Negotiating discord in sustainability transformations.

Policy action for sustainability transformation faces inherent and ever-present sources of conflict, pushback, and resistance (i.e., discord). However, conceptual frameworks and policy prescriptions for sustainability transformations often reflect an undue image of accord. This involves simplified assumptions about consensus, steering, friction, discreteness, and additiveness of policy action, conferring an unrealistic view of the potential to deliberately realize transformation. Instead, negotiating discord through continuously finding partial political settlements among divided actors needs to become a key focus of policy action for sustainability transformations. Doing so can help to navigate deeply political settings through imperfect but workable steps that loosen deadlock, generate momentum for further policy action, and avoid complete derailment of transformation agendas when discord arises.

A CDK activity buffer ensures mitotic completion.

The eukaryotic cell cycle is driven by the activity of cyclin-dependent kinases (CDKs). CDK activity rises over 50-fold during the cell cycle, from a low level in G1 to a high level in mitosis. However, it is not known whether the entire range of CDK activity is necessary for cell cycle progression, or whether cells can tolerate a reduction in CDK activity level. Here, in fission yeast, we show that sublethal CDK inhibition lengthens the time cells spend in mitosis but does not cause misordering of mitotic events. Maximum attainable CDK activity exceeds the amount necessary for mitosis, and thus forms a CDK activity buffer between sufficient and maximal possible CDK activities. This CDK activity buffer is needed for mitotic completion when CDK activity is compromised, and CDK inhibition only becomes lethal to cells when this buffer is exhausted. Finally, we explore what factors influence this CDK activity buffer, and find that it is influenced by CDK-counteracting phosphatases. Therefore, maximum attainable CDK activity is not necessary for mitosis but provides robustness to CDK activity reduction to ensure mitotic completion.

Contemporary outcomes for arterial reconstruction with non-saphenous vein cryo-preserved conduits.

OBJECTIVE: Cryopreserved (CP) products are utilized during challenging cases when autogenous or prosthetic conduit use is not feasible. Despite decades of experience with cadaveric greater saphenous vein (GSV), there is limited available data regarding the outcomes and patency of other CP products, specifically arterial and deep venous grafts. This study was designed to evaluate outcomes of non-GSV CP conduits in patients undergoing urgent, emergent, and elective arterial reconstruction at our institution. We hypothesized that non-GSV CP allografts have adequate patency and outcomes and are therefore a feasible alternative to GSV in settings where autologous graft is unavailable or prosthetic grafts are contraindicated. METHODS: This study was approved by the Institutional Review Board at our institution. We retrospectively reviewed charts of patients undergoing arterial reconstructions using CP conduits from 2010 to 2022. Data collected included demographics, comorbidities, smoking status, indications for surgery, indication for CP conduit use, anatomic reconstruction, urgency of procedure, and blood loss. Time-to-event outcomes included primary and secondary graft patency rates, follow-up amputations, and mortality; other complications included follow-up infection/reinfection and 30-day complications, including return to the operating room and perioperative mortality. Time-to-event analyses were evaluated using product-limit survival estimates. RESULTS: Of 96 identified patients receiving CP conduits, 56 patients received non-GSV conduits for 66 arterial reconstructions. The most common type of non-GSV CP product used was femoral artery (31 patients), followed by aorto-iliac artery (22 patients), and femoral vein (19 patients), with some patients receiving more than one reconstruction or CP product. Patients were mostly male (75%), with a mean age of 63.1 years and a mean body mass index of 26.7 kg/m2. Indications for CP conduit use included infection in 53 patients, hostile environment in 36 patients, contaminated field in 30 patients, tissue coverage concerns in 30 patients, inadequate conduit in nine patients, and patient preference in one patient. Notably, multiple patients had more than one indication. Most surgeries (95%) were performed in urgent or emergent settings. Supra-inguinal reconstructions were most common (53%), followed by extra-anatomic bypasses (47%). Thirty-day mortality occurred in 10 patients (19%). Fifteen patients (27%) required return to the operating room for indications related to the vascular reconstructions, with 10 (18%) cases being unplanned and five (9%) cases planned/staged. Overall survival at 6, 12, and 24 months was 80%, 68%, and 59%, respectively. Primary patency at 6, 12, and 24 months was 86%, 70%, and 62%, respectively. Amputation freedom at 6 months, 12 months, and 24 months was 98%, 95%, and 86%, respectively for non-traumatic indications. CONCLUSIONS: Non-GSV CP products may be used in complex arterial reconstructions when autogenous or prosthetic options are not feasible or available.

