Advances in the Continuous Flow Synthesis of 3- and 4-Membered Ring Systems.

Small carbo- and heterocyclic ring systems have experienced a significant increase in importance in recent years due to their relevance in modern pharmaceuticals, as building blocks for designer materials or as synthetic intermediates. This necessitated the development of new synthetic methods for the preparation of these strained ring systems focusing on effectiveness and scalability. The high ring strain of these entities as well as the use of high-energy reagents and intermediates has often challenged their synthesis. Continuous flow approaches have thus emerged as highly effective means to safely and reliably access these strained scaffolds. In this short review, key developments in this field are summarised showcasing the power of continuous flow approaches for accessing 3- and 4-membered ring systems via thermal, photo- and electrochemical processes.

A dual telescoping lag screw nailing system for intertrochanteric fractures: retrospective analysis of clinical and radiologic outcomes.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate whether this system is associated with a reduced rate of failure and complications in patients treated for proximal femoral fractures with intramedullary nailing. MATERIALS AND METHODS: 742 Patients with AO-OTA 31-A intertrochanteric fractures were enrolled at a single Institution. Functional evaluation was assessed through the Functional Independence Measure (FIM™) instrument and Parker's New Mobility Score (NMS). Radiological follow-up included the degree of the reduction according to the Baumgartner criteria, the Tip-Apex Distance, and the shortening of the telescoping screws and its lateral protrusion. RESULTS: Pre-operative mean FIM™ and NMS were 4.3 (range 1-9) and 98.7 (range 22-126), respectively. At the 12-month follow-up the average FIM™ and NMS were 95.3 (range 22-126) and 3.7 (range 1-9), respectively. Mean shortening of the lag screws was 4.3 mm (range 1-8) and mean lateral protrusion was 1.7 mm (range 0-3). 3 Cases (0.70%) of non-consolidation requiring reoperation were recorded. 1 Case (0.24%) of these cases was also characterized by nail breakage. No case of cut-out has been reported at our follow-up. CONCLUSIONS: This dual telescoping nail system is effective and safe. The sliding of the telescoping screws within the barrel is able to decrease strain from the femoral head during weight bearing reducing the risk of cut-out.

Recommendations for an Approach to Random Skin Biopsy in the Diagnosis of Intravascular B-Cell Lymphoma.

Intravascular B-Cell Lymphoma (IVBCL) is a rare type of extranodal large B-cell lymphoma where clonal B-cells selectively home to and replicate in the lumen of small vessels. Random skin biopsy (RSB) of uninvolved skin is a reputable tool to diagnose this protean entity and thus dermatologists are involved in its diagnosis. A literature review was completed to derive an approach to RSB in these patients to maximize diagnostic yield of IVBCL and minimize morbidity. Based on this review, data from 27 patients where clinical signs and symptoms and results of investigations were able to be linked to a positive diagnosis of IVBCL from RSB from 11 papers from 2003 to 2021 were analyzed. Following this analysis, RSB should be considered when there are no clinical skin findings and there is an elevated lactate dehydrogenase in the absence of lymphadenopathy and presence of fever of unknown origin, thrombocytopenia, anemia, and ferritinemia. Three to four RSBs from the thigh, abdomen and/or posterior upper arm should be performed via either incisional or telescoping punch biopsies and should include senile/cherry angioma(s) if present. If RSB results in a diagnosis of IVBCL, hematology should be consulted for further management. Consideration of a false negative biopsy or alternative diagnoses should be explored if RSB is negative for IVBCL. Following a standard approach for RSB in these patients will increase diagnostic yield of IVBCL while decreasing the risk of harm to the patient.

Intussusception Allograft Prosthetic Composites in Total Hip Arthroplasty: A Salvage Operation for Extensive Femoral Bone Loss.

