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Industrial automation and control systems (IACSs) are important for supporting the U.S. critical infrastructure and maintaining national security. IACS owners and operators continue to face threats from a variety of adversaries, whose intentions include gathering intelligence, stealing intellectual property, obtaining financial compensation through ransom, and disrupting national critical infrastructures. The IACSs discussed do not just include control systems but often include electrical assets (microprocessor-based relays, trip units, etc.) that have been networked together using various communication protocols. Previous IEEE IAS Petroleum and Chemical Industry Technical Conference (PCIC) articles have mentioned cybersecurity without providing details on how to secure an IACS. This article describes the issues that IACS owners and operators face and introduces the International Society of Automation (ISA)/International Electrotechnical Commission (IEC) 62443 [1], [2], [3], [4], [5], [6], [7], [8], [9] series of standards as the basis for an effective cybersecurity program. These standards have been developed by the ISA99 committee of the ISA and IEC Technical Committee 65 Working Group 10 (TC65 WG10).

Adoption of new digital measures for clinical trials and practice has been hindered by lack of actionable qualitative data demonstrating relevance of these metrics to people with Parkinson’s disease. This study evaluated of relevance of WATCH-PD digital measures to monitoring meaningful symptoms and impacts of early Parkinson’s disease from the patient perspective. Participants with early Parkinson’s disease (N = 40) completed surveys and 1:1 online-interviews. Interviews combined: 1) symptom mapping to delineate meaningful symptoms/impacts of disease, 2) cognitive interviewing to assess content validity of digital measures, and 3) mapping of digital measures back to personal symptoms to assess relevance from the patient perspective. Content analysis and descriptive techniques were used to analyze data. Participants perceived mapping as deeply engaging, with 39/40 reporting improved ability to communicate important symptoms and relevance of measures. Most measures (9/10) were rated relevant by both cognitive interviewing (70–92.5%) and mapping (80–100%). Two measures related to actively bothersome symptoms for more than 80% of participants (Tremor, Shape rotation).Tasks were generally deemed relevant if they met three participant context criteria: 1) understanding what the task measured, 2) believing it targeted an important symptom of PD (past, present, or future), and 3) believing the task was a good test of that important symptom. Participants did not require that a task relate to active symptoms or “real” life to be relevant. Digital measures of tremor and hand dexterity were rated most relevant in early PD. Use of mapping enabled precise quantification of qualitative data for more rigorous evaluation of new measures.

Patient perspectives on meaningful symptoms and impacts in early Parkinson’s disease (PD) are lacking and are urgently needed to clarify priority areas for monitoring, management, and new therapies. To examine experiences of people with early-stage PD, systematically describe meaningful symptoms and impacts, and determine which are most bothersome or important. Forty adults with early PD who participated in a study evaluating smartwatch and smartphone digital measures (WATCH-PD study) completed online interviews with symptom mapping to hierarchically delineate symptoms and impacts of disease from “Most bothersome” to “Not present,” and to identify which of these were viewed as most important and why. Individual symptom maps were coded for types, frequencies, and bothersomeness of symptoms and their impacts, with thematic analysis of narratives to explore perceptions. The three most bothersome and important symptoms were tremor, fine motor difficulties, and slow movements. Symptoms had the greatest impact on sleep, job functioning, exercise, communication, relationships, and self-concept— commonly expressed as a sense of being limited by PD. Thematically, most bothersome symptoms were those that were personally limiting with broadest negative impact on well-being and activities. However, symptoms could be important to patients even when notpresent or limiting (e.g., speech, cognition). Meaningful symptoms of early PD can include symptoms that are present or anticipated future symptoms that are important to the individual. Systematic assessment of meaningful symptoms should aim to assess the extent to which symptoms are personally important, present, bothersome,and limiting

KRAS G12Cmutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS–MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n= 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n= 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12Cvariant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.

