Perspectives on incorporating expert feedback into model updates.

Machine learning (ML) practitioners are increasingly tasked with developing models that are aligned with non-technical experts' values and goals. However, there has been insufficient consideration of how practitioners should translate domain expertise into ML updates. In this review, we consider how to capture interactions between practitioners and experts systematically. We devise a taxonomy to match expert feedback types with practitioner updates. A practitioner may receive feedback from an expert at the observation or domain level and then convert this feedback into updates to the dataset, loss function, or parameter space. We review existing work from ML and human-computer interaction to describe this feedback-update taxonomy and highlight the insufficient consideration given to incorporating feedback from non-technical experts. We end with a set of open questions that naturally arise from our proposed taxonomy and subsequent survey.

Pelvic Floor Dysfunction After Hysterectomy: Moving the Investigation Forward.

The role of hysterectomy in the development of pelvic floor dysfunction (PFD) remains widely disputed. The controversy is fueled by two key factors. The first is conflicting association studies that make it difficult to establish whether a link truly exists. Although many retrospective studies report a correlation between hysterectomy and increased risk of stress urinary incontinence (SUI) or pelvic organ prolapse (POP), prospective studies often fail to replicate these results, leading some to conclude that no association exists. However, most prospective studies do not follow up for a sufficient length of time to account for the long latency of PFD and cannot unilaterally prove the absence of an association. The second source of controversy is the absence of a plausible mechanism to explain how hysterectomy could predispose patients to PFD. In this paper, we investigate autonomic innervation and smooth muscle in the three layers of pelvic floor support and propose a mechanism through which autonomic damage from hysterectomy could predispose patients to PFD. We then identify key research areas needed to evaluate this theory. This report aims to inspire a discussion on how to further the collective understanding of the relationship between hysterectomy and PFD. Clarifying the nature of this connection could have enormous consequences in redefining the risks and benefits of hysterectomy.

Development and modelling of realistic retrofitted Nature-based Solution scenarios to reduce flood occurrence at the catchment scale.

Decentralized Nature-based Solutions such as Urban Green Infrastructures (UGI) are increasingly promoted to reduce flooding in urban areas. Many studies have shown the effectiveness of flood control of UGI at a plot or neighbourhood level. Modelling approaches that extrapolate their flood reducing impact to larger catchment scales are often based on a simplistic assumption of different percentages of UGI implementation. Additionally, such approaches typically do not consider the suitable space for UGI and potential implementation constraints. This study proposes a scenario development and modelling approach for a more realistic upscaling of UGI based on empirical insights from a representative neighbourhood. The results from this study, conducted in the metropolitan area of Costa Rica, show that upscaling the full potential for UGI could significantly reduce surface runoff, peak flows, and flood volumes. In particular, the permeable pavement has the highest potential for flood reducing in public space while cisterns perform best at the property level. These results can guide the formation of policies that promote UGI.

Measurement of filtration efficiencies of healthcare and consumer materials using modified respirator fit tester setup.

During the current SARS-CoV-2 pandemic there is unprecedented demand for personal protective equipment (PPE), especially N95 respirators and surgical masks. The ability of SARS-CoV-2 to be transmitted via respiratory droplets from asymptomatic individuals has necessitated increased usage of both N95 respirators in the healthcare setting and masks (both surgical and homemade) in public spaces. These precautions rely on two fundamental principles of transmission prevention: particle filtration and droplet containment. The former is the focus of NIOSH N95 testing guidelines, and the latter is an FDA guideline for respirators and surgical masks. While studies have investigated droplet containment to provide guidance for homemade mask production, limited work has been done to characterize the filtration efficiency (FE) of materials used in home mask making. In this work, we demonstrate the low-cost (<$300) conversion of standard equipment used to fit-test respirators in hospital and industrial settings into a setup that measures quantitative FEs of materials based on NIOSH N95 guidelines, and subsequently measure FEs of materials found in healthcare and consumer spaces. These materials demonstrate significant variability in filtration characteristics, even for visually similar materials. We demonstrate a FE of 96.49% and pressure drop of 25.4 mmH20 for a double-layer of sterilization wrap used in surgical suites and a FE of 90.37% for a combination of consumer-grade materials. The excellent filtration characteristics of the former demonstrate potential utility for emergent situations when N95 respirators are not available, while those of the latter demonstrate that a high FE can be achieved using publicly available materials.

