Cutaneous immune-related adverse events from immune checkpoint inhibitor therapy: Moving beyond "maculopapular rash".

Uncoupling toxicity from therapeutic effect lies at the foundation of the current state of the field of cutaneous immune-related adverse events to immune checkpoint inhibitor therapy. This will be achieved through understanding the drivers of toxicity, tumor response, and resistance via large, well-powered population-level studies, institutional cohort data, and cellular-level data. Increasing diagnostic specificity through the application of consensus disease definitions has the power to improve clinical care and each approach to research. Cutaneous immune-related adverse events are associated with increased survival, and their treatment must invoke the maintenance of a delicate balance between immunosuppression, anti-tumor effect of immune checkpoint inhibitor therapy, and quality of life. The multidisciplinary care of cancer patients with adverse events is critical to optimizing clinical and translational research outcomes and, as such, dermatologists are vital to moving the study of cutaneous adverse events forward.

The impact of clean intermittent catheterization on students and families in the school environment.

INTRODUCTION: Clean intermittent catheterization (CIC) is often used for bladder emptying in children with lower urinary tract dysfunction. Until recently, the emphasis in assessing the effects of CIC has been on preserving kidney function, reducing urinary tract infection, and achieving urinary continence. Few studies have investigated the impact of CIC on students and families in a school setting. This study sought to examine what students and caregivers experienced when CIC was required during the school day and how schools adjusted to a student needing to perform it. MATERIALS AND METHODS: A phenomenological approach utilizing semistructured interviews was performed to understand the impact of CIC on students. Purposeful sampling identified eligible families. A guide was developed from expert opinion validated by a pilot sample with feedback collated into a family/provider codesigned questionnaire. Interviews emphasized the impact and challenges students faced at school. Transcripts were coded using Dedoose software with emerging themes identified and a code book was created for closed coding that led to thematic analysis. RESULTS: A total of 40 families (52 caregivers and children > 12 years) were interviewed. Emergent themes included: Caregivers and students felt (1) school personnel were not always aware of nor prepared regarding the implications of CIC; (2) school bathrooms were often less than ideal (e.g., location, size, cleanliness, privacy, and availability); and (3) student participation in extracurricular activities was challenging. CONCLUSIONS: This study identifies potential areas of intervention in meeting the needs of students who require CIC and the importance of having collaborative efforts of caregivers, health care providers, and school personnel in addressing and meeting CIC needs. Care coordination that involves consistent communication and careful planning between health care teams, school personnel, students, and caregivers can optimize a student's educational experience.

Diagnosis and Management of Dermatologic Adverse Events from Systemic Melanoma Therapies.

The advent of protein kinase inhibitors and immunotherapy has profoundly improved the management of advanced melanoma. However, with these therapeutic advancements also come drug-related toxicities that have the potential to affect various organ systems. We review dermatologic adverse events from targeted (including BRAF and MEK inhibitor-related) and less commonly used melanoma treatments, with a focus on diagnosis and management. As immunotherapy-related toxicities have been extensively reviewed, herein, we discuss injectable talimogene laherparepvec and touch on recent breakthroughs in the immunotherapy space. Dermatologic adverse events may severely impact quality of life and are associated with response and survival. It is therefore essential that clinicians are aware of their diverse presentations and management strategies.

Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.

Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), restricts growth and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Both TAL and AR are confined to the cytosol; however, their inactivation distorts mitochondrial redox homeostasis in opposite directions. The results suggest that AR acts as a rheostat of carbon recycling and NADPH output of the PPP with broad implications for disease progression from cirrhosis to HCC.

In situ measurements of reef squid polarization patterns using two-dimensional polarization data mapped onto three-dimensional tessellated surfaces.

Reef squids belong to a group reputed for polarization sensitivity, yet polarization patterns of reef squid have not been quantified in situ. To quantify polarization patterns from video polarimetric data, we developed a protocol to map two-dimensional polarization data onto squid-shaped three-dimensional tessellated surfaces. This protocol provided a robust data container used to investigate three-dimensional regions-of-interest, producing data lineouts derived from the squid's geometry. This protocol also extracted polarimeter and squid body orientations and the solar heading from polarization images. When averaged over the solar heading, the ventral midline gave a low degree of polarization (2.4 ± 5.3%), and the area between the ventral and flank midlines had higher values (9.0 ± 5.3%). These averaged data had a large discontinuity in the angle of polarization (AoP) at the mantle's ventral midline (64 ± 55°), with larger discontinuities measured on individual squid. Ray-tracing calculations demonstrated that the AoP pattern was not related to the squid's surface-normal geometry. However, the AoP followed virtual striation axes on the squid's surface oriented 24° to the squid's long axis, similar in angle (27°) to the striations of birefringent collagen fibres documented in other squid species' skin.

