a professional relationship between the patient and the physician.

The Scandinavian Total Ankle Replacement (STAR, DJO, Dallas, TX) is a three-part, mobile-bearing ankle implant that has been approved by the Food and Drug Administration for implantation in the United States. Due to the prevalent usage and length of time that the STAR implant has been available, it is one of the most reviewed and researched TAR prostheses. The three-piece design of the STAR prosthesis consists of a flat metallic tibial component with two dorsal dowels, a cylindrical metallic talar component with a small central ridge and a central component composed of high-density polyethylene gliding core. As we become more sophisticated with our techniques and implants, we may find that certain indications are evolving. Currently, implantation of the STAR may be used for the treatment of end-stage ankle arthritis in adult patients. Contraindications include active ankle infection, neuropathic joint, significant areas of avascular osteonecrosis of the talus or distal tibia, complete paralysis of the operative limb, inadequate soft tissue coverage, vascular insufficiency, severe deformity that cannot be corrected, and skeletal immaturity. In this chapter, we provide an in-depth description of the procedure technique including surgical pearls from the authors. To date, a number of studies have reviewed the long-term results and 15-year survivorship of the STAR. Additional long-term studies are needed to further understand the survivability of this implant.

Karnataka, a state in south India, reported its first case of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection on March 8, 2020, more than a month after the first case was reported in India. We used a combination of contact tracing and genomic epidemiology to trace the spread of SARS-CoV-2 in the state up until May 21, 2020 (1578 cases). We obtained 91 genomes of SARS-CoV-2 which clustered into seven lineages (Pangolin lineages—A, B, B.1, B.1.80, B.1.1, B.4, and B.6). The lineages in Karnataka were known to be circulating in China, Southeast Asia, Iran, Europe and other parts of India and are likely to have been imported into the state both by international and domestic travel. Our sequences grouped into 17 contact clusters and 24 cases with no known contacts. We found 14 of the 17 contact clusters had a single lineage of the virus, consistent with multiple introductions and most (12/17) were contained within a single district, reflecting local spread. In most of the 17 clusters, the index case (12/17) and spreaders (11/17) were symptomatic. Of the 91 sequences, 47 belonged to the B.6 lineage, including eleven of 24 cases with no known contact, indicating ongoing transmission of this lineage in the state. Genomic epidemiology of SARS-CoV-2 in Karnataka suggests multiple introductions of the virus followed by local transmission in parallel with ongoing viral evolution. This is the first study from India combining genomic data with epidemiological information emphasizing the need for an integrated approach to outbreak response.

Karnataka, a state in south India, reported its first case of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) on March 8, 2020, more than a month after the first case was reported in India. We used a combination of contact tracing and genomic epidemiology to trace the spread of SARS-CoV-2 in the state up until May 21, 2020 (1578 cases). We obtained 47 full genomes of SARS-CoV-2 which clustered into six lineages (Pangolin lineages-A, B, B.1, B.1.1, B.4, and B.6). The lineages in Karnataka were known to be circulating in China, Southeast Asia, Iran, Europe and other parts of India and are likely to have been imported into the state both by international and domestic travel. Our sequences grouped into 12 contact clusters and 11 cases with no known contacts. We found nine of the 12 contact clusters had a single lineage of the virus, consistent with multiple introductions and most (8/12) were contained within a single district, consistent with local spread. In most of the twelve clusters, the index case (9/12) and spreaders (8/12) were symptomatic. Of the 47 sequences, 31 belonged to the B/B.6 lineage, including seven of eleven cases with no known contact, this is consistent with the ongoing transmission of this lineage in the state. Genomic epidemiology of SARS-CoV-2 in Karnataka is consistent with multiple introductions of the virus followed by local transmission in parallel with ongoing viral evolution. This is the first study from India combining genomic data with epidemiological information emphasizing the need for an integrated approach to outbreak response.