Characterization of organic crystals for second-harmonic generation.

Second-harmonic generation (SHG) is a common technique with many applications. Common inorganic single-crystalline materials used to produce SHG light are effective using short IR/visible wavelengths but generally do not perform well at longer, technologically relevant IR wavelengths such as 1300, 1550, and 2000 nm. Efficient SHG materials possess many of the same key material properties as terahertz (THz) generators, and certain single-crystalline organic THz generation materials have been reported to perform at longer IR wavelengths. Consequently, this work focuses on characterizing three efficient organic THz generators for SHG, namely, DAST (trans-4-[4-(dimethylamino)-N-methylstilbazolium] p-tosylate), DSTMS (4-N,N-dimethylamino-4'-N'-methylstilbazolium 2,4,6-trimethylbenzenesulfonate), and the recently discovered generator PNPA ((E)-4-((4-nitrobenzylidene)amino)-N-phenylaniline). All three of these crystals outperform the beta-barium borate (BBO), an inorganic material commonly used for SHG, using IR pump wavelengths (1200-2000 nm).

ERCP findings provide further justification for a "surgery-first" mindset in choledocholithiasis.

INTRODUCTION: Choledocholithiasis is most often managed in a two-procedure pathway including endoscopic retrograde cholangiopancreatography (ERCP) followed by laparoscopic cholecystectomy (LC). In contrast, a single-stage, surgery-first approach consisting of LC, cholangiogram, and laparoscopic common bile duct exploration (LCBDE) is associated with reduced hospital stays and equivalent morbidity. Despite this, nationwide referral patterns heavily favor ERCP, obscuring those undergoing ERCP with obstructions amenable to simple intraoperative interventions. We hypothesized that most patients had endoscopic findings consistent with simple sludge or small-to-medium stones, which could have been cleared by basic LCBDE maneuvers. METHODS: We retrospectively reviewed 294 patients > 18 years old who underwent preoperative ERCP for the management of suspected choledocholithiasis. Exclusion criteria included: failed ERCP, cholangitis, prior cholecystectomy, patient refusal of surgery, or medical conditions precluding surgical candidacy. Stone size was categorized as small (0-4 mm), medium (5-7 mm), and large (≥ 8 mm). RESULTS: At the time of ERCP, 37 (20.1%) patients had sludge only, 96 (52.2%) had stones only, 42 (22.8%) had sludge and stones, and 9 (4.8%) had no stones. Of the 138 patients with any stones, 37 (26.8%) had small stones, 41 (29.7%) medium, 43 (31.2%) large, and 17 (12.3%) had uncharacterizable stones. Overall, 74.3% of patients had findings of sludge, stones (0-7 mm), or negative ERCP. CONCLUSION: The majority of patients who underwent preoperative ERCP for suspected choledocholithiasis had findings that are amenable to simple intraoperative interventions. In fact, over a quarter of the patients had a negative ERCP, sludge, or small stones which would likely be cleared by flushing/glucagon precluding any further instrumentation. While large stones may require more advanced techniques, this represents a small percentage of patients. Surgery-first management for suspected choledocholithiasis can offer an efficient alternative for the majority of patients.

Plasma hydrogen sulfide: A biomarker of Alzheimer's disease and related dementias.

While heart disease remains a common cause of mortality, cerebrovascular disease also increases with age, and has been implicated in Alzheimer's disease and related dementias (ADRD). We have described hydrogen sulfide (H2 S), a signaling molecule important in vascular homeostasis, as a biomarker of cardiovascular disease. We hypothesize that plasma H2 S and its metabolites also relate to vascular and cognitive dysfunction in ADRD. We used analytical biochemical methods to measure plasma H2 S metabolites and MRI to evaluate indicators of microvascular disease in ADRD. Levels of total H2 S and specific metabolites were increased in ADRD versus controls. Cognition and microvascular disease indices were correlated with H2 S levels. Total plasma sulfide was the strongest indicator of ADRD, and partially drove the relationship between cognitive dysfunction and white matter lesion volume, an indicator of microvascular disease. Our findings show that H2 S is dysregulated in dementia, providing a potential biomarker for diagnosis and intervention.