ABSTRACTObjectivesCyclodextrins (CDs) play a pivotal role in the controlled release of drugs; however, their ability to gradually release drugs is here interrogated: can cyclodextrins, even those that form strong inclusion complexes, sustain a prolonged release of drugs?MethodsAn original chromatographic approach was developed and accordingly we classified and determined drugs that form the most stable inclusion complexes with cyclodextrins. β-CD and hydroxypropyl-β-CD (HP-β-CD) were coupled to pullulan (Pul) microspheres and packed into a chromatographic column. Then, different drugs or model compounds were eluted, and values of the retention time (RT) were determined. In vitrorelease studies were performed for drugs that form the most stable inclusion complexes.ResultsThe drugs with the longest RTvalue form the most stable inclusion complexes with Pul/β-CD and Pul/HP-β-CD microspheres. Pul/β-CD microspheres form more stable inclusion complexes than Pul/HP-β-CD microspheres. However, in spite of their high stability, they were not able to gradually release the included drug (15 min release time). The cross-chromatographic experiments confirmed the hypothesis that in aqueous solution, drug/cyclodextrin complexes are continuously associated and dissociated.ConclusionsIf the dissociation of the guest molecule is very rapid, why is it expected that these complexes gradually release the drug?

Background: Post-herniorrhaphy pain is common with an estimated 8–10% incidence of mesh-related complications, requiring mesh explantation in up to 6% of cases, most commonly after inguinal hernia repairs. Reoperation for mesh explantation poses a surgical challenge due to adhesions, scarring and mesh incorporation to the surrounding tissues. Robotic technology provides a versatile platform for enhanced exposure to tackle these complex cases. We aim to share our experience with a novel robotic approach to address these complex cases. Methods: A descriptive, retrospective analysis of patients undergoing a robotic mesh explantation (RoME) for mesh-related chronic pain, or recurrent ventral hernia by two surgeons between the period of March 2016 and January of 2020. The patients were evaluated for resolution of mesh related abdominal pain as well as early post-operative complications. RoME was performed with concomitant hernia repair in cases of recurrences. Results: Twenty-nine patients underwent a robotic mesh explantation (RoME) for mesh-related chronic pain, or recurrent ventral hernia between March 2016 and January of 2020. Nineteen patients (65.5%) had a prior inguinal hernia repair and 10 patients (34.5%) had a prior ventral hernia repair. Indications for mesh removal included chronic pain with or without hernia recurrence. Seventeen patients (58.6%) reported improvement or resolution of pain postoperatively (63% with a prior inguinal hernia repair and 50% of patients with a prior ventral hernia repair). Five patients (17.2%) required mesh reinforcement after explantation. Nineteen patients (65.5%) underwent mesh explantation with primary fascial closure or no mesh reinforcement. The mean follow-up was 36.4 days. The most common postoperative complication was seroma formation (6.8%), with one reported recurrence (3.4%). Conclusion: Robotic mesh explantation in challenging cases due to the effect of chronic scarring, adhesions and mesh incorporation to the surrounding tissues is safe and provides an advantageous platform for concomitant hernia repair in these complex cases.

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Background: The use of the surgical robot has increased annually since its introduction, especially in general surgery. Despite the tremendous increase in utilization, there are currently no validated curricula to train residents in robotic surgery, and the effects of robotic surgery on general surgery residency training are not well defined. In this study, we aim to explore the perceptions of resident and attending surgeons toward robotic surgery education in general surgery residency training. Methods: We performed a qualitative thematic analysis of in-person, one-on-one, semi-structured interviews with general surgery residents and attending surgeons at a large academic health system. Convenient and purposeful sampling was performed in order to ensure diverse demographics, experiences, and opinions were represented. Data were analyzed continuously, and interviews were conducted until thematic saturation was reached, which occurred after 20 residents and seven attendings. Results: All interviewees agreed that dual consoles are necessary to maximize the teaching potential of the robotic platform, and the importance of simulation and simulators in robotic surgery education is paramount. However, further work to ensure proper access to simulation resources for residents is necessary. While most recognize that bedside-assist skills are essential, most think its educational value plateaus quickly. Lastly, residents believe that earlier exposure to robotic surgery is necessary and that almost every case has a portion that is level-appropriate for residents to perform on the robot. Conclusions: As robotic surgery transitions from novelty to ubiquity, the importance of effective general surgery robotic surgery training during residency is paramount. Through in-depth interviews, this study provides examples of effective educational tools and techniques, highlights the importance of simulation, and explores opinions regarding the role of the resident in robotic surgery education. We hope the insights gained from this study can be used to develop and/or refine robotic surgery curricula.