Background Life Goals Programme (LGP) was developed as a psychological intervention for bipolar disorder, with its structured 6-session psychoeducation phase (Phase 1) targeting understanding of the disorder, medication adherence, early warning signs, and coping with symptoms and triggers. The present study tested the efficacy of Phase 1 of the LGP on symptom recovery and moment-by-moment mood stability, as well as medication adherence and quality of life. Methods Adults with bipolar disorder were randomly allocated to the LGP condition (six weekly group sessions) or the waitlist condition (six weeks of standard care, followed by the same LGP intervention). Participants were assessed before and after treatment, and at 6-month follow up. Waitlist participants were additionally assessed at baseline. Assessment included a clinical interview (SCID, MADRS, YMRS, and HAM-A), self-reported questionnaires, and 6-day experience sampling assessment on a mobile device. Results 64 out-patients with bipolar disorder (44 Bipolar I and 20 Bipolar II subtypes) participated in this study. LGP was well received and attended. Following LGP, there were significant improvements in knowledge about illness and level of anxiety, which were of large effect sizes and sustained at 6-month follow-up. Experience sampling assessment revealed small but significant improvements in moment-by-moment mood stability. Improvement in medication adherence was significant at 6 months and was of a moderate-to-large effect size. Changes in anxiety and mood stability were significantly greater following LGP than standard care. Limitations Our results warrant further testing against active control. Conclusions There was a robust improvement in emotional regulation following the 6-week LGP.

Background: Given findings that generally support the benefits of information and communication technology (ICT) for older adults’ psychosocial adjustment, one might surmise that lonely older adults, who have a stronger need for psychological support, would reap more psychosocial benefits from ICT use. However, scant research has examined this view, much less the likelihood that ICT use might worsen the psychological well-being of lonely older adults, as has been shown to be the case in younger adults. Objective: To examine whether the association between ICT use and psychological adjustment (i.e., psychological distress and sense of community [SOC]) among older adults depends on their loneliness levels. Methods: A representative sample of 738 Hong Kong SAR Chinese older adults aged 60 years or older (56% female) was interviewed in 2017 on loneliness, frequency of ICT use (i.e., Internet and smart devices), psychological distress (6-item Kessler scale; K6), and SOC. Results: Regression analyses showed that loneliness significantly moderated the relationship between ICT use frequency and psychological adjustment (psychological distress and SOC); more frequent ICT use was associated with more psychological distress and less SOC, with higher levels of loneliness. Conclusion: These findings suggest that ICT use may be a mixed blessing for older adults, i.e., using more ICT might predict worse psychological adjustment among lonelier older adults. Efforts that promote ICT use among older adults should take their loneliness levels into account.

Ankle fractures are common orthopedic injuries. Although operative indications and subsequent stabilization of these fractures have not significantly changed, postoperative protocols remain highly variable. Effects of early weight bearing (EWB) on fracture characteristics in operatively stabilized bimalleolar and bimalleolar equivalent ankle fractures remain poorly publicized. This study seeks to clarify postoperative fracture union rates, rates of hardware loosening or failure, and radiographic medial clear space changes when comparing EWB to late weight bearing (LWB) following open reduction and internal fixation (ORIF). A total of 95 patients with either bimalleolar (66%) or bimalleolar equivalent (34%) fractures who underwent ORIF were retrospectively reviewed. Weight bearing was allowed at three weeks in the EWB group and when signs of radiographic union were noted in the LWB group. Postoperatively, patients were evaluated at regular intervals for fracture union, signs of implant failure, and evidence of medial clear space widening radiographically. There were 38 patients (40%) in the EWB group and 57 patients (60%) comprising the LWB cohort. There were no significant demographic differences between groups. The EWB group on average began to weight bear at 3.1 + 1.4 weeks postoperatively, whereas the LWB group began at 7.2 + 2.1 weeks postoperatively (p0.1 at all time intervals) were not notably different between groups. No differences in medial clear space were detected at any postoperative interval between groups (p>0.1 at all time intervals). This study suggests that EWB at three weeks postoperatively does not increase markers of radiographic failure compared to six weeks of non-weight bearing (NWB), which has been regarded as the gold standard of treatment to allow for healing; this may represent an improvement to rehabilitation protocols after bimalleolar ankle ORIF of unstable ankle fractures.

In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated.Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti-PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti-PD-1/PD-L1 agent.

Introduction: There is an ongoing debate about whether negative affect are consequences or triggers of paranoid thinking. It has also been suggested that aberrant salience is central to the development of delusions. This study modelled the moment-to-moment relationships between negative affect, aberrant salience, and paranoia in acute inpatients with psychosis.Methods: Participants with active paranoid delusions were assessed using clinical rating scales and experience sampling method (ESM) over 14 days. ESM data were analysed using time-lagged multilevel regression modelling.Results: Both negative affect and aberrant salience predicted an increase in paranoia at the next time point. Conversely, the level of paranoia did not predict subsequent changes in negative affect or aberrant salience. Negative affect predicted an increase in aberrant salience at the next time point, and vice versa.Conclusions: Negative affect and aberrant salience appear to drive and exacerbate paranoia, rather than being merely the sequelae of the symptom. Our results suggest both direct and indirect (via aberrant salience) pathways from negative affect to paranoia.