Current Insights in the Evaluation and Treatment of Infected Total Knee Arthroplasty.

Total knee arthroplasty is a widely successful procedure, but a small percentage of patients have a postoperative course complicated by periprosthetic joint infection (PJI). PJI is a difficult problem to diagnose and to treat, and the management of PJI differs, depending on the acuity of the infection. This paper discusses the established and newer technologies developed for the diagnosis of PJI as well as different treatment considerations and surgical solutions currently available.

What is the Level of Evidence Substantiating Commercial Payers' Coverage Policies for Total Joint Arthroplasty?

BACKGROUND: The prevalence of total joint arthroplasty (TJA) in the United States has drawn the attention of health care stakeholders. The payers have also used a variety of strategies to regulate the medical necessity of these procedures. The purpose of this study was to examine the level of evidence of the coverage policies being used by commercial payers in the United States. METHODS: The references of the coverage policies of four commercial insurance companies were reviewed for type of document, level of evidence, applicability to a TJA population, and success of nonoperative treatment in patients with severe degenerative joint disease. RESULTS: 282 documents were reviewed. 45.8% were primary journal articles, 14.2% were level I or II, 41.2% were applicable to patients who were candidates for TJA, and 9.9% discussed the success of nonoperative treatment in patients who would be candidates for TJA. CONCLUSION: Most of the references cited by commercial payers are of a lower level of scientific evidence and not applicable to patients considered to be candidates for TJA. This is relatively uniform across the reviewed payers. The dearth of high-quality literature cited by commercial payers reflects the lack of evidence and difficulty in conducting high level studies on the outcomes of nonoperative versus operative treatment for patients with severe, symptomatic osteoarthritis. Patients, surgeons, and payers would all benefit from such studies and we encourage professional societies to strive toward that end through multicenter collaboration.

Resorbable Pins to Enhance Scaffold Retention in a Porcine Chondral Defect Model.

OBJECTIVE: Cartilage repair strategies have seen improvement in recent years, especially with the use of scaffolds that serve as a template for cartilage formation. However, current fixation strategies are inconsistent with regards to retention, may be technically challenging, or may damage adjacent tissues or the implant itself. Therefore, the goal of this study was to evaluate the retention and repair potential of cartilage scaffolds fixed with an easy-to-implement bioresorbable pin. DESIGN: Electrospun hyaluronic acid scaffolds were implanted into trochlear groove defects in 3 juvenile and 3 adult pigs to evaluate short-term retention (2 weeks; pin fixation vs. press-fit and fibrin fixation) and long-term repair (8 months; scaffold vs. microfracture), respectively. RESULTS: For the retention study, press-fit and fibrin fixation resulted in short-term scaffold dislodgment (n = 2 each), whereas pin fixation retained all scaffolds that were implanted (n = 6). Pin fixation did not cause any damage to the opposing patellar surface, and only minor changes in the subchondral bone were observed. For long-term repair, no differences were observed between microfracture and scaffold groups, in terms of second-look arthroscopy and indentation testing. On closer visualization with micro computed tomography and histology, a high degree of variability was observed between animals with regard to subchondral bone changes and cartilage repair quality, yet each Scaffold repair displayed similar properties to its matched microfracture control. CONCLUSIONS: In this study, pin fixation did not cause adverse events in either the short- or the long-term relative to controls, indicating that pin fixation successfully retained scaffolds within defects without inhibiting repair.

Five-year survival in patients with nodular and superficial spreading melanomas in the US population.

BACKGROUND: Although superficial spreading melanomas (SSM) are diagnosed as thinner lesions, nodular melanomas (NM) have a more rapid growth rate and are biologically more aggressive compared with other histologic subtypes. OBJECTIVE: To determine the difference in 5-year relative survival in patients with NM and SSM at the same Breslow depth and TNM stage. METHODS: A population-based cross-sectional analysis compared the 5-year relative survival of patients with NM and SSM using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)∗Stat software (version 8.2.1-8.3.5). Chi-square tests compared the proportions, and Kaplan-Meier method with Z-score compared 5-year relative survival. RESULTS: For patients receiving a diagnosis between 2004 and 2009, 5-year relative survival was lower in NM compared with SSM (53.7% vs 87.3%; Z score, -41.35; P < .001). Similarly, for patients receiving a diagnosis between 2010 and 2015, 5-year relative survival was lower in NM compared with SSM (61.5% vs 89.7%; Z score, -2.7078; P < .01). Subgroup analyses showed inferior survival in NM in T1b, and survival differences remained significant after excluding patients with nodal or distant metastases. CONCLUSIONS: Five-year relative survival is worse in NM compared with SSM especially in T1b, T2a, and T2b melanomas. Melanoma subtype should be taken into consideration when making treatment recommendations.