Membrane orientation and oligomerization of the melanocortin receptor accessory protein 2.

The melanocortin receptor accessory protein 2 (MRAP2) plays a pivotal role in the regulation of several G protein-coupled receptors that are essential for energy balance and food intake. MRAP2 loss-of-function results in obesity in mammals. MRAP2 and its homolog MRAP1 have an unusual membrane topology and are the only known eukaryotic proteins that thread into the membrane in both orientations. In this study, we demonstrate that the conserved polybasic motif that dictates the membrane topology and dimerization of MRAP1 does not control the membrane orientation and dimerization of MRAP2. We also show that MRAP2 dimerizes through its transmembrane domain and can form higher-order oligomers that arrange MRAP2 monomers in a parallel orientation. Investigating the molecular details of MRAP2 structure is essential for understanding the mechanism by which it regulates G protein-coupled receptors and will aid in elucidating the pathways involved in metabolic dysfunction.

Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding.

The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ increases the affinity and potency of the endogenous agonist α-melanocyte-stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)-independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein-coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.

Are systemic antibiotics required during and after dacryocystitis-related dacryocystorhinostomy?

PURPOSE: To compare the outcomes of patients with and without a history of dacryocystitis that undergo dacryocystorhinostomy without systemic intra- and post-operative antibiotics. METHODS: A retrospective review was performed to identify all cases of patients that received surgery under this paradigm and had at least three months of follow up care. Key demographic and outcome data were captured, and a statistical analysis was performed via a dedicated software package (Microsoft Excel, Redmond, WA). RESULTS: For the study period, 83 patients without and 69 patients with a history of dacryocystitis were identified, and the two groups were not statistically significantly different in age, gender, or postoperative follow up duration (mean = 6.4 months for patients without and 6.3 months for those with dacryocystitis, respectively). No patient developed a postoperative infection or a recurrence of dacryocystitis during the follow up period. DISCUSSION: While many surgeons routinely use systemic antibiotics in patients with a history of dacryocystitis who undergo dacryocystorhinostomy, these agents may not be necessary. As a result, patients may be able to avoid the complications and side effects inherent to systemic antibiotics. Large-scale, prospective studies will likely help to further clarify this issue.

Charge Characteristics of Agouti-Related Protein Implicate Potent Involvement of Heparan Sulfate Proteoglycans in Metabolic Function.

The endogenous melanocortin peptide agouti-related protein (AgRP) plays a well-known role in foraging, but its contribution to metabolic regulation is less understood. Mature AgRP(83-132) has distinct residues for melanocortin receptor binding and heparan sulfate interactions. Here, we show that AgRP increases ad libitum feeding and operant responding for food in mice, decreases oxygen consumption, and lowers body temperature and activity, indicating lower energy expenditure. AgRP increased the respiratory exchange ratio, indicating a reduction of fat oxidation and a shift toward carbohydrates as the primary fuel source. The duration and intensity of AgRP's effects depended on the density of its positively charged amino acids, suggesting that its orexigenic and metabolic effects depend on its affinity for heparan sulfate. These findings may have major clinical implications by unveiling the critical involvement of interactions between AgRP and heparan sulfate to the central regulation of energy expenditure, fat utilization, and possibly their contribution to metabolic disease.

Preoperative Intravenous Ketorolac Safely Reduces Postoperative Pain in Levator Advancement Surgery.