Crohn’s disease exacerbations can often be associated with bacterial infections causing gastroenteritis. We report a child who experienced exacerbation of his Crohn’s disease associated with a positive stool culture forEdwardsiella tarda (E. tarda). Endoscopy showed features of moderate inflammation similar to exacerbation of Crohn’s disease. The patient was treated simultaneously with intravenous steroids and antibiotics, and his symptoms resolved. This case report highlights the importance of clinicians being able to promptly recognize and treat concurrent bacterial infections in Crohn’s disease exacerbations.

Background The primary analysis of the STAT study demonstrated the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting through 24 weeks, with therapy adjustments for baseline resistance or hepatitis B virus (HBV) co-infection. Here we present secondary analyses through Week 48 of virologic outcomes in participants by baseline viral load (VL). Methods STAT is a single-arm study of treatment-naive adults with HIV-1 infection who initiated DTG/3TC ≤ 14 days after HIV-1 diagnosis without availability of screening/baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance < 30 mL/min/1.73 m2, then antiretroviral therapy (ART) was potentially adjusted and participants remained on study. Efficacy analyses included proportion of participants with HIV-1 RNA < 50 c/mL regardless of ART regimen at Week 48, among all participants (ITT-E missing = failure analysis) and among participants with available HIV-1 RNA data at Week 48 (observed analysis). Results Of 131 enrolled, DTG/3TC treatment was adjusted in 10 participants, and of those with available data (n=7), all (100%) achieved HIV-1 RNA < 50 c/mL at Week 48. At Week 48, 82% (107/131) of all participants (Figure 1) and 97% (107/110) of those with available data (Figure 2) achieved HIV-1 RNA < 50 c/mL. Of participants with baseline VL ≥ 500,000 c/mL, 89% (17/19) achieved HIV-1 RNA < 50 c/mL at Week 48; the remaining 2 withdrew from study. Of participants with baseline VL ≥ 1,000,000 c/mL, 90% (9/10) achieved HIV-1 RNA < 50 c/mL at Week 48 (Table); the remaining participant withdrew consent. Of the 17 participants with baseline VL ≥ 500,000 c/mL with available data through Week 48, 76% (13/17) achieved virologic suppression by Week 24. One participant with baseline VL ≥ 500,000 c/mL switched from DTG/3TC before the Week 48 assessment. Of the 9 participants with baseline VL ≥ 1,000,000 c/mL with available data through Week 48, most participants (8/9; 89%) were suppressed by Week 24. Figure 1. Virologic outcomes at Week 48, overall and by baseline VL and CD4+ cell count: ITT-E missing = failure analysis. Figure 2. Virologic outcomes at Week 48, overall and by baseline VL and CD4+ cell count: observed analysis. Table. Viral Load by Study Visit Among Participants with Baseline HIV-1 RNA ≥1,000,000 c/mL Conclusion These data provide evidence for the efficacy and feasibility of using DTG/3TC as a first-line regimen in a test-and-treat setting, including among participants with very high baseline VL. Disclosures Charlotte-Paige M. Rolle, MD MPH, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)Janssen Infectious Disease (Scientific Research Study Investigator, Advisor or Review Panel member)ViiV Healthcare (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau) Tulika Singh, MD MS AAHIVS, Gilead (Grant/Research Support, Advisor or Review Panel member)ViiV (Grant/Research Support, Advisor or Review Panel member, Speaker's Bureau) Moti Ramgopal, MD FIDSA, Abbvie (Scientific Research Study Investigator, Speaker's Bureau)Gilead (Consultant, Scientific Research Study Investigator, Speaker's Bureau)Janssen (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker's Bureau)Merck (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator, Speaker's Bureau) Dushyantha Jayaweera, MD, mrcog(uk), face, Gilead (Research Grant or Support)Janssen (Research Grant or Support)viiv (Research Grant or Support) Peter Leone, MD, viiv healthcare (Employee) Jessica Matthews, BS, ViiV Healthcare (Employee) Michael Cupo, Ph.D., GlaxoSmithKline (Employee) Mark Underwood, PhD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kostas Angelis, PhD, GSK (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee, Shareholder, I have shares in GSK, the part owner of ViiV) Deanna Merrill, PharmD, MBA, AAHIVP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Christopher T. Nguyen, MD, ViiV Healthcare (Employee) Jean A. van Wyk, MB,ChB, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Andrew Zolopa, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