A novel surgical margin (1 cm) might be from benefit for patients with dysplastic nevi, thin melanomas, and melanoma in situ: Analysis based on clinical cases.

Malignant melanoma is an oncologic disease, whose current management among others includes surgical and immunological therapy. According to the current recommendations of the American Joint Committee on Cancer, the surgical excision of the primary tumor should be performed in two operative sessions, which has several consequences. The following paper will present and discuss six cases of pigmented lesions and the advantages of the one-step melanoma surgery in their management.

Granulomatous slack skin mycosis fungoides developing simultaneously with sarcoid-like lesions in a patient with repeated anabolic injections in the past?

We present a 32-year-old man with successful treatment and remission of mycosis fungoides of both axillae in 2016 after PUVA therapy and systemic and local administration of corticosteroids. Subsequently, in 2017, the patient also achieved remission of a T-cell CD 30 positive, ALK-1 negative large-cell lymphoma of a retroperitoneal and inguinal lymph node after chemotherapy and radiotherapy. One year later, in 2018, the patient presented to our clinic with progression of skin lesions in both axillary areas and the appearance of а tumor in the right gluteal region.Dermatological examination showed livid-to-erythematous, partly sclerotic plaques in the right inguinal area, cutis laxa-like plaque formations in the right axillary region with similar but less-developed changes in the left axillary fold, a solitary subcutaneous tumor formation affecting the entire right gluteal region, and enlarged, palpable lymph nodes in the right para-axillary area. Biopsies were obtained from an axillary lesion and the surgically removed axillary lymph nodes, and histological examination revealed changes of granulomatous slack skin in the axilla and reactive inflammatory changes in the lymph nodes. Histology of gluteal tissue showed a "foreign body" type of reaction with sarcoid-like features, where the patient in the past have been injected with anabolic and steroidal drugs. Herein we describe a patient with simultaneous occurrence of granulomatous slack skin type mycosis fungoides and a sarcoid-like reaction. The question remains open whether this represents the so-called sarcoidosis-lymphoma syndrome or, more likely, granulomatous slack skin MF associated with a sarcoid-like reaction of "foreign body" type. The possibility that disturbance of tissue homeostasis by incorporation of certain adjuvants within injections (for example) in the past might have been an inducer of cutaneous T cell lymphoma and sarcoidosis/sarcoid like lesions seems reasonable but also speculative.

The 2018 Nobel Prize in Physics: optical tweezers and chirped pulse amplification.

The 2018 Nobel Prize in Physics was awarded to Arthur Ashkin (prize share ½), Gérard Mourou (prize share »), and Donna Strickland (prize share ») for "groundbreaking inventions in the field of laser physics." This feature article summarizes the development of "optical tweezers and their application to biological systems" by Arthur Ashkin, as well as the Mourou/Strickland method of "generating high-intensity, ultrashort optical pulses" known as chirped pulse amplification. Further developments are also briefly discussed.

Cutaneous paraneoplastic syndromes.

A variety of cutaneous abnormalities can be seen in patients with malignant diseases, some of which are infectious, with others representing direct involvement of the skin by the underlying disorder. Yet another group of lesions can be regarded as associated markers of the malignant process, and, as such, are termed "paraneoplastic." This review considers the latter collection of conditions, grouping them by the generic type of malignancy that is usually linked to the paraneoplasia. Some of the processes show a predominant association with alimentary tract malignancies (acanthosis nigricans, acrodermatitis paraneoplastica, florid cutaneous papillomatosis, necrolytic migratory erythema, palmoplantar keratoderma, pancreatic fat necrosis, and pityriasis rotunda). Others are usually linked to a hematolymphoid malignancy (acquired ichthyosis, exfoliative erythroderma, necrobiotic xanthogranuloma, pemphigus paraneoplastica, plane xanthoma, pyoderma gangrenosum, scleromyxedema, Sweet syndrome, and leukocytoclastic vasculitis). Finally, yet another collection of paraneoplastic skin disorders can associate themselves with anatomically-diverse malignancies (Leser-Trelat syndrome, Trousseau syndrome, dermatomyositis, erythema gyratum repens, hypertrichosis lanuginosa acquisita, papuloerythroderma of Ofuji, tripe palms, and multicentric reticulohistiocytosis). Recognition of these processes by the pathologist can be a valuable step in the characterization of underlying malignant diseases.