PURPOSE: To assess the impact of intravenous ketorolac (IVK) on self-reported pain scores, requirements for opioid analgesic and anti-emetic medications, and bleeding complications in the setting of levator advancement surgery METHODS:: A prospective randomized controlled trial was performed among adult patients undergoing levator advancement surgery. Pain scores were measured immediately after surgery, prior to discharge from the surgical facility, and on the first postoperative day. The requirements for postoperative analgesic and anti-emetic medications were recorded. Statistical comparisons were performed via a dedicated computerized software package. RESULTS: Fifty patients (20 males, 30 females, mean age = 65.7 years, standard deviation = 11.9 years) underwent levator advancement without IVK and acted as controls. An additional 50 patients received IVK (19 males, 31 females, mean age = 64.6 years, standard deviation = 12.0 years). As compared with control patients, IVK resulted in statistically significant reductions in pain score immediately after surgery (4.62 vs. 1.44, p = 0.0001) and on postoperative day 1 (3.22 vs. 1.24, p = 0.0001). Fourteen patients (28%) in the control and 4 patients (8%) in the group that received IVK required opioid analgesics (p = 0.017). Seven patients (14%) in the control group and 1 patient in the group that received IVK required anti-emetic medications (p = 0.059). No patient experienced a hemorrhagic complication. CONCLUSIONS: In the setting of levator advancement surgery, IVK results in a dramatic reduction in self-reported pain score immediately after surgery and on postoperative day 1 and the requirement for opioid analgesics. This medication may be safely utilized for ptosis repair.

Late onset obesity in mice with targeted deletion of potassium inward rectifier Kir7.1 from cells expressing the melanocortin-4 receptor.

Energy stores in fat tissue are determined in part by the activity of hypothalamic neurones expressing the melanocortin-4 receptor (MC4R). Even a partial reduction in MC4R expression levels in mice, rats or humans produces hyperphagia and morbid obesity. Thus, it is of great interest to understand the molecular basis of neuromodulation by the MC4R. The MC4R is a G protein-coupled receptor that signals efficiently through GαS , and this signalling pathway is essential for normal MC4R function in vivo. However, previous data from hypothalamic slice preparations indicated that activation of the MC4R depolarised neurones via G protein-independent regulation of the ion channel Kir7.1. In the present study, we show that deletion of Kcnj13 (ie, the gene encoding Kir7.1) specifically from MC4R neurones produced resistance to melanocortin peptide-induced depolarisation of MC4R paraventricular nucleus neurones in brain slices, resistance to the sustained anorexic effect of exogenously administered melanocortin peptides, late onset obesity, increased linear growth and glucose intolerance. Some MC4R-mediated phenotypes appeared intact, including Agouti-related peptide-induced stimulation of food intake and MC4R-mediated induction of peptide YY release from intestinal L cells. Thus, a subset of the consequences of MC4R signalling in vivo appears to be dependent on expression of the Kir7.1 channel in MC4R cells.

Review of periorbital nerve enlargement and biopsy techniques.

Periorbital nerve enlargement commonly indicates perineural invasion of malignancy or inflammatory conditions. This study reviews the role of supraorbital and infraorbital nerve biopsies in patients presenting with radiographic enlargement and to elucidate the surgical technique involved. A retrospective chart review (1997-2014) was performed at a single tertiary center. Patients with radiographic confirmation of enlarged supraorbital/infraorbital nerves that underwent biopsy were included. Charts were reviewed for: patient demographics and history, clinical symptoms and findings, radiographic findings, surgical method, and treatment. Five patients (4 female, 1 male) met inclusion criteria. Average age was 72.4 years (range 36-90). Four patients had history of cutaneous malignancy. All presented with diplopia and/or dysesthesias. Clinical examination confirmed decreased V1 and/or V2 sensation for 4 patients. Imaging revealed enlargement of V1, V2, and/or V3 in all patients. Infraorbital nerve biopsies were performed in 3 patients via transconjunctival fornix-based orbitotomy with subperiosteal dissection along orbital floor followed by unroofing of infraorbital canal. The remaining 2 underwent supraorbital nerve biopsy via sub-brow incision onto superior orbital rim with reflection of periosteum. Biopsies confirmed squamous cell carcinoma(3), mucoepidermoid carcinoma(1), and idiopathic orbital inflammation(1). Three patients initiated treatment in <1 month. One decided to follow-up closer to home, one was lost to follow-up. For patients presenting with enlarged supraorbital/infraorbital nerves, biopsy can rapidly confirm the underlying condition and facilitate early treatment. A sub-brow approach offers direct access to supraorbital nerve while transconjunctival fornix-based anterior orbitotomy with canal unroofing allows access to infraorbital nerve.