There is a lack of consensus in the literature regarding optimal treatment methods for Lisfranc injuries, and recent literature has emphasized the need to compare open reduction and internal fixation (ORIF) with primary arthrodesis (PA). The purpose of the current study is to compare reoperation and complication rates between ORIF and PA following Lisfranc injury in a private, outpatient, orthopaedic practice. A retrospective chart review was performed on patients undergoing operative intervention for Lisfranc injury between January 2009 and September 2015. A total of 196 patients met the inclusion criteria (130 ORIF, 66 PA), with a mean follow-up of 61.3 and 81.7 weeks, respectively. The ORIF group had a higher reoperation rate than the PA group, due to hardware removal. When hardware removals were excluded, the reoperation rate was similar. Postsurgical complications were compared between the 2 groups with no significant difference. In conclusion, ORIF and PA had similar complication rates. When hardware removals were excluded, the reoperation rates were similar, although hardware removals were more common in the ORIF group compared with the PA group. Levels of Evidence: Level III

Background: Research suggests that diabetes mellitus (DM) has a negative impact on employment and workplace injury, but there is little data within the Canadian context. Objective: To determine if DM has an impact on various occupational health outcomes using the Canadian Community Health Survey (CCHS). Methods: CCHS data between 2001 and 2014 were used to assess the relationships between DM and various occupational health outcomes. The final sample size for the 14-year study period was 505 606, which represented 159 432 239 employed Canadians aged 15–75 years during this period. Results: We found significant associations between people with diabetes and their type of occupation (business, finance, administration: 2009, p=0.002; 2010, p=0.002; trades, transportation, equipment: 2008, p=0.025; 2011, p=0.002; primary industry, processing, manufacturing, utility: 2013, p=0.018), reasons for missing work (looking for work: 2001, p=0.024; school or education: 2003, p=0.04; family responsibilities: 2014, p=0.015; other reasons: 2001, p

Background Black Americans are disproportionately impacted by HIV. The BRAAVE 2020 study, evaluated the safety and efficacy of switching to the guidelines-recommended single-tablet regimen bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) in Black adults through week (W) 48. Methods Adults with HIV who self-identified as Black or African American and were virologically suppressed on 2 NRTIs plus a 3rd agent were randomized (2:1) to switch to open-label B/F/TAF once daily or stay on their baseline regimen (SBR). Prior virologic failure was allowed except failure on an INSTI. Prior resistance to NNRTIs, PIs and/or NRTIs was permitted except K65R/E/N, ≥3 thymidine analog mutations or T69-insertions. Primary INSTI-resistance was excluded. SBR participants switched to B/F/TAF at W24. Efficacy was assessed at the W24 (1○ endpoint, noninferiority margin 6%) and at W48 as the proportion with HIV-1 RNA ≥ 50 c/mL by FDA Snapshot and by changes in CD4 count. Safety was assessed by adverse events (AE) and lab results. Results 495 were randomized and treated (B/F/TAF n=330, SBR n=165): 32% cis women, 2% transgender women, median age 49 y (range 18-79), 10% had pre-existing M184V/I mutation (Table 1), and 62% lived in the US South. At W24, 1% (2/328) on B/F/TAF vs 2% (3/165) on SBR had HIV-1 RNA ≥50 c/mL (difference -1.2%; 95% CI -4.8% to 0.9%) demonstrating noninferiority of B/F/TAF; 2 with pre-existing primary INSTI resistance were excluded from analysis. 163 assigned to SBR completed W24 and switched to B/F/TAF (SBR to B/F/TAF). At W48 1% (3/328) originally randomized to B/F/TAF and 0 SBR to B/F/TAF had HIV-1 RNA ≥ 50 c/mL (Table 2). The presence of baseline NRTI resistance did not affect the efficacy of B/F/TAF. No treatment emergent resistance was detected. The mean (SD) changes in CD4 were +7 cells/mm3 (189) for B/F/TAF and -8 cells/mm3 (159) for SBR to B/F/TAF. Median (IQR) weight increased 0.9 kg (-1.5, 4.1) and 0.6 kg (-1.0, 3.1) for B/F/TAF and SBR to B/F/TAF groups, respectively. Study drug-related AEs occurred in 10% of participants while on B/F/TAF; most were grade 1. Table 1. Table 2. Conclusion Switching to B/F/TAF was highly effective for Black adults regardless of baseline regimen or pre-existing NRTI resistance and was associated with few treatment related AEs or discontinuations. Disclosures Debbie Hagins, MD, Gilead Sciences Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)Janssen (Grant/Research Support)Merck (Consultant, Grant/Research Support, Advisor or Review Panel member)Viiv Healthcare (Consultant, Grant/Research Support, Advisor or Review Panel member) Princy Kumar, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Michael Saag, MD, Gilead Sciences Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator)Merck (Consultant, Grant/Research Support)Proteus (Grant/Research Support)Viiv Healthcare (Consultant, Grant/Research Support) Anson K. Wurapa, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)GlaxoSmithKline (Grant/Research Support)Janssen (Grant/Research Support, Advisor or Review Panel member)Pfizer (Grant/Research Support) Indira Brar, MD, Gilead (Speaker’s Bureau)janssen (Speaker’s Bureau)ViiV (Speaker’s Bureau) Daniel Berger, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Olayemi Osiyemi, M.D, GlaxoSmithKline (Advisor or Review Panel member, Speaker’s Bureau)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Corrilynn Hileman, MD, Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator) Moti Ramgopal, MD FACP FIDSA, AbbVie (Speaker’s Bureau)Allergan (Speaker’s Bureau)Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Speaker’s Bureau)Janssen (Speaker’s Bureau)Merck (Consultant)Viiv Healthcare (Consultant) Cheryl McDonald, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)Janssen (Grant/Research Support)Merck (Grant/Research Support, Speaker’s Bureau)Viiv Healthcare (Grant/Research Support) Christiana Blair, MS, Gilead Sciences (Employee, Shareholder) Kristen Andreatta, MSc, Gilead Sciences (Employee, Shareholder) Sean E. Collins, MD, MS, Gilead Sciences (Employee) Diana M. Brainard, MD, Gilead Sciences (Employee) Hal Martin, MD, MPH, Gilead Sciences Inc. (Employee, Shareholder)