Mumps Outbreak in a Highly Vaccinated University-Affiliated Setting Before and After a Measles-Mumps-Rubella Vaccination Campaign-Iowa, July 2015-May 2016.

Background: In response to a mumps outbreak at the University of Iowa and surrounding community, university, state, and local health officials implemented a vaccination campaign targeting students <25 years of age with an additional dose of measles-mumps-rubella (MMR) vaccine. More than 4700 vaccine campaign doses were administered; 97% were documented third doses. We describe the epidemiology of the outbreak before and after the campaign, focusing on cases in university students. Methods: Mumps cases were identified from reportable disease databases and university health system records. Detailed information on student cases was obtained from interviews, medical chart abstractions, university and state vaccination records, and state public health laboratory results. Pre- and postcampaign incidence among students, university faculty/staff, and community members <25 vs ≥25 years old were compared using Fisher exact test. Multivariable regression modeling was performed to identify variables associated with a positive mumps polymerase chain reaction test. Results: Of 453 cases in the county, 301 (66%) occurred in university students. Student cases were primarily undergraduates (90%) and highly vaccinated (86% had 2 MMR doses, and 12% had 3 MMR doses). Fewer cases occurred in students after the campaign (75 [25%]) than before (226 [75%]). Cases in the target group (students <25 years of age) declined 9% postcampaign (P=.01). A positive mumps polymerase chain reaction test was associated with the presence of parotitis and early sample collection, and inversely associated with recent receipt of MMR vaccine. Conclusions: Following a large additional dose MMR vaccination campaign, fewer mumps cases occurred overall and in the target population.

Diagnostic histochemistry in non-neoplastic skin diseases.

Non-neoplastic skin lesions comprise a sizable group of disorders with variable etiologies and clinical manifestations. They can be grouped into vesiculopustular dermatitides; spongiotic and psoriasiform diseases; lichenoid dermatitides; lymphoid infiltrates of the dermis; granulomatous processes; bullous disorders; vasculopathies; panniculitides; deposition disorders; and defects in maintenance of dermal connective tissue. The use of histochemical methods continues to be an indispensable adjunct to conventional microscopy in the further characterization of such lesions. This review considers that topic.

Interdigital melanoma simultaneously affecting two neighboring interdigital spaces : First description in the medical literature.

BACKGROUND: Interdigital melanoma, as a subtype of acral lentiginous melanoma, is relatively uncommon in the Caucasian population. It frequently goes unrecognized for a prolonged period of time prior to diagnosis, due to its asymptomatic nature and variable clinical appearance. METHODS: We report the case of a 67-year-old Caucasian woman who presented with interdigital malignant melanoma affecting two neighboring interdigital spaces. It had evolved over a period of more than 15 years and had been initially misdiagnosed as tinea pedis due to the macerated appearance of the lesion and a positive mycologic examination. RESULTS: We highlight the striking involvement of two adjacent interdigital spaces and the neighboring area of the sole of the foot by the tumor. The melanoma was staged as IIIC, with pathologic grading T4bN2bM CONCLUSIONS: The involvement of two adjacent interdigital spaces is unusual and, to our knowledge, has not been previously highlighted in the medical literature. It may be explained, in part, by the longstanding nature of the lesion in our patient.

PSMA-targeted bispecific Fab conjugates that engage T cells.

Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an αCD3 Fab enabled installation of either the PSMA-targeting small molecule DUPA (SynFab) or the attachment of an αPSMA Fab (BisFab) by covalent linkage. Optimization of the reducing conditions was critical for selective interchain disulfide reduction and good bioconjugate yield. Activity of αPSMA/CD3 Fab conjugates was tested by in vitro cytotoxicity assays using prostate cancer cell lines. Both bispecific formats demonstrated excellent potency and antigen selectivity.

Chemically generated IgG2 bispecific antibodies through disulfide bridging.

Bispecific antibodies (BsAbs) are designed to engage two antigens simultaneously, thus, effectively expanding the ability of antibody-based therapeutics to target multiple pathways within the same cell, engage two separate soluble antigens, bind the same antigen with distinct paratopes, or crosslink two different cell types. Many recombinant BsAb formats have emerged, however, expression and purification of such constructs can often be challenging. To this end, we have developed a chemical strategy for generating BsAbs using native IgG2 architecture. Full-length antibodies can be conjugated via disulfide bridging with linkers bearing orthogonal groups to produce BsAbs. We report that an αHER2/EGFR BsAb was successfully generated by this approach and retained the ability to bind both antigens with no significant loss of potency.