A Concomitant Case of Orbital Granuloma Faciale and Eosinophilic Angiocentric Fibrosis.

Granuloma faciale is an eosinophilic dermatosis that typically presents as red-brown facial plaques of middle-aged white men, while eosinophilic angiocentric fibrosis is a histologically similar fibrotic condition affecting the respiratory mucosa. Both are very uncommon conditions and pose a therapeutic challenge. While a handful of reports have reported concurrent presentation, the authors present the first case of eyelid granuloma faciale with eosinophlilic angiocentric fibrosis.

Correction: Human ß-D-3 Exacerbates MDA5 but Suppresses TLR3 Responses to the Viral Molecular Pattern Mimic Polyinosinic:Polycytidylic Acid.

[This corrects the article DOI: 10.1371/journal.pgen.1005673.].

Human ß-Defensin 3 [corrected] Exacerbates MDA5 but Suppresses TLR3 Responses to the Viral Molecular Pattern Mimic Polyinosinic:Polycytidylic Acid.

Human ß-defensin 3 (hBD3) is a cationic host defence peptide and is part of the innate immune response. HBD3 is present on a highly copy number variable block of six ß-defensin genes, and increased copy number is associated with the autoimmune disease psoriasis. It is not known how this increase influences disease development, but psoriasis is a T cell-mediated disease and activation of the innate immune system is required for the initial trigger that leads to the amplification stage. We investigated the effect of hBD3 on the response of primary macrophages to various TLR agonists. HBD3 exacerbated the production of type I Interferon-ß in response to the viral ligand mimic polyinosinic:polycytidylic acid (polyI:C) in both human and mouse primary cells, although production of the chemokine CXCL10 was suppressed. Compared to polyI:C alone, mice injected with both hBD3 peptide and polyI:C also showed an enhanced increase in Interferon-ß. Mice expressing a transgene encoding hBD3 had elevated basal levels of Interferon-ß, and challenge with polyI:C further increased this response. HBD3 peptide increased uptake of polyI:C by macrophages, however the cellular response and localisation of polyI:C in cells treated contemporaneously with hBD3 or cationic liposome differed. Immunohistochemistry showed that hBD3 and polyI:C do not co-localise, but in the presence of hBD3 less polyI:C localises to the early endosome. Using bone marrow derived macrophages from knockout mice we demonstrate that hBD3 suppresses the polyI:C-induced TLR3 response mediated by TICAM1 (TRIF), while exacerbating the cytoplasmic response through MDA5 (IFIH1) and MAVS (IPS1/CARDIF). Thus, hBD3, a highly copy number variable gene in human, influences cellular responses to the viral mimic polyI:C implying that copy number may have a significant phenotypic effect on the response to viral infection and development of autoimmunity in humans.

Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products.

Many cyclic peptide natural products are larger and structurally more complex than conventional small molecule drugs. Although some molecules in this class are known to possess favorable pharmacokinetic properties, there have been few reports on the membrane permeabilities of cyclic peptide natural products. Here, we present the passive membrane permeabilities of 39 cyclic peptide natural products, and interpret the results using a computational permeability prediction algorithm based on their known or calculated 3D conformations. We found that the permeabilities of these compounds, measured in a parallel artificial membrane permeability assay, spanned a wide range and demonstrated the important influence of conformation on membrane permeability. These results will aid in the development of these compounds as a viable drug paradigm.

The effect of noise-cancelling headphones or music on pain perception and anxiety in men undergoing transrectal prostate biopsy.