BACKGROUND: Allograft prosthetic composites (APCs) have been used to perform revision total hip arthroplasty (THA) for massive femoral bone loss or deformity. Intussusception, or "telescoping", APC techniques have been proposed to enhance the contact area of this interface and provide superior mechanical fixation over conventional methods. The purpose of this study is to present to our knowledge, the largest series of telescoping APC THAs, along with surgical technique details and midterm (average 5-10 years) clinical results. METHODS: Between 1994 and 2015, 46 revision THAs performed with proximal femoral telescoping APCs were retrospectively reviewed at a single institution. Overall survival, reoperation-free survival, and construct survival rates were calculated via Kaplan-Meier methods. In addition, radiographic analyses were performed to evaluate for component loosening, union at the APC-host interface, and resorption of the allograft. RESULTS: At 10 years, the overall patient survival was 58%, reoperation-free survival was 76%, and construct survival was 95%. Reoperation was performed in 20% (n = 9) and only 2 constructs required resection. Radiographic analyses performed at latest follow-up revealed no instances of radiographic femoral stem loosening, an 86% union rate at the APC-host site, 23% with signs of some allograft resorption, and a 54% trochanteric union. The mean postoperative Harris hip score was 71 points (range, 46-100). CONCLUSION: Telescoping APCs are technically demanding, but provide reliable mechanical fixation for the reconstructing of large proximal femoral bone deficits in revision THA with excellent construct survivorship, acceptable reoperation rates, and good clinical outcomes. LEVEL OF EVIDENCE: IV.

Risk factors for over-telescoping in reverse oblique intertrochanteric fractures.

PURPOSE: Postoperative over-telescoping (OT) with lag screws is often observed in reverse oblique intertrochanteric fractures. This study aimed to clarify the risk factors of OT in patients with reverse oblique intertrochanteric fractures. METHODS: Electronic medical records of patients diagnosed with reverse oblique intertrochanteric fractures using plain radiography who underwent operative fixation with an intramedullary nail between August 2013 and December 2019 were reviewed. Patients were classified into two groups according to the Futamura classification: lateral wall pattern (LW) and reverse oblique pattern (RO). The incidence of OT in the LW and RO groups was compared. Also, we compared the incidence of OT for each reduction type in the LW group. RESULTS: Twenty patients had LW, and nine had RO. OT was observed in eight fractures (42.1%) in the LW group but not in the RO group. The incidence of OT was significantly higher in the LW group than in the RO group (P = 0.0261). Among the 19 fractures with LW, OT was observed in 7 of 10 and 1 of 9 fractures with postoperative reduction in the intramedullary and extramedullary or anatomical types, respectively. In the LW group, the incidence of OT was significantly higher in fractures with postoperative reduction in the intramedullary type than in those of the extramedullary or anatomical type (P = 0.0198). CONCLUSION: Our study showed that the incidence of OT was significantly higher in LW than in RO and that postoperative reduction in the intramedullary type in LW was a risk factor for OT.

Colonoscopic reduction of a transanal prolapsed ileocolic intussusception.

Transanal protrusion of intussusception (TAPI; also known as prolapsed intussusception) is a rare complication. Here, we present a successful colonoscopic reduction of ileocolic intussusception presented with transanal prolapse. An 8­month male child, weighing 8 kg, was referred to our hospital presenting with a mass in his anal canal, diarrhea and rectal bleeding for two days. The sonographic evaluation revealed an ileocolic intussusception in the rectosigmoid area. The patient was treated using colonoscopic reduction. To our knowledge, this is the first study reporting colonoscopic reduction for transanal prolapsed intussusceptions. Our study suggests gastroenterologists to consider colonoscopy as a therapeutic method for prolapsed intussusceptions and encourages them to attempt reducing the invagination using this method before laparotomy, especially in cases presenting within 48 h of onset of symptoms and no peritonitis symptoms.

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography.

An efficient continuous flow process is reported for the synthesis of various 1,3,4-oxadiazoles via an iodine-mediated oxidative cyclisation approach. This entails the use of a heated packed-bed reactor filled with solid K2CO3 as a base. Using DMSO as solvent, this flow method generates the target heterocycles within short residence times of 10 minutes and in yields up to 93%. Scale-up of this flow process was achieved (34 mmol/h) and featured an integrated quenching and extraction step. Lastly, the use of an automated in-line chromatography system was exploited to realise a powerful flow platform for the generation of the heterocyclic targets.

New synthesis of a late-stage tetracyclic key intermediate of lumateperone.

New approaches have been tested for the synthesis of lumateperone intermediates. As a result of these efforts, a novel synthesis of the late-stage tetracyclic key intermediate of lumateperone starting from the commercially available quinoxaline is described. The tetracyclic skeleton was constructed by the reaction of 1-trifluoroacetyl-4-aminoquinoxaline with ethyl 4-oxopiperidine-1-carboxylate in a Fischer indole synthesis. The inexpensive starting material, the efficient synthetic steps, and the avoidance of the borane-based reduction step provide a reasonable potential for scalability.

