Ising model partition-function computation as a weighted counting problem.

While the Ising model is most often used to understand physical phenomena, its natural connection to combinatorial reasoning also makes it one of the best models to probe complex systems in science and engineering. We bring a computational lens to the study of Ising models, where our computer-science perspective is twofold: On the one hand, we show that partition function computation (#Ising) can be reduced to weighted model counting (WMC). This enables us to take off-the-shelf model counters and apply them to #Ising. We show that one model counter (TensorOrder) outperforms state-of-the-art tools for #Ising on midsize and topologically unstructured instances, suggesting the tool would be a useful addition to a portfolio of partition function solvers. On the other hand, we consider the computational complexity of #Ising and relate it to the logic-based counting of constraint-satisfaction problems or #CSP. We show that known dichotomy results for #CSP give an easy proof of the hardness of #Ising and provide intuition on where the difficulty of #Ising comes from.

[THE UNIMAGINABLE CONNECTION BETWEEN JEWISH DOCTORS AND THE GERMAN MEDICAL TRAINING SYSTEM DURING THE NAZI REGIME].

INTRODUCTION: In his important article, Prof. G. Eshel describes the story of three Jewish physicians who returned to Nazi Germany to complete their MD thesis despite laws prohibiting Jewish students from German Universities. The three physicians completed their MD thesis examination with the help of three German Professors who supported them regardless of the laws banning Jewish students. The three physicians risked their lives by returning to Nazi Germany, as did the three professors who supported them. The three physicians returned to Palestine upon completion of the requirement for their medical licensing and continued to contribute to the medical system for many years in the State of Israel. The determination of the three Jewish physicians and their courage teaches us an important lesson on the motivation of young doctors to complete their education and practice medicine. The support of the German professors created some lights in the great darkness of the Nazi regime. Generations of physicians took a stand on non-medical issues and contributed to social justice and the wellbeing of individuals beyond medical care. We should all continue this legacy.

Outcome of transcatheter aortic valve replacement in Israeli Jews and Arabs.

Background: Ethnic minorities may face disparities in access to health care and clinical outcomes. Transcatheter aortic valve replacement (TAVR) has an established role in treatment of patients with severe symptomatic aortic stenosis, however outcome of these procedures among different demographics within the multi-ethnic Israeli society is unknown. We sought to compare mortality following TAVR between Jewish and Arab patients in Israel. Methods: A prospective single-center TAVR registry in northern Israel was analyzed. We compared post-procedural survival among Arab and Jewish patients who underwent TAVR, presenting the estimated hazard ratio (HR) using Cox regression. Results: Of 923 subjects who underwent TAVR between 2010-2021, 172 (19%) were Arab and 751 (81%) were Jewish. The Arab patient population was younger (mean 77 vs. 81 years, P<0.001), had lower prevalence of coronary artery disease (34%, vs. 43%, P=0.02), hypertension (80% vs. 88%, P<0.01) and calculated procedural mortality (EuroScore II: mean 4.6 vs. 4.9, P=0.02), and higher percentage of females (65% vs. 53%, P=0.01), body mass index (mean 30 vs. 28, P<0.001) and creatinine clearance (mean 67 vs. 59 mL/min, P<0.001). Arab patients had similar post-procedural mortality compared to Jewish patients [7-day mortality: adjusted HR 1.51, 95% confidence interval (CI): 0.39-5.77, P=0.55; 30-day mortality: adjusted HR 1.79, 95% CI: 0.62-5.18, P=0.29; 1-year mortality: adjusted HR 1.24, 95% CI: 0.72-2.12, P=0.43]. Conclusions: Arab patients undergoing TAVR were younger and had lower predicted mortality than Jewish counterparts, however, these characteristics did not translate into improved post-procedural survival.

Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial.