Assessing the effectiveness of a pediatrician-led newborn parenting class on maternal newborn-care knowledge, confidence and anxiety: A quasi-randomized controlled trial.

BACKGROUND: The postpartum hospital stay is a unique opportunity for clinicians to educate parents on the importance of promoting early child development. Pediatricians are well-positioned to address both medical and developmental concerns during critical periods of development, yet very few parenting interventions are led by pediatricians. AIMS: To assess the impact of a novel one-hour long pediatrician-led Newborn Class on maternal knowledge, confidence, and anxiety. METHODS: We conducted a quasi-randomized controlled trial to evaluate the effectiveness of the Newborn Class. First-time mothers who delivered a full-term singleton vaginally with no major complications and attended the class were recruited. Mothers who expressed a desire to attend the class but were discharged before a class was offered served as controls. OUTCOME MEASURES: Maternal self-perceived parental confidence and anxiety were measured using standardized scales [Karitane Parenting Confidence Scale (KPCS) and State-Trait Anxiety Inventory for Adults (STAI-AD)]. Knowledge on newborn care was assessed using a novel scale. RESULTS: A total of 84 participants (intervention n = 36, control n = 48) were included in the study. Mothers who attended the class showed significantly higher levels of knowledge compared to the control group (Knowledge test, Two-tailed t-test, mean [SD], 8.08 [1.06] vs 6.78 [1.25]; P<0.001) as well as significantly higher parenting confidence levels (KPCS, Two-tailed t-test, mean [SD], 39.31 [3.88] vs 35.20 [3.99]; P<0.001). No change was observed in the overall level of anxiety (STAI-AD, Two-tailed t-test, mean [SD], 35.50 [8.73] vs 38.5 [9.53]; P=0.164). CONCLUSIONS: A short pediatrician-led parenting intervention may be an effective tool in improving maternal confidence and newborn care knowledge. Given the importance of the newborn period in establishing healthy developmental trajectories, there is a crucial need for cost- and time-effective intervention that can be widely implemented to promote parental knowledge and confidence with the ultimate goal of fostering healthy development in children.

The journey to advanced practice: An Interpretative Phenomenological Analysis of reaching destination and beyond for reporting radiographers in Scotland.

INTRODUCTION: Optimising radiographer and radiologist skill-mix is essential to increase efficiency and ensure quality patient care and safety in radiology services. Radiographer reporting, well established within the UK, has been legally and legitimately identified within the scope of radiographer practice for many years. Little research however has focused on perceptions and experiences of practitioners as they journey towards advanced practice in skeletal trauma reporting. METHODS: A two-phase qualitative approach, utilising Interpretative Phenomenological Analysis (IPA), included a homogenous group of radiographer practitioners (n = 12). Phase 1 thematically analysed personal reflective diaries. Phase 2 included one-one, semi-structured interviews which were recorded, transcribed verbatim and reviewed using the IPA six stage thematic analysis. RESULTS: Three super-ordinate themes emerged. This paper reflects the IPA generated from Super-ordinate Theme 3; Review upon and action for the role. Participants had reached destination and beyond with a focus on development of role, self and others. As reporting became firmly embedded, there was increased acceptance, educational development and positive impact on service. Reflections indicated motivation, drive, commitment, increased confidence and self-esteem CONCLUSION: This study provides an insight in to the participant journey towards advanced practice and skeletal trauma reporting in Scotland as participants reached destination and beyond. IMPLICATIONS FOR PRACTICE: Developments within the NHS continue to rapidly evolve and diagnostic imaging, with advancing technology, practice and changing policies, continues to remain in a constant state of change. Continued support and investment for role development, framed within a culture of effective teamworking, positive engagement and professional respect is essential.

Theory and application of research principles and philosophical underpinning for a study utilising interpretative phenomenological analysis.