Flow Diversion in Acute Sub Arachnoid Haemorrhage: A Single Centre Five Year Experience.

OBJECTIVES: The role of flow-diversion in acute sub-arachnoid haemorrhage (SAH) is controversial. Many of the published data warns of high rates of procedure-related complications and aneurysmal rebleed. This study evaluates the safety, efficacy, clinical and angiographic outcomes of acute flow-diversion at our institute. METHODS: The institutional database from June 2015 to June 2020 was retrospectively reviewed for aneurysmal SAH (aSAH) treated with flow diversion. Clinical presentation, procedural details, complications, anti-platelet usage, rebleeding and aneurysm occlusion rates and outcomes were recorded. RESULTS: 22 (59% females; median age 56 years) consecutive patients were identified. None of them were on regular antiplatelets/anticoagulation in the 15-days preceding the treatment. The mean aneurysm diameter was 5.4 mm and the median delay to flow-diversion was 2 days. Almost 73% (16/22) of patients had adjunctive coiling in the same session. There was no aneurysmal rebleed at a median follow up of 8.5 months and 86.3% (19/22 patients) had good clinical outcomes (3-month MRS 0-2). Adverse events related to the flow diversion procedure were seen in 3 patients; none of them had a medium to long-term clinical consequence. Three patients died from complications of SAH, unrelated to the procedure. Vascular imaging follow-up was available for 20 patients and the complete aneurysm occlusion rate was 95%. CONCLUSION: Flow-diversion could be a reasonably safe and effective technique for treating ruptured aneurysms in appropriately selected patients when conventional options of surgical clipping and coiling are considered challenging.

Continuous Flow Synthesis of Anticancer Drugs.

Continuous flow chemistry is by now an established and valued synthesis technology regularly exploited in academic and industrial laboratories to bring about the improved preparation of a variety of molecular structures. Benefits such as better heat and mass transfer, improved process control and safety, a small equipment footprint, as well as the ability to integrate in-line analysis and purification tools into telescoped sequences are often cited when comparing flow to analogous batch processes. In this short review, the latest developments regarding the exploitation of continuous flow protocols towards the synthesis of anticancer drugs are evaluated. Our efforts focus predominately on the period of 2016-2021 and highlight key case studies where either the final active pharmaceutical ingredient (API) or its building blocks were produced continuously. It is hoped that this manuscript will serve as a useful synopsis showcasing the impact of continuous flow chemistry towards the generation of important anticancer drugs.

S-shaped titanium endomedullary nail reduces telescoping of comminuted midshaft clavicular fractures.

BACKGROUND: The surgical treatment of displaced midshaft clavicular fractures (DMCF) is clinically relevant and a much discussed topic. The axial stability of DMCF after intramedullary nailing (IMN) is still a matter of debate. OBJECTIVE: Our objective was to present a modification of IMN of DMCF with S-shaped titanium endomedullary nail (TEN) and determine fracture telescoping from day one after surgery to the time of fracture healing. METHOD: In a prospective analytic cohort study over a 6-year period (2012-2017) at a Level II trauma care centre, a total of 128 patients with DMCF were included and classified according to the AO/OTA classification system. Group I was AO/OTA type 15.2A/15.2B (N = 68) and group II was AO/OTA type 15.2C (N = 60). After a modified open stabilization technique of each DMCF with IMN (S-shaped TEN), the dynamics of radiological assessed telescoping until union and rate of surgical adverse events were measured. Significance was assumed for p < 0.05. RESULTS: One day after surgery, fractured clavicles were lengthened slightly in both groups compared to the unfractured clavicules (group I: 1.2%; group II: 0.9%). After osseus consolidation, the fractured clavicules were significantly shortened in both groups (group I: - 2.9%; group II: - 3.6%). Measurement of the clavicular shortening at one day postsurgically and at consolidation revealed a mean telescoping of - 3.99% in group I and of - 4.6% in group II. The difference between the two groups was not significant (P = 0.522). The overall rate of major surgical adverse events was 2.3%. CONCLUSION: The proposed operative technique of IMN (stabilization of the DMCF with a long, S-shaped, tight-fitting TEN) provides enough axial stability to prevent significant telescoping of the comminuted fractures. The rate of nonunion is low and the overall rate of major adverse events is similar to the reported events after plate fixation in the literature.