Multiple myeloma (MM) is a plasma cell malignancy expressing B cell maturation antigen (BCMA). Elranatamab, a bispecific antibody, engages BCMA on MM and CD3 on T cells. The MagnetisMM-1 trial evaluated its safety, pharmacokinetics and efficacy. Primary endpoints, including the incidence of dose-limiting toxicities as well as objective response rate (ORR) and duration of response (DOR), were met. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Eighty-eight patients with relapsed or refractory MM received elranatamab monotherapy, and 55 patients received elranatamab at efficacious doses. Patients had received a median of five prior regimens; 90.9% were triple-class refractory, 29.1% had high cytogenetic risk and 23.6% received prior BCMA-directed therapy. No dose-limiting toxicities were observed during dose escalation. Adverse events included cytopenias and cytokine release syndrome. Exposure was dose proportional. With a median follow-up of 12.0 months, the ORR was 63.6% and 38.2% of patients achieving complete response or better. For responders, the median DOR was 17.1 months. All 13 patients evaluable for minimal residual disease achieved negativity. Even after prior BCMA-directed therapy, 53.8% achieved response. For all 55 patients, median PFS was 11.8 months, and median OS was 21.2 months. Elranatamab achieved durable responses, manageable safety and promising survival for patients with MM. ClinicalTrials.gov Identifier: NCT03269136 .

Glitter Effects of Nail Art on Optical Coherence Tomography.

Optical coherence tomography (OCT) is a noninvasive imaging technology that can visualize nail morphology in diseases such as psoriatic arthritis or onychomycosis. We recommend removal of glitter nail art to properly assess nail pathology and decrease diagnostic delay.

A phase II multi-arm study of magrolimab combinations in patients with relapsed/refractory multiple myeloma.

Magrolimab is a monoclonal antibody that blocks CD47, a 'do not eat me' signal overexpressed on tumor cells. CD47 is overexpressed in multiple myeloma (MM), which contributes to its pathogenesis. Preclinical studies have shown that CD47 blockade induces macrophage activation, resulting in elimination of myeloma cells, and that there is synergy between magrolimab and certain anticancer therapies. These findings suggest that magrolimab-based combinations may have a therapeutic benefit in MM. This phase II study investigates magrolimab in combination with commonly used myeloma therapies in patients with relapsed/refractory MM and includes a safety run-in phase followed by a dose-expansion phase. Primary end points include the incidence of dose-limiting toxicities and adverse events (safety run-in) and the objective response rate (dose expansion).

Magrolimab is a therapy that blocks a 'do not eat me' signal overexpressed by certain cancers, including multiple myeloma (MM) cells. Studies have shown that blocking this signal leads to destruction of myeloma cells and that this cancer-killing effect may be increased by combining magrolimab with certain additional anticancer therapies. These findings suggest that magrolimab-based combinations may have a therapeutic benefit in MM. This study is investigating magrolimab in combination with commonly used myeloma therapies in patients with MM who have persistent disease despite prior treatment. Goals of the trial include assessing safety and response to treatment. Clinical Trial Registration: NCT04892446 (ClinicalTrials.gov).

Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study.

BACKGROUND: We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies. METHODS: This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437. FINDINGS: Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6). INTERPRETATION: Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib. FUNDING: BeiGene.

The two envelopes method for active learning.

Purpose: Active learning improves knowledge acquisition and provides medical students with learning habits that become an integral part of their behavior. As an integral element of our institution's transition from a lecture hall teaching culture to active learning, the current project, conducted with fourth year students, aimed to examine the effects of the two envelopes method of teaching on students' knowledge. Method: The class of 120 students was divided into 12 groups of 10 students each. Six experienced senior cardiologists were assigned to teach the 12 groups. When the students arrived at the classroom, they received two envelopes. Students were instructed to open the first envelope and answer a 10-question test in 15 minutes. After completing the test, they returned the tests to the envelope, sealed it, and then opened the second envelope which included the same test and relevant patient information. They then spent the next 30 minutes discussing the test as a group and familiarizing themselves with the patients' case histories and clinical data. After completion of the group discussion, the tutor entered the room for a two-hour discussion of the patients' disease entities including the anatomy, physiology, pathology, clinical presentation, diagnostic measures, and potential therapies. Results: We compared grades and standard deviations of grades between two classes: one learned in the lecture hall format (2018) and the other learned employing the two-envelopes method (2019). There was a non-statistically significant trend toward better grades with reduced dispersion of grades in the class that learned with the two-envelope method. Conclusions: We describe a novel method for active learning that enhances self-learning and peer learning, and we observed better knowledge acquisition and reduced knowledge dispersion that were not statistically significant.

A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma.