The article offers a brief history of pitted keratolysis (PK), research regarding PK etiology, evaluation of PK, and current treatment modalities. The main objective of this article focuses on the current literature on PK, its presentation and symptomatology, prevalence, and available therapeutic options. We present a case report and review on PK of a patient treated with an over the counter antiperspirant, topical erythromycin, oral erythromycin, and proper education on hygiene, with complete resolution and without recurrence after a follow up of greater than 12 months.

Since the inception of the first surgical training system by Sir William Stewart Halsted, resident surgical skill development has been promulgated in teaching hospitals. Currently, the Council on Podiatric Medical Education does not mandate the availability of a cadaver lab as a residency curriculum requirement. The purpose of the present study is to assess the structure of the cadaver lab and availability in the current podiatric surgical training programs. A survey was sent electronically to 229 American Association of Colleges of Podiatric Medicine–approved residency programs, excluding OhioHealth, across all residency programs. A total of 173 (6.9%) residents from 74 (32.3%) residency programs completed the survey. This survey analyzed the characteristics and perception of the current state of cadaver lab in podiatric residency. The most reported type of cadaver labs available were medical company sponsored and hospital sponsored. Other hands-on training, including inanimate simulators (n = 24) and animal models (n = 5), was also reported. Overall, 87.9% of the surveyed residents found that cadaver lab is either extremely beneficial (57.8%) or somewhat beneficial (30.1%). The most important factors perceived in a successful cadaver lab were faculty instruction (n = 78), accessibility of lab (n = 46), and availability of instrumentation/hardware (n = 26). This qualitative survey is the first study to address the uniformity, perception, and potential value of the cadaver lab in a podiatric surgical residency.

There is an increase in interest in the relationships between loneliness and psychosis. The notion of psychosis continuum implies that psychotic experiences extend from clinical populations with psychotic disorders to non-clinical populations. This meta-analytic review aimed to examine the respective associations of loneliness with positive and negative psychotic experiences along the psychosis continuum. A systematic database search was conducted and a total of 30 studies were included in the first meta-analysis and 15 studies were included in the second meta-analysis. There was a medium association between loneliness and positive psychotic experiences (r = 0.302, p r = 0.448, p r = 0.347, p