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and ß-amino acid derivatives.

A continuous flow process is presented that couples a Curtius rearrangement step with a biocatalytic impurity tagging strategy to produce a series of valuable Cbz-carbamate products. Immobilized CALB was exploited as a robust hydrolase to transform residual benzyl alcohol into easily separable benzyl butyrate. The resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity. The derivatization of these products via complementary flow-based Michael addition reactions furthermore demonstrated the creation of ß-amino acid species. This strategy thus highlights the applicability of this work towards the creation of important chemical building blocks for the pharmaceutical and speciality chemical industries.

Change in telescoping leg strategy with varying walking speed to modulate force advantage.

Human walking consists of two major sequential events (i.e., single- and double-support phases). Although there have been many studies relating to basic principles of the each stage, how the two distinct but continuous phases interact with each other remains to be clarified. We examined the change in walking strategy with varying walking speed on a local reference frame with telescoping and tangential axes; we expect that the telescoping directional dynamics at the end of a single-support phase change with walking speed to facilitate the modulation of the push-off work during a double-support phase. The telescoping directional force and power are calculated using two methods: model simulation and kinematic configuration. The empirical walking data for eight healthy young subjects and the corresponding model parameters obtained from a data-fit optimization were used to investigate the changing trend of each factor (i.e., force and power) with the increase in speed. The resulting force at the end of the single-support phase significantly increased with the walking speed for both methods, whereas the resulting power remained nearly unchanged and was close to zero for the entire range of walking speeds. This result implies that the positive amount of the telescoping directional force at the end of the single-support phase may be a certain type of preparation for the double-support phase, which can contribute to a larger push-off.

Dissecting distal cerebellar artery aneurysms: options beyond a parent vessel sacrifice.

Parent vessel occlusion (PVO) is the conventional endovascular treatment (EVT) for dissecting distal cerebellar artery aneurysms (DCAA). The associated ischemic sequelae are often well-tolerated. However, at the outset, the magnitude of this risk is uncertain. Meanwhile, non-PVO endovascular treatments (EVT) are deemed to provide incomplete protection from a rebleed. This study reviews our experience in the management of dissecting DCAA with emphasis on the effectiveness of parent vessel-preserving endovascular strategies as compared to PVO. Our institutional database was reviewed for all the dissecting DCAA aneurysms treated by endovascular means between Nov 2015 and Oct 2018. Their clinical presentations, imaging findings, EVT techniques, and clinical outcomes were retrospectively evaluated. Eighteen dissecting DCAA were identified: 13 in the posterior-inferior cerebellar artery (PICA), 3 in anterior-inferior cerebellar artery (AICA), and 2 in superior cerebellar artery (SCA). Median patient age was 61 years (range 40-86; average 60.7 years) with a 5:1 female predominance. Nine (6 in the PICA and 3 in the AICA) patients were managed by parent vessel-preserving strategies (6 with isolated endosaccular coiling and 3 with telescoping stents) while the remaining 9 (7 in the PICA and 2 in the SCA) were treated by PVO.The frequency of early rebleed was the same (11%) in both the treatment arms. One patient from the PVO arm suffered an extensive cerebellar infarct that mandated decompressive craniectomy and adversely affected her recovery. There were no such complications in patients treated with parent vessel-preserving strategies. No recurrence/rebleed was encountered in the 3 aneurysms secured using telescoping stents. Overall, excellent clinical outcomes (mRS of 0 and 1) were sparsely seen in the patients who had PVO (89 vs 23%). In dissecting DCAA, aforedescribed, parent vessel-preserving strategies are as effective as the more frequently used option of PVO in preventing an early rebleed. However, these are technically challenging, may be feasible in a smaller proportion of patients, and would need meticulous imaging follow-up in the acute period. When successfully implemented, these strategies can deliver excellent clinical outcomes and eliminate the uncertain risk of ischemic complications associated with PVO.

Looking at the past through a telescope: adults postdated their earliest childhood memories.