Acalabrutinib, a Bruton tyrosine kinase inhibitor, demonstrated greater selectivity and improved safety versus ibrutinib in a head-to-head trial in relapsed/refractory (R/R) chronic lymphocytic leukaemia. In the R/R marginal zone lymphoma (MZL) cohort (phase 2) of a phase 1b/2 trial (NCT02180711), 43 patients with MZL and at least one prior therapy received acalabrutinib 100 mg twice daily until disease progression or unacceptable toxicity [median age 69 years (range 42-84); median one (1-4) prior systemic regimens]. Median follow-up was 13.3 months (range 0.5-45.5). Among 40 patients evaluable for response, investigator-assessed overall response rate was 53% [95% confidence interval (CI) 36%-69%] with five (13%) complete responses. Tumour reduction occurred in 40 (93%) of the treated patients. Median time to response was 2.9 months (median duration of response not estimable). Estimated median progression-free survival (PFS) was 27.4 months (12-month PFS rate, 67%). Five patients died (disease progression, n = 4; septic shock, n = 1). Seventeen patients (40%) had grade 3 or higher adverse events (AEs), most commonly neutropenia (14%), anaemia, dyspnoea (7% each), fatigue and thrombocytopenia (5% each). Hypertension occurred in 5%; atrial fibrillation/flutter and major haemorrhage were not reported. AEs led to treatment discontinuation in three (7%) patients. Acalabrutinib was active and well tolerated in patients with R/R MZL.

Age and weight considerations for the use of continuous positive airway pressure therapy in pediatric populations: an American Academy of Sleep Medicine position statement.

This position statement provides guidance for age and weight considerations for using continuous positive airway pressure therapy in pediatric populations. The American Academy of Sleep Medicine commissioned a task force of experts in pediatric sleep medicine to review the medical literature and develop a position statement based on a thorough review of these studies and their clinical expertise. The American Academy of Sleep Medicine Board of Directors approved the final position statement. It is the position of the American Academy of Sleep Medicine that continuous positive airway pressure can be safe and effective for the treatment of obstructive sleep apnea for pediatric patients, even in children of younger ages and lower weights, when managed by a clinician with expertise in evaluating and treating pediatric obstructive sleep apnea. The clinician must make the ultimate judgment regarding any specific care in light of the individual circumstances presented by the patient, accessible treatment options, patient/parental preference, and resources. CITATION: Amos L, Afolabi-Brown O, Gault D, et al. Age and weight considerations for the use of continuous positive airway pressure therapy in pediatric populations: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2022;18(8):2041-2043.

Transforming the treatment of psoriasis to the 21st century: Detecting subclinical therapeutic response to secukinumab using optical coherence tomography as a prognostic indicator.

BACKGROUND: Optical coherence tomography (OCT) is a noninvasive imaging device that scans the skin up to 2 mm in depth. OCT can capture real-time epidermal thickness (ET) measurements and detect subclinical changes in inflammatory skin diseases like eczema and psoriasis. © 2022 Wiley Periodicals LLC. OBJECTIVE: To determine if measuring ET with OCT can detect a subclinical therapeutic response in psoriasis treated with the biological therapy, secukinumab (an IL-17A antagonist). DESIGN: Phase IV, single-center, open-label, and single-arm study. PARTICIPANTS: Twenty-six consecutive patients with moderate to severe plaque psoriasis. MEASUREMENTS: Clinical, dermoscopic, and OCT images were obtained at each visit. The clinician measured disease severity with the Investigator's Global Assessment (IGA) and Psoriasis Area And Severity Index (PASI). OCT was used to scan the ET at the center of lesional skin (ET-L), along the border, and normal skin (ET-N) on the same body plane; their difference was noted as ΔET. RESULTS: Initially, ET-L was greater than ET-N (p < 0.0001), their differences decreased throughout the study, and there were no significant differences at Week 16 (p = 0.48). Twenty-four (92%) patients achieved a 50% reduction in PASI score (PASI50); they had lower ΔET at Weeks 0, 1, 3, 4, and 8 compared to those who did not clear (p < 0.04). Having a lower ΔET at Week 4 was associated with a shorter time to reach PASI50 (p = 0.02). CONCLUSION: ET measurements using OCT can detect an early subclinical response to secukinumab compared to clinical scoring and identify nonresponders as early as 4 weeks.

Continuous Decline in Myocardial Infarction and Heart Failure Hospitalizations during the First 12 Months of the COVID-19 Pandemic in Israel.