OBJECTIVE: To assess the effect of noise-cancelling headphones with or without music on patient pain and anxiety associated with routine, office-based transrectal ultrasound (TRUS)-guided prostate biopsy in a prospective randomized study. METHODS: Patients scheduled for prostate biopsy as a result of elevated prostate-specific antigen and/or abnormal digital rectal examination were prospectively enrolled and randomized into a control, noise-cancelling headphones, or music-headphones group. Patients completed pain and anxiety questionnaires and had their physiological parameters assessed before and after the procedure and compared across groups. RESULTS: Eighty-eight patients were enrolled. Pain scores increased from baseline across all study groups, with the lowest mean score in the music group. No appreciable change was noted in anxiety scores after the procedure between groups (P>.05). Although postbiopsy systolic blood pressure values remained comparable with baseline levels in all groups, postbiopsy diastolic blood pressure increased in the control and headphones groups (P=.062 and .088, respectively) but remained stable in the music group (P=.552) after biopsy, indicating lesser physiological response to anxiety and pain in this group. CONCLUSION: Music-induced attention shift during prostate biopsy may have a beneficial impact on procedural anxiety and pain perception, but no apparent effect was noted for use of headphones alone. Further studies are necessary to explore strategies to reduce perceived anxiety and pain in men undergoing prostate biopsy.

Complications of laparoscopic and percutaneous renal cryoablation in a single tertiary referral center.

BACKGROUND: Laparoscopic cryoablation (LCA) and percutaneous cryoablation (PCA) of small renal masses have gained popularity, but only limited data exist on the complication rates. OBJECTIVES: In this study, we report on postoperative complications associated with LCA and PCA in a single tertiary center experience. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective review of electronic medical records for patients undergoing LCA or PCA between 2001 and 2008 at our institution. INTERVENTIONS: All patients underwent LCA or PCA. MEASUREMENTS: Demographics, radiographic variables, and complication rates were compared between the two groups. Complications were classified according to the modified Clavien system. RESULTS AND LIMITATIONS: Of a total of 195 patients included in this study, 72 underwent LCA and 123 underwent PCA. There were no differences in demographics between the groups. We observed complications in 10 LCA procedures (13.9%) and 26 PCA procedures (21.1%) (p=0.253). The distribution of the complications differed significantly between the groups with mild complications (grades 1 and 2) more common in the PCA group (20.3% vs 5.6%, respectively; p=0.001), whereas severe events (grades 3 and 4) were more frequent in the LCA group (8.3% vs 0.8%, respectively; p=0.011). On multivariate analysis, age and body mass index were inversely associated with complications, whereas female gender, multiple tumors, and preexisting comorbidities showed a trend toward increased risk. CONCLUSIONS: LCA and PCA, although minimally invasive, are not void of complications. Most of the complications encountered are mild; however, severe (grade 3 or 4) events may occur in up to 3.6% of patients. PCA may be associated with a higher rate of complications, although most of these are mild and transient. However, on multivariate analysis, the chosen ablative approach (laparoscopic or percutaneous) is not associated with the risk of complications.

Utility of a 3-dimensional transrectal ultrasound-guided prostate biopsy system for prostate cancer detection.

The 3-D transrectal ultrasound (TRUS)-guided prostate biopsy system is a novel device that allows precise needle placement in a template fashion. We evaluate its utility for prostate cancer (PCa) detection. A retrospective analysis was performed evaluating 68 prospective patients at the Duke Prostate Center who underwent a prostate biopsy using a 3-D TRUS-guided system. After creation of a three-dimensional map of the prostate, a computer algorithm identified an ideal biopsy scheme based on the measured dimensions of the prostate. The system then used a fixed template that allowed prostate biopsy at specific locations with the ability to target the same region of the prostate in the future if needed. For all patients, a 12-core biopsy pattern was used to cover medial and lateral areas of the base, mid-gland, and apex. In total, 68 patients underwent 3-D TRUS-guided prostate biopsies between April 2006 and November 2007 for prostate cancer detection. The indication for prostate biopsy was PSA > or = 4.0 ng/ml in 47 (69%) patients, abnormal digital rectal examination (DRE) in 17 (25%), and atypia on previous biopsy in 4 (6%) patients. Prostate cancer was detected in 18 patients (26.5%) and 7 (10.3%) had atypical small acinar proliferation (ASAP). The highest frequency (55.5%) from all cases of cancer detected was identified when 3-D TRUS biopsy was used as the initial biopsy. This study demonstrates that a 3-D TRUS-guided biopsy system translates to a more frequent detection of prostate cancer among patients undergoing an initial prostate biopsy than a subsequent one. More comprehensive studies are warranted to corroborate and extend the results of this study.