We propose a robust spectrum sensing framework based on deep learning. The received signals at the secondary user’s receiver are filtered, sampled and then directly fed into a convolutional neural network. Although this deep sensing is effective when operating in the same scenario as the collected training data, the sensing performance is degraded when it is applied in a different scenario with different wireless signals and propagation. We incorporate transfer learning into the framework to improve the robustness. Results validate the effectiveness as well as the robustness of the proposed deep spectrum sensing framework.

To determine barriers associated with the transition from bedside assistant to console surgeon for general surgery residents in the era of robotic surgery in general surgery training.

Operative management of complex ventral hernia still remains a significant challenge for surgeons. Closure of large defects in the unprepared abdomen has serious pathophysiological consequences due to chronic contraction and retraction of the lateral abdominal wall muscles. We report outcomes of 56 consecutive patients who had preoperative Botulinum toxin A (BTA) abdominal wall relaxation facilitating closure and repair. This was a prospective observational study of 56 patients who underwent ultrasound-guided BTA into the lateral abdominal oblique muscles prior to elective ventral hernia repair between November 2012 and January 2017. Serial non-contrast abdominal CT imaging was performed to evaluate changes in lateral oblique muscle length and thickness. All hernias were repaired laparoscopically, or laparoscopic-open-laparoscopic (LOL) using intraperitoneal onlay mesh. 56 patients received BTA injections at predetermined sites to the lateral oblique muscles, which were well tolerated. Mean patient age was 59.7 years, and mean BMI was 30.9 kg/m2(range 21.8–54.0). Maximum defect size was 24 × 27 cm. A subset of 18 patients underwent preoperative pneumoperitoneum as an adjunct procedure. A comparison of pre-BTA to post-BTA imaging demonstrated an increase in mean lateral abdominal wall length from 16.1 cm to 20.1 cm per side, a mean gain of 4.0 cm/side (range 1.0–11.7 cm/side) (p< 0.0001). This corresponds to an unstretchedmean length gain of 8.0 cm of the lateral abdominal wall. Laparoscopic/LOL primary closure was achieved in all cases, with no clinical evidence of raised intra-abdominal pressures. One patient presented with a new fascial defect 26 months post-operative. Preoperative BTA to the lateral abdominal wall muscles is a safe and effective technique for the preparation of patients prior to operative management of complex ventral hernias. BTA temporary flaccid paralysis relaxes, elongates and thins the chronically contracted abdominal musculature. This in turn reduces lateral traction forces facilitating laparoscopic repair and fascial closure of large defects under minimal tension.

As technologies develop for acquiring gaze behavior in real world social settings, robust methods are needed that minimize the time required for a trained observer to code behaviors. We record gaze behavior from a subject wearing eye-tracking glasses during a naturalistic interaction with three other people, with multiple objects that are referred to or manipulated during the interaction. The resulting gaze-in-world video from each interaction can be manually coded for different behaviors, but this is extremely time-consuming and requires trained behavioral coders. Instead, we use a neural network to detect objects, and a Viola-Jones framework with feature tracking to detect faces. The time sequence of gazes landing within the object/face bounding boxes is processed for run lengths to determine “looks,” and we discuss optimization of run length parameters. Algorithm performance is compared against an expert holistic ground truth.

In ACTIVExtend, reductions in fracture risk and increases in BMD achieved with 18 months of abaloparatide for postmenopausal osteoporosis were sustained through 24 months of subsequent alendronate.