Cutaneous and visceral leishmaniasis during anti-TNFα therapy.

The long-term use of novel antipsoriatic systemic biotechnological drugs may increase susceptibility to opportunistic infections. Several cases of visceral leishmaniasis have been reported in immunosuppressed individuals, including those who have been treated with tumour necrosis factor alpha (TNFα) blocking agents. Simultaneous occurrence of cutaneous and visceral involvement has been more rarely recorded in the medical literature. Herein, we describe a case of mucosal leishmaniasis occurring in a farmer living in an endemic region, who was treated with golimumab because of psoriatic arthritis. This highlights the importance of recognizing cutaneous lesions as a first indicator of possible underlying kala-azar disease.

Undermining plastic surgery as a possible option for treating basal cell carcinoma of the forehead.

Basal cell carcinoma (BCC) is the most common cutaneous cancer. Although most cases can be cured with simple surgical procedures and are associated with a good prognosis, a minority of BCCs may pose significant therapeutic challenges. This occurs mostly in cases of so-called advanced BCC, which a loosely defined term that encompasses locally advanced lesions and tumors with metastatic spread. Treatment of these cases is often complex and sometimes may need combinations of therapeutic modalities, including surgery, radiotherapy and/or targeted therapy directed towards sonic hedgehog (SHH) signaling pathways, such as vismodegib. We herein present the case of a 74-year-old man presenting with a large basal cell of the forehead evolving for more than 7 years. The patient underwent excision of the lesion with clear surgical margins. Reconstruction of the defect was performed after extensive undermining of the skin allowing subsequent direct closure with a simple suture, which resulted in an acceptable cosmetic outcome. We discuss the potential advantages, disadvantages, and applicability of this relatively simple surgical maneuver in the reconstruction of defects resulting from excision of considerably large cutaneous tumors.

Sclerosing epithelioid fibrosarcoma.

We report the case of a 55-year-old woman who developed a mass in the soft tissue of the anterior right proximal thigh. Microscopic findings in the biopsy specimen supported the diagnosis of sclerosing epithelioid fibrosarcoma (SEF). This entity is part of a spectrum of lesions that includes low-grade fibromyxoid sarcoma (LGFMS) and hyalinizing spindle cell tumor with giant rosettes (HSCTGR). It shares with LGFMS occasional overlapping histopathologic features and immunopositivity for MUC4. Although FUS and CREB3L2 gene rearrangements, characteristics of LGFMS, have been found in hybrid tumors (those with features of both SEF and LGFMS) and in examples of LGFMS with relapses showing SEF morphology, it appears that EWSR1 and CREB3L1 rearrangements predominate over FUS and CREB3L2 rearrangements among "pure" SEF tumors. Recent information about SEF is briefly reviewed.

Radiation-induced lichen sclerosus of the vulva : First report in the medical literature.

A 67-year-old woman presented with a firm plaque in the perineal region, 16 months after diagnosis of a high-grade basaloid squamous cell carcinoma of the vagina and treatment by external beam radiation therapy and vaginal cuff brachytherapy. The differential diagnosis included radiation-induced morphea, radiation dermatitis, or, possibly, radiation-induced lichen sclerosus. Biopsy findings, including special staining, confirmed the diagnosis of radiation-induced lichen sclerosus. To our knowledge, this is the first report of radiation-induced lichen sclerosus of the vulvar region.

Human Serum Albumin Domain I Fusion Protein for Antibody Conjugation.

Bioorthogonal labeling of antibodies enables the conjugation of compounds, such as small molecules or peptides, which expand targeting capacity or enhance cytotoxicity. Taking advantage of a cyclohexene sulfonamide compound that site-selectively labels Lys64 in human serum albumin (HSA), we demonstrate that domain I of HSA can be used as a fusion protein for the preparation of antibody conjugates. Trastuzumab fusions were expressed at the N-terminus of the light chain or the C-terminus of the heavy chain enabling conjugation to small molecules. Moreover, these conjugates retained HER2 binding and proved to be highly stable in human plasma. Antibody conjugation via HSA domain I fusion should therefore have broad utility for making serum-stable antibody conjugates, particularly for antibody-drug conjugates.