Our previous studies have consistently shown a telescoping error in children's dating of earliest childhood memories. Preschool children through adolescents systematically date their earliest memories at older ages, in comparison with the age estimates provided by their parents or by themselves previously. In the current study, we examined the dating of earliest childhood memories in two samples of college adults and collected independent age estimates from their parents. Consistent with our findings with children, adults significantly postdated their earlier memories by approximately 12 months (Study 1) and 6 months (Study 2). The actual age of earliest memories was 2.5 years after adjusted for telescoping errors, 1 year earlier than what is commonly believed at 3.5 years. These findings challenge commonly held theoretical assumptions about childhood amnesia and highlight critical methodological issues in the study of childhood memory.

Technique to Facilitate Retrograde Puncture of Mid to Upper Calf Tibial Vessels.

PURPOSE: To describe a simple maneuver to facilitate the retrograde puncture of challenging tibial vessels in the lower leg. TECHNIQUE: Because of the depth of the tibial vessels at the mid to upper calf, especially in obese or muscular patients, a 7- or 9-cm, 21-G micropuncture needle is often needed to reach the artery. However, the low profile of the needle contributes to its flexibility and therefore the tendency to bend as it progresses through the deep tissues, hindering access to the target vessel. To overcome this obstacle, a 4- to 5-cm, 18-G needle is initially placed pointing to the artery. The 21-G needle is advanced through it to the target site. This simple maneuver increases the support to the 21-G needle, preventing its bending and facilitating arterial puncture in the presence of calcified vessels. CONCLUSION: The telescoping needle technique may be considered as a bailout procedure in the retrograde tibial approach after failed attempts secondary to needle bending or calcified vessels.

The Telescoping Phenomenon: Origins in Gender Bias and Implications for Contemporary Scientific Inquiry.

BACKGROUND: In an article published in International Journal of the Addictions in 1989, Nick Piazza and his coauthors described "telescoping," an accelerated progression through "landmark symptoms" of alcoholism, among a sample of recovering women. OBJECTIVES: The aim of this critical analysis is to apply a feminist philosophy of science to examine the origins of the framework of telescoping research and its implications for contemporary scientific inquiry. METHODS: A feminist philosophy of science framework is outlined and applied to key source publications of telescoping literature drawn from international and United States-based peer-reviewed journals published beginning in 1952. RESULTS: A feminist philosophy of science framework identifies gender bias in telescoping research in three ways. First, gender bias was present in the early conventions that laid the groundwork for telescoping research. Second, a "masculine" framework was present in the methodology guiding telescoping research. Third, gender bias was present in the interpretation of results as evidenced by biased comparative language. CONCLUSIONS: Telescoping research contributed to early evidence of critical sex and gender differences helping to usher in women's substance abuse research more broadly. However, it also utilized a "masculine" framework that perpetuated gender bias and limited generative, novel research that can arise from women-focused research and practice. A feminist philosophy of science identifies gender bias in telescoping research and provides an alternative, more productive approach for substance abuse researchers and clinicians.

Anteromedial cortical support reduction in unstable pertrochanteric fractures: a comparison of intra-operative fluoroscopy and post-operative three dimensional computerised tomography reconstruction.

PURPOSE: Anteromedial cortical support reduction is favourable for secondary stability after limited sliding in unstable pertrochanteric fractures. The aim of this study was to compare the accuracy and agreement between intra-operative fluoroscopy and post-operative 3D reconstruction. MATERIALS AND METHODS: A retrospective analysis of 28 patients (mean 81.6 years) treated with short cephalomedullary nails was performed. All patients had full sets of intra-operative fluoroscopy and post-operative 3D CT images. Observation was focused on the position of the anteromedial cortices of the inferior corner between the head-neck fragment and femoral shaft, and their relationship was categorised into three types: positive, neutral and negative. The percentage of subsequent changes in cortical reduction quality between fluoroscopy and 3D CT was calculated and compared. RESULTS: There were 24 positive (85.7%), four neutral and no negative positions in the anteroposterior (AP) view and one positive, 20 neutral (71.4%) and seven negative positions in the lateral view from fluoroscopy. On post-operative 3D CT images with a full range of rotation, definitive anteromedial cortical contact (positive and neutral support) was observed in 18 cases (64.3%). Ten cases lost the anteromedial cortical buttress. With the posteromedial region of the lesser trochanter detached, a positive AP cortical position combined with a positive/neutral lateral position on fluoroscopy (17 cases) was highly predictive