The effects of obesity on bone metabolism are complex, and may be mediated by consumption of a high fat diet and/or by obesity-induced metabolic dysregulation. To test the hypothesis that both high fat (HF) diet and diet-induced metabolic disease independently decrease skeletal acquisition, we compared effects of HF diet on bone mass and microarchitecture in two mouse strains: diet-induced obesity (DIO)-susceptible C57BL/6J (B6) and DIO-resistant FVB/NJ (FVB). At 3 wks of age we weaned 120 female FVB and B6 mice onto normal (N, 10% Kcal/fat) or HF diet (45% Kcal/fat) and euthanized them at 6, 12 and 20 weeks of age (N = 10/grp). Outcomes included body mass; percent fat and whole-body bone mineral density (WBBMD, g/cm2) via DXA; cortical and trabecular bone architecture at the midshaft and distal femur via μCT; and marrow adiposity via histomorphometry. In FVB HF, body mass, percent body fat, WBBMD and marrow adiposity did not differ vs. N, but trabecular bone mass was lower at 6 wks of age only (p < 0.05), cortical bone geometric properties were lower at 12 wks only, and bone strength was lower at 20 wks of age only in HF vs. N (p < 0.05). In contrast, B6 HF had higher body mass, percent body fat, and leptin vs. N. B6 HF also had higher WBBMD (p < 0.05) at 9 and 12 wks of age but lower distal femur trabecular bone mass at 12 wks of age, and lower body mass-adjusted cortical bone properties at 20 wks of age compared to N (p < 0.05). Marrow adiposity was also markedly higher in B6 HF vs. N. Overall, HF diet negatively affected bone mass in both strains, but was more deleterious to trabecular bone microarchitecture and marrow adiposity in B6 than in FVB mice. These data suggest that in addition to fat consumption itself, the metabolic response to high fat diet independently alters skeletal acquisition in obesity.

Component separation (CS) is a technique which mobilizes flaps of innervated, vascularized tissue, enabling closure of large ventral hernia defects using autologous tissue. Disadvantages include extensive tissue dissection when creating these myofascial advancement flaps, with potential consequences of significant post-operative skin and wound complications. This study examines the benefit of a novel, ultra-minimally invasive single port anterior CS technique. This was a prospective study of 16 external oblique (EO) releases performed in 9 patients and 4 releases performed in 3 fresh frozen cadavers. All patients presented with recurrent complex ventral hernias, and were administered preoperative Botulinum Toxin Ato their lateral oblique muscles to facilitate defect closure. At the time of elective laparoscopic repair, patients underwent single port endoscopic EO release using a single 20-mm incision on each side of the abdomen. Measurements were taken using real-time ultrasound. Postoperatively, patients underwent serial examination and abdominal CT assessment. Single port endoscopic EO release achieved a maximum of 50-mm myofascial advancement per side (measured at the umbilicus). No complications involving wound infection, hematoma, or laxity/bulge have been noted. All patients proceeded to laparoscopic or laparoscopic-open-laparoscopic intraperitoneal mesh repair of their hernia, with no hernia recurrences to date. Single port endoscopic EO release holds potential as an adjunct in the repair of large ventral hernia defects. It is easy to perform, is safe and efficient, and entails minimal disruption of tissue planes and preserves abdominal wall perforating vessels. It requires only one port-sized incision on each side of the abdomen, thus minimizing potential for complications. Further detailed quantification of advancement gains and morbidity from this technique is warranted, both with and without prior administration of Botulinum Toxin Ato facilitate closure.

The cytosolic iron–sulfur cluster assembly (CIA) system assembles iron–sulfur (FeS) cluster cofactors and inserts them into >20 apoprotein targets residing in the cytosol and nucleus. Three CIA proteins, called Cia1, Cia2, and Met18 in yeast, form the targeting complex responsible for apo-target recognition. There is little information about the structure of this complex or its mechanism of CIA substrate recognition. Herein, we exploit affinity co-purification and size exclusion chromatography to determine the subunit connectivity and stoichiometry of the CIA targeting complex. We conclude that Cia2 is the organizing center of the targeting complex, which contains one Met18, two Cia1, and four Cia2 polypeptides. To probe target recognition specificity, we utilize the CIA substrates Leu1 and Rad3 as well as the Escherichia coliFeS-binding transcription factor FNR (fumerate nitrate reductase). We demonstrate that both of the yeast CIA substrates are recognized, whereas the bacterial protein is not. Thus, while the targeting complex exhibits flexible target recognition in vitro, it cannot promiscuously recognize any FeS protein. Additionally, we demonstrate that the full CIA targeting complex is required to stably bind Leu1 in vitro, whereas the Met18–Cia2 subcomplex is sufficient to recognize Rad3. Together, these results allow us to propose a unifying model for the architecture of this highly conserved complex and demonstrate what component or subcomplexes are vital for target identification.