Affinity optimization of monoclonal antibodies (mAbs) is essential for developing drug candidates with the highest likelihood of clinical success; however, a quantitative approach for setting affinity requirements is often lacking. In this study, we computationally analyzed the in vivo mAb-target binding kinetics to delineate general principles for defining optimal equilibrium dissociation constant (\( {K}_D^{opt} \)) of mAbs against soluble and membrane-bound targets. Our analysis shows that in general \( {K}_D^{opt} \) to achieve 90% coverage for a soluble target is one tenth of its baseline concentration (\( {K}_D^{opt}=0.1\times {S}_0 \)), and is independent of the dosing interval, target turnover rate or the presence of competing ligands. For membrane-bound internalizing targets, it is equal to the ratio of internalization rate of mAb-target complex and association rate constant (\( {K}_D^{opt}=\raisebox{1ex}{${k}_{elDM}$}\!\left/ \!\raisebox{-1ex}{${k}_{on}$}\right. \)). In cases where soluble and membrane-bound forms of the target co-exist, \( {K}_D^{opt} \) lies within a range determined by the internalization rate (\( {k}_{elDM} \)) of the mAb-membrane target complex and the ratio of baseline concentrations of soluble and membrane-bound forms (\( \raisebox{1ex}{${S}_0$}\!\left/ \!\raisebox{-1ex}{${M}_0$}\right. \)). Finally, to demonstrate practical application of these general rules, we collected target expression and turnover data to project \( {K}_D^{opt} \) for a number of marketed mAbs against soluble (TNFα, RANKL, and VEGF) and membrane-bound targets (CD20, EGFR, and HER2).

Understanding pharmacological target coverage is fundamental in drug discovery and development as it helps establish a sequence of research activities, from laboratory objectives to clinical doses. To this end, we evaluated the impact of tissue target concentration data on the level of confidence in tissue coverage predictions using a site of action (SoA) model for antibodies. By fitting the model to increasing amounts of synthetic tissue data and comparing the uncertainty in SoA coverage predictions, we confirmed that, in general, uncertainty decreases with longitudinal tissue data. Furthermore, a global sensitivity analysis showed that coverage is sensitive to experimentally identifiable parameters, such as baseline target concentration in plasma and target turnover half‐life and fixing them reduces uncertainty in coverage predictions. Overall, our computational analysis indicates that measurement of baseline tissue target concentration reduces the uncertainty in coverage predictions and identifies target‐related parameters that greatly impact the confidence in coverage predictions.

Clinical development of biotherapeutics for combination therapy requires monitoring the concentrations of both drugs in biological samples. Traditionally, two assays are required to measure drug levels one at a time, which poses challenges in sample management, data reporting, and cost. The Meso Scale Discovery (MSD®) U-PLEX™ platform provides a simple and flexible way to create custom multiplex ligand binding assays (LBAs). We developed and fully validated a two-plex assay on the U-PLEX platform where two therapeutic monoclonal antibodies (mAbs) in Merck's pipeline, which we call MK-A and MK-B in this manuscript, can be measured simultaneously in one sample. Our results demonstrated that the multiplexed pharmacokinetic (PK) assay has performances, including accuracy, precision, and cross-reactivity, that meet requirements in regulatory guidance. Furthermore, results of MK-A from the multiplex assay are comparable to results from a previously validated MK-A single-plex assay with 80% of samples tested in both assays having concentration differences < 30% relative to the mean of the two measurements. The multiplex assay was used to support a phase I MK-A/MK-B combination therapy clinical study and generated results consistent with historical MK-A monotherapy PK data. The ability to measure both biotherapeutics in a multiplexed assay is beneficial in that it improves consistency and efficiency while reduces sample volume and cost. With the number of combination therapies increasing in development, multiplexed assays can potentially have wide applications in biologics bioanalysis.

Background: Current treatment for HIV-infected individuals with renal failure on haemodialysis frequently requires complex regimens with multiple pills. A daily single-tablet regimen of coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is approved in Europe, the USA, and in other regions for use in HIV-1-infected individuals with mild-to-moderate chronic kidney disease (creatinine clearance 30–69 mL/min). We aimed to assess the safety, efficacy, and pharmacokinetics of this regimen in HIV-infected adults with end-stage renal disease on chronic haemodialysis. Methods: We did an open-label, single-arm, multicentre, phase 3b trial at 26 outpatient clinics in Austria, France, Germany, and the USA. Participants were HIV-1-infected adults with end-stage renal disease (creatinine clearance

The development of hallux interphalangeal joint (IPJ) arthritis after an arthrodesis of the first metatarsophalangeal joint has been established in the literature. However, the significance has not been well reported. A retrospective, radiographic review of patients who had undergone a first metatarsophalangeal joint arthrodesis was performed. The Coughlin classification for degree of arthritic degeneration, hallux abductus angle, and hallux interphalangeus angle were measured in 107 radiographs of 103 patients preoperatively and postoperatively. Postoperative angles were measured immediately following surgery at approximately 6 weeks, 3 months, 6 months, 12 months, and 24 months. We found that the hallux abductus angle had decreased in the patients postoperatively; however, the hallux abductus interphalangeus angle increased on average after first metatarsophalangeal fusion. The majority of patients started with a Coughlin classification I of the hallux IPJ, which remained unchanged over the postoperative period, with no statistically significant difference in IPJ degeneration in the patients with or without fusion of the first metatarsophalangeal joint. In addition, no patients had a symptomatic hallux IPJ postoperatively within our limited study period. Further prospective studies would be beneficial with longer follow-up times to assess IPJ degeneration following first metatarsophalangeal joint fusions. Levels of Evidence: Level III: Retrospective, comparative study