BACKGROUND: A decline in cardiovascular hospitalizations was observed during the initial phases of the COVID-19 pandemic. We examine the continuous effect of the COVID-19 pandemic in reducing cardiovascular hospitalization and associated mortality rates during the first year of the pandemic in Israel. METHODS: We conduct a retrospective cohort study using the data of Clalit Health Services, the largest healthcare organization in Israel. We divide the Corona year into six periods (three lockdowns and three post-lockdowns) and compare the incidence rates of cardiovascular hospitalizations and 30-day all-cause mortality during each period to the previous three years. RESULTS: The number of non-STEMI hospitalizations during the first year of the pandemic was 13.7% lower than the average of the previous three years (95% CI 11-17%); STEMI hospitalizations were 15.7% lower (95% CI 13-19%); CHF (Congestive heart failure) hospitalizations were 23.9% lower (95%, CI 21-27%). No significant differences in 30-day all-cause mortality rates were observed among AMI (acute myocardial infarction) patients during most of the periods, whereas the annual 30-day all-cause mortality rate among CHF patients was 23% higher. CONCLUSIONS: AMI and CHF hospitalizations were significantly lower during the first year of the pandemic relative to 2017-9. Mortality rates were higher in the case of CHF patients but not in the case of AMI patients, possibly due to a change in the clinical acuity of patients arriving at the hospitals. We conclude that targeted public health messaging should be implemented together with proactive monitoring, in order to identify residual disability in patients who may have received non-optimal treatment during the pandemic.

Change in Hospitalizations and 30-Day Mortality of Patients With Acute Myocardial Infarction During the First COVID-19 Lockdown - A Pure Social Isolation Effect?

BACKGROUND: The COVID-19 pandemic has had diverse effects on population health and psychology in relation to non-COVID-19 diseases, as well as on COVID-19 infection. Fewer patients with acute myocardial infarction (AMI) sought medical attention during the first lockdown of the pandemic. METHODS AND RESULTS: We conducted a retrospective cohort study of Clalit Health Services patients treated in multiple hospitals for AMI. We examined the numbers and characteristics of the patients and 30-day mortality during three 5-week phases of the first wave of the COVID-19 pandemic in Israel: pre-lockdown (N = 702), lockdown (N = 584), and lockdown-lift (N = 669). We compared data for the same period in 2018 and 2019. We stratified the data by ST-elevation myocardial infarction (STEMI) and non-STEMI. AMI hospitalizations during the lockdown were 17% lower than in the pre-lockdown period (rate ratio-0.83, 95% CI 0.74-0.93), and 22% and 31% lower than in the corresponding periods in 2018 and 2019, respectively. The reduction was mainly attributed to non-STEMI hospitalizations (26% lower than the pre-lockdown period in 2020). Hospitalizations due to both STEMI and non-STEMI were moderately reduced during the post-lockdown period compared to the corresponding periods in 2018 and 2019. Thirty-day mortality rate was similar for all the periods assessed. CONCLUSIONS: The number of hospitalized patients with AMI during the first COVID-19 lockdown and post-lockdown periods was significantly reduced, without significant changes in 30-day mortality rates.

Combining Nd:YAG laser with optical coherence tomography for nonsurgical treatment of basal cell carcinoma.

BACKGROUND: Effective and aesthetically appealing management options are needed for basal cell carcinoma (BCC), the most common skin cancer. The Nd:YAG laser shows promise, but most studies use biopsy to demonstrate tumor clearance. Optical coherence tomography (OCT) could allow good tumor margin control while enabling recurrence monitoring. OBJECTIVE: Determine the efficacy of the Nd:YAG laser to treat BCCs while controlling for tumor margin with OCT. METHODS: A 1064-nm Nd:YAG laser was applied to treat 119 BCCs in 102 patients, where tumor margins were approximated using OCT. Lesions were treated every 2 months until no residual tumor remained; patients were monitored for 1 year after treatment completion for clinical and subclinical recurrences. Outcomes were analyzed retrospectively. RESULTS: Most BCCs cleared after one treatment (85/119, 70.4%). Several factors were significantly associated with a suboptimal response, that is, those with recurrence or requiring ≥2 treatments: lesion size >5 mm (p = 0.03), focal sclerosing subtype (p = 0.018), and immunosuppression (p = 0.039). Midface location, patient compliance, and diagnosis method were codependent variables (r2 = 0.2011, p = 0.0008). All BCCs (119/119) demonstrated complete clinical and subclinical tumor clearance 2 months after final laser treatment. By 1 year, overall clinical recurrence rate (RR) was 1.7% (2/119) and cumulative subclinical RR was 4.2% (5/119). Upon excluding immunosuppressed patients, clinical RR and combined subclinical RR for primary BCC were 1% (1/98) and 2% (2/98), respectively, and 0% (0/17) and 11.8% (2/17), respectively, for recurrent BCC. CONCLUSIONS: The Nd:YAG nonablative laser can offer an effective treatment for BCCs when used with noninvasive diagnostic tools such as OCT.