Simultaneous inhibition of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) with bispecific antibodies may improve efficacy over single-agent treatment while limiting toxicity. Cadonilimab is a humanized, bispecific antibody targeting PD-1 and CTLA-4. This is a phase 1 study of cadonilimab including dose escalation (n = 39) and dose expansion (n = 80). One dose-limiting toxicity event is observed, with the maximum tolerated dose not reached. 6 mg/kg cadonilimab once every 2 weeks is established as the recommended dose for future studies. The most common treatment-related adverse event is infusion-related reaction (18.5%), mostly grade 1/2 in severity. The incidences of any grade and grade ≥3 immune-related adverse events are 44.5% and 6.7%, respectively. The confirmed overall response rate is 13.4%, and the median duration of response is 12.9 months. Cadonilimab is well tolerated and showed promising efficacy in patients with advanced solid tumors. This study is registered with ClinicalTrials.gov: NCT03261011.

We assessed osteoporosis management in patients admitted for rehabilitation of acute hip fracture to an open system community hospital before and after institution of a fracture liaison service (FLS). Pre-FLS, we surveyed 60 patients 4–6 months after hip fracture. Subsequently, the FLS program performed routine consultations, and recommended lab, bone density testing (BMD) and osteoporosis medication. FLS program outcomes were assessed by survey in 75 patients after hip fracture. In the pre-FLS population, after hip fracture, 55 % changed calcium intake, 48 % changed vitamin D intake, and 35 % obtained a BMD. Osteoporosis medication was taken by 38 % before and 33 % after hip fracture. Post-FLS, 56 % changed calcium intake, 68 % changed vitamin D intake and 65 % obtained a BMD. Post-FLS, osteoporosis medication was taken by 21 % of patients before and 19 % after hip fracture. Our FLS program in hip fracture patients improved non-pharmacologic measures, but not the use of osteoporosis medication.

To assess the efficacy and safety of 18 months of subcutaneous abaloparatide (ABL-SC) or placebo (PBO) followed by 6 months of alendronate (ALN) (preplanned interim analysis).

Repair of complex ventral hernia can be very challenging for surgeons. Closure of large defects can have serious pathophysiological consequences. Botulinum toxin A(BTA) has recently been described to provide flaccid paralysis to abdominal muscles prior to surgery, facilitating closure and repair. This was a prospective observational study of 32 patients who underwent ultrasound-guided injections of BTA to the lateral abdominal wall muscles prior to elective repair of complex ventral hernia between January 2013 and December 2015. Serial non-contrast abdominal CT imaging was performed to measure changes in fascial defect size, abdominal wall muscle length and thickness. All hernias were repaired laparoscopically or laparoscopic-assisted with placement of intra-peritoneal mesh. Thirty-two patients received BTA injections which were well tolerated with no complications. A comparison of baseline (preBTA) CT imaging with postBTA imaging demonstrated an increase in mean baseline abdominal wall length from 16.4 to 20.4 cm per side(p< 0.0001), which translates to a gain in mean transverse length of the unstretchedanterolateral abdominal wall muscles of 4.0 cm/side (range 0–11.7 cm/side). Fascial closure was achieved in all cases, with no instances of raised intra-abdominal pressures or its sequelae, and there have been no hernia recurrences to date. Preoperative BTA injection to the muscles of the anterolateral abdominal wall is a safe and effective technique for the preoperative preparation of patients prior to laparoscopic mesh repair of complex ventral hernia. This technique elongates and thins the contracted and retracted musculature, enabling closure of large defects.