Hallux interphalangeal joint arthrodesis is an effective procedure to treat pain and provide stability and is often performed for intrinsic pain to the hallux interphalangeal joint. Additionally, this procedure is typically used in concert with the Jones tenosuspension. Although this as an accepted technique, the available data are scant, and questions remain regarding nonunion rates and contributory factors to poor healing. A systematic review of the reported data were undertaken to determine the rate of nonunion for hallux interphalangeal joint arthrodesis. Seven studies involving 313 hallux interphalangeal joint arthrodeses met the inclusion criteria. The nonunion rate was 28.3% at a weighted mean follow-up period of 8.4 months. The overall complication rate was 33.0%. Considering the increased rate of complications and nonunion rate for this commonly used procedure, additional prospective comparative analyses are needed regarding this topic to identify important patient demographic data and determine superior fixation constructs.

Bispecific antibodies (BAbs) are novel constructs that are under development and show promise as new therapeutic modalities for cancer and autoimmune disorders. The aim of this study is to develop a semi-mechanistic modeling approach to elucidate the disposition of BAbs in plasma and possible sites of action in humans. Here we present two case studies that showcase the use of modeling to guide BAb development. In case one, a BAb is directed against a soluble and a membrane-bound ligand for treating systemic lupus erythematosus, and in case two, a BAb targets two soluble ligands as a potential treatment for ulcerative colitis and asthma. Model simulations revealed important differences between plasma and tissues, when evaluated for drug disposition and target suppression. Target concentrations at tissue sites and type (soluble vs membrane-bound), tissue-site binding, and binding affinity are all major determinants of BAb disposition and subsequently target suppression. For the presented case studies, higher doses and/or frequent dosing regimens are required to achieve 80 % target suppression in site specific tissue (the more relevant matrix) as compared to plasma. Site-specific target-mediated models may serve to guide the selection of first-in-human doses for new BAbs.

Information and communicative technology (ICT) use is a potential vehicle for improving the psychological well-being (PWB) of older people. We examined the roles of age, frailty, and social connectedness in the relationship between ICT use and PWB.Telephone interviews were conducted in mid-2016 with 1201 participants aged 50 and above (55.7% female) residing in Hong Kong, China. The participants reported PWB, ICT use (frequency of using the Internet and smart devices), frailty status, contact with family, friends, and neighbors, self-rated health, subjective financial sufficiency, education level, and employment status.We found that the association between ICT and PWB was moderated by age: ICT was associated with PWB only among old-olds (75+), but not in other age groups. This moderation was mediated by contact with family, but not with friends or neighbors. The moderation was further qualified by frailty status: the ICT-by-age moderation was found only among frail, but not pre-frail or robust older adults.The findings suggest that ICT use can potentially enhance the PWB of older adults aged 75+ through facilitating their contact with family members. These benefits might be particularly salient for those who were frail. Improving ICT access and literacy among older adults may be promising.

Loneliness is a common experience among older people that is associated with health risks and negative well-being. As a psychological phenomenon, it has typically been defined in Western research literature as the discrepancy between desired and actual interpersonal relations. In our qualitative study in Hong Kong, we offer insight into ageing and loneliness in an urban environment of the non-Western world and propose to reconceptualise loneliness by exploring older people's experience of alienation at the societal level as an important but often neglected dimension of their loneliness. Thirty-seven community-dwelling, Chinese adults aged 65 and above were interviewed in focus groups and their accounts analysed and interpreted using a phenomenological approach. Findings revealed that focus group participants perceived insufficient care for older people, a growing distance between themselves and society, and their disintegrating identity in society to be primary sources of societal alienation. In response, older people adopted a more passive lifestyle, attributed marginalisation and inequality to old age, and developed negative feelings including unease towards ageing, vulnerability and helplessness, and anger. The emergence of these key components and underlying themes of societal alienation illuminated neglected facets of the psychological phenomenon of loneliness and highlighted new implications for policy, practice, and research from a societal perspective to address older people's loneliness in urban settings.

Background: The objective of this study is to find temporal trends in the associations between cardiovascular disease and occupational risk factors in the context of the Canadian population. Methods: Population data were analyzed from the Canadian Community Health Survey (CCHS) collected between 2001 and 2014 for trends over time between heart disease and various occupational risk factors: hours worked, physical exertion at work, and occupation type (management/arts/education, business/finance, sales/services, trades/transportations, and primary industry/processing). Results: We found no significant difference in the average number of hours worked/wk between individuals who report having heart disease in all years of data except in 2011 (F1,96 = 7.02, p = 0.009) and 2012 (F1,96 = 8.86, p = 0.004). We also found a significant difference in the degree of physical exertion at work in 2001 (F1,79 = 7.45, p = 0.008). There were statistically significant results of occupation type on self-reported heart disease from 2003 to 2014. Conclusion: Canadian data from the CCHS do not exhibit a trend toward an association between heart disease and the number of hours worked/wk. There is an association between heart disease and physical exertion at work, but the trend is inconsistent. The data indicate a trend toward an association between heart disease and occupation type, but further analysis is required to determine which occupation type may be associated with heart disease. Keywords: occupational health, occupation type, physical exertion, self-reported cardiovascular disease

Prediction of human pharmacokinetics (PK) can be challenging for monoclonal antibodies (mAbs) exhibiting target-mediated drug disposition (TMDD). In this study, we performed a quantitative analysis of a diverse set of six mAbs exhibiting TMDD to explore translational rules that can be utilized to predict human PK. A TMDD model with rapid-binding approximation was utilized to fit PK and PD (i.e., free and/or total target levels) data, and average absolute fold error (AAFE) was calculated for each model parameter. Based on the comparative analysis, translational rules were developed and applied to a test antibody not included in the original analysis. AAFE of less than two-fold was observed between monkey and human for baseline target levels (R 0), body-weight (BW) normalized central elimination rate (K el/BW(-0.25)) and central volume (V c/BW(1.0)). AAFE of less than three-fold was estimated for the binding affinity constant (K D). The other four parameters, i.e., complex turnover rate (K int), target turnover rate (K deg), central to peripheral distribution rate constant (K pt) and peripheral to central rate constant (K tp) were poorly correlated between monkey and human. The projected human PK of test antibody based on the translation rules was in good agreement with the observed nonlinear PK. In conclusion, we recommend a TMDD model-based prediction approach that integrates in vitro human biomeasures and in vivo preclinical data using translation rules developed in this study.

Practitioners of pharmacokinetic/pharmacodynamic modeling routinely employ various software packages that enable them to fit differential equation based mechanistic or empirical models to biological/pharmacological data. The availability and choice of different analytical tools, while enabling, can also pose a significant challenge in terms of both, implementation and transferability. A package has been developed that addresses these issues by creating a simple text-based format, which provides methods to reduce coding complexity and enables the modeler to describe the components of the model based on the underlying physiochemical processes. A Perl script builds the system for multiple formats (ADAPT, MATLAB, Berkeley Madonna, etc.), enabling analysis across several software packages and reducing the chance for transcription error. Workflows can then be built around this package, which can increase efficiency and model availability. As a proof of concept, tools are included that allow models constructed in this format to be run with MATLAB both at the scripting level and through a generic graphical application that can be compiled and run as a stand-alone application.

Background: Given findings that generally support the benefits of information and communication technology (ICT) for older adults’ psychosocial adjustment, one might surmise that lonely older adults, who have a stronger need for psychological support, would reap more psychosocial benefits from ICT use. However, scant research has examined this view, much less the likelihood that ICT use might worsen the psychological well-being of lonely older adults, as has been shown to be the case in younger adults. Objective: To examine whether the association between ICT use and psychological adjustment (i.e., psychological distress and sense of community [SOC]) among older adults depends on their loneliness levels. Methods: A representative sample of 738 Hong Kong SAR Chinese older adults aged 60 years or older (56% female) was interviewed in 2017 on loneliness, frequency of ICT use (i.e., Internet and smart devices), psychological distress (6-item Kessler scale; K6), and SOC. Results: Regression analyses showed that loneliness significantly moderated the relationship between ICT use frequency and psychological adjustment (psychological distress and SOC); more frequent ICT use was associated with more psychological distress and less SOC, with higher levels of loneliness. Conclusion: These findings suggest that ICT use may be a mixed blessing for older adults, i.e., using more ICT might predict worse psychological adjustment among lonelier older adults. Efforts that promote ICT use among older adults should take their loneliness levels into account.