INTRODUCTION: Qualitative research approaches have potential to provide unique and valuable insights intoperceptions, experiences and behaviours. Reports however indicate that papers often fail to sufficiently detail the underlying principles that explain the philosophical assumptions and ontological, epistemological and methodological perspectives. Primarily directed towards radiographers considering a qualitative approach for doctoral research, this paper will also be informative for other health and social care practitioners. METHOD: Part 1 discusses research principles broadly and how philosophical assumptions can be used for selection of the approach and methodology to explore a particular topic. Part 2 provides a worked example applied in context for a qualitative approach utilising Interpretative Phenomenological Analysis (IPA), that explored perceptions and experiences of lived experiences of radiographers on a journey to advanced practice in skeletal trauma reporting. RESULTS: The paper identifies the need for understanding of the theory and application of research principles broadly. Explanation and justification of choice is expected for the selection of research approach, paradigm, philosophical underpinning, underlying assumptions and methodology, to best answer the research question and inform participant selection, data collection, data analysis and interpretation methods CONCLUSION: Coherent research requires synthesis of ontology, epistemology and methodology with the choice of research design based on the most appropriate approach. Qualitative research has greatly enhanced its reputation for methodological rigour and the uptake of IPA is increasing within health and social care. IMPLICATIONS FOR PRACTICE: Future research within the Interpretative paradigm, utilising IPA as a methodology has potential to expand the body of evidence for Radiography research.

Lower Extremity Total Joint Arthroplasty Has Minimal Effect on Golf Handicap.

Although the vast majority of arthroplasty surgeons allow patients to return to participation in golf following total knee arthroplasty (TKA) and total hip arthroplasty (THA), there is relatively little published data regarding how TKA or THA affects a patient's golfing ability. The purpose of this study was to determine how golfers' handicaps change following TKA and THA. We mailed a questionnaire to patients who had underwent primary TKA or THA at our institution and asked whether they played golf and for their golf handicap information network (GHIN) number. We then obtained handicap data for each patient that provided a GHIN number. Handicap increased 0.9 strokes 1 year following THA; however, this difference was not statistically significant (p = 0.20). Handicap increased 0.3 strokes 1 year following TKA; however, this difference was not statistically significant (p = 0.29). Our study demonstrates that despite improved implants, surgical techniques, and rehabilitation protocols that golf handicap does not change significantly following lower extremity total joint arthroplasty (TJA). (Journal of Surgical Orthopaedic Advances 29(4):216-218, 2020).

Phosphorylation-dependent protein design: design of a minimal protein kinase-inducible domain.

Protein kinases and phosphatases modulate protein structure and function, which in turn regulate cellular activities. The development of novel proteins and protein motifs that are responsive to protein phosphorylation provides new ways to probe the functions of individual protein kinases and the intracellular effects of their activation and downregulation. Herein we develop a minimal motif that is responsive to protein phosphorylation, termed a minimal protein kinase-inducible domain. The encodable protein motif comprises a 7- or 8-residue sequence (DKDADXW or DKDADXXW), derived from EF-Hand calcium-binding domains, that is necessary but not sufficient for binding terbium, combined with a protein phosphorylation site (Ser or Thr at residue 9) that, upon phosphorylation, completes the metal-binding motif. Thus, the motif binds metal poorly and exhibits weak terbium luminescence when not phosphorylated. Upon phosphorylation, the peptide binds metal with significantly higher affinity and exhibits robust terbium luminescence. Phosphorylation results in up to a 23× increase in terbium luminescence. Minimal phosphorylation-dependent motifs as small as 9 residues (DKDADGWIS) were developed. NMR spectroscopy on this lanthanum(iii)·phosphopeptide complex confirmed that binding occurs in a manner similar to that in an EF-Hand, despite the absence of the conserved Glu12 typically present in an EF-Hand. By combining molecular design with known protein kinase recognition sequences, minimal protein kinase-inducible domains were developed that were responsive to phosphorylation by Protein Kinase A (PKA: DKDADRRW(S/pS)IIAK), Protein Kinase C (PKC: DKDADGWI(T/pT)FRRKA), and Casein Kinase 1 (CK1: DKDADDWA(S/pS)I). Phosphorylation by PKA was quantified in HeLa cell extracts, with a 4.4× increase in fluorescence (terbium luminescence) observed at 544 nm. The optimized minimal motif includes alternating aspartate residues at positions 1, 3, and 5, plus binding through the main-chain carbonyl at position 7; a lysine at position 2 to provide electrostatic balance and reduce binding in the absence of phosphorylation; an alanine at residue 4 to promote the αL conformation observed at that position of the EF Hand; a tryptophan at residue 7 or 8 to sensitize terbium luminescence; and a phosphorylation site with serine or threonine at residue 9. Residues at positions 6; 7 or 8; and 10 or later may be changed to provide kinase specificity. In the CK1-responsive peptide, the acidic residues in the proto-terbium-binding motif are employed as part of the kinase recognition sequence. This work thus presents fundamental rules for the design of compact phosphorylation-responsive terbium-binding motifs, with potential further application to motifs responsive to other protein post-translational modifications.