Bridging Care Transition After Hospitalization for Atrial Fibrillation and Coronary Interventions.

ABSTRACT: Treatment fragmentation between hospitals and the community can result in catastrophic outcomes; uninterrupted treatment with anticoagulant and platelet aggregation inhibitors is particularly important. We assessed the proportion and characteristics of patients who did not visit their primary community-based physician within 1 week of discharge from our department of cardiovascular medicine and the proportion that failed to procure essential drugs at the community pharmacy. We prospectively studied 423 patients who were discharged from our department. They were provided detailed explanations, tablets for 7 days, prescriptions, and a printed drug plan. We traced the time from discharge until a visit with a primary community-based physician, and the time until the procurement of medications, using our computerized community-hospital-integrated system. Complete data were available for 313 patients, of whom 220 were treated with anticoagulants or platelet aggregation inhibitors. For 175 patients, these drugs were initiated during index hospitalizations. Only 1 patient did not receive platelet aggregation inhibitors despite recommendations. Seventy-nine patients (25%) first visited their primary care physicians more than 1 week after discharge. Predictors for delayed visits were living alone (hazard ratio 1.91) and having an in-house caregiver (hazard ratio 2.01). In conclusion, all but 1 patient continued drug therapy after discharge from the hospital. The simple predischarge steps included patient education and provision of a 1-week supply of tablets and prescriptions. Treatment continuation was independent of visits to the community-based primary physician. Patients living alone or with an in-house caregiver more often delayed visits to primary physicians yet continued relevant drug therapy.

History-taking revisited: Simple techniques to foster patient collaboration, improve data attainment, and establish trust with the patient.

The relevance and importance of the medical interview has been challenged with improved imaging technologies, web-based medicine, and use of artificial intelligence. The medical interview has three goals: Acquiring accurate medical data about the patient and the etiology of symptoms and signs, learning about the patient's personality, culture, and beliefs, and creating and building trust with the patient. Reduced human resources in the medical system and increased crowding in the interview setting, such as the emergency room and outpatient clinics, have strengthened the need for high quality and efficient interviews that fulfils the three goals of the interview. This manuscript proposes a structured six methods that contribute to the quality and efficiency of the medical interview with special focus on learning about the patients' life and creating trust with him.

[TEACHING INTERNAL MEDICINE IN THE SHADOW OF THE COVID-19 OUTBREAK - THE EXPERIENCE OF THE TECHNION FACULTY OF MEDICINE].

INTRODUCTION: The clerkship of internal medicine is pursued in the 2nd semester of the 4th year at the Technion Medical School. Following the COVID-19 outbreak, frontal and bedside teaching was interrupted. Therefore, we decided to provide distant teaching until having the opportunity to resume clinical bedside teaching. A team of tutors composed a course of weekly units, each week assigned to a different subject in internal medicine. A total of 120 students were divided into 15 groups of 8 students, each group guided by a personal tutor. The format of each unit included online pretest, clinical virtual cases and two separate 2 hour ZOOM sessions with the tutor. The pretest was based on 1-3 chapters from Harrison's Internal Medicine textbook, 20th edition, and consisted of both clinical reasoning and knowledge questions. During ZOOM sessions with the tutor, the students practiced clinical problem solving. In addition, all the students were granted free access to the commercial "Aquifer" case-based virtual course for more practice. The students' feedback at the end of the learning period revealed that, although frustrated in being away from the clinics, the overall level of satisfaction from the course was good (rated 5 or 4/5 by 65% of responders) and the time was used efficiently. In conclusion, the students received a positive proactive learning experience of both theoretical aspects and clinical reasoning skills in internal medicine. There is no doubt that bedside teaching in medicine is invaluable and can't be replaced by any other means, however, given the circumstances, our format provided a reasonable temporary alternative.