Association of sedentary behavior and metabolic syndrome.

OBJECTIVES: To examine the association of sedentary behavior (SB) with metabolic syndrome (MetS) in adults, as well as to identify the impact of physical inactivity and economic condition on such association. STUDY DESIGN: This is a cross-sectional study. METHODS: This study was conducted in the city of Bauru, São Paulo State, Brazil (n = 970). Television (TV) viewing and physical activity (PA) were assessed by questionnaire. MetS was assessed via medical records. Descriptive statistics and binary logistic regression were used in data analyses. RESULTS: Participants with moderate TV viewing were associated with MetS when compared with low TV viewing group, even after adjustments for age, sex, economic status, smoking, and PA (odds ratio [OR] = 1.49 [95% confidence interval {CI}: 1.01-2.20]). The fully adjusted model showed an association between high exposure to TV viewing with MetS (OR = 1.77 [95%CI: 1.11-2.82]). The combination of physical inactivity and high TV viewing boosted the likelihood of having MetS (OR = 1.89 [95%CI: 1.08-3.29]). CONCLUSION: The results of the present study suggest that moderate and high TV viewing time is associated with the presence of MetS, mainly in insufficiently active adults and those living in lower economic condition.

Interpersonal Violence and Maxillofacial Fractures.

PURPOSE: Accident Compensation Corporation statistics shows that maxillofacial fracture affects 11,000 people with an approximate $90 million annual cost in New Zealand dollars (NZD). Previous studies have demonstrated interpersonal violence (IPV), road traffic accidents (RTAs), sports injury, and falls being the common causes of maxillofacial fracture. This study investigated the causes and associated alcohol and/or drug use and fracture patterns in patients presenting with maxillofacial fractures in the Wellington region. SUBJECTS AND METHODS: Demographic data of the patients, the cause of maxillofacial fracture and associated alcohol and/or drug use, and the fracture patterns were culled from our prospective maxillofacial fracture database at Hutt Hospital for a 5-year period from January 01, 2013, to December 31, 2017 and analyzed. RESULTS: A total of 1535 patients were referred with maxillofacial fractures during the study. 38% of the maxillofacial fractures were caused by IPV, followed by sports injury (24%), falls (24%), and RTA (6%), with 33.4% associated with alcohol and/or drug use. Males were six times more likely to present with IPV-related maxillofacial fractures, compared to females. The 16-30-year age group was the most prevalent in the IPV group with NZ Maori attributing to significantly more maxillofacial fractures compared to NZ European, 54.6% vs. 32.0% (P < 0.0001). CONCLUSIONS: IPV, especially involving alcohol and/or drug use, is the most common cause of maxillofacial fractures in the Wellington region, especially in NZ Maori males aged 16-30 years. Public health strategies are needed to decrease IPV as a cause of maxillofacial fractures.

Individuals with obesity but no other metabolic risk factors are not at significantly elevated all-cause mortality risk in men and women.

Studies have examined mortality risk for metabolically healthy obesity, defined as zero or one metabolic risk factors but not as zero risk factors. Thus, we sought to determine the independent mortality risk associated with obesity or elevated glucose, blood pressure or lipids in isolation or clustered together. The sample included 54 089 men and women from five cohort studies (follow-up = 12.8 ± 7.2 years and 4864 [9.0%] deaths). Individuals were categorized as having obesity or elevated glucose, blood pressure or lipids alone or clustered with obesity or another metabolic factor. In our study sample, 6% of individuals presented with obesity but no other metabolic abnormalities. General obesity (hazard ratios [HR], 95% CI = 1.10, 0.8-1.6) and abdominal obesity (HR = 1.24, 0.9-1.7) in the absence of metabolic risk factors were not associated with mortality risk compared to lean individuals. Conversely, diabetes, hypertension and dyslipidaemia in isolation were significantly associated with mortality risk (HR range = 1.17-1.94, P < 0.05). However, when using traditional approaches, obesity (HR = 1.12, 1.02-1.23) is independently associated with mortality risk after statistical adjustment for the other metabolic risk factors. Similarly, metabolically healthy obesity, when defined as zero or one risk factor, is also associated with increased mortality risk (HR = 1.15, 1.01-1.32) as compared to lean healthy individuals. Obesity in the absence of metabolic abnormalities may not be associated with higher risk for all-cause mortality compared to lean healthy individuals. Conversely, elevation of even a single metabolic risk factor is associated with increased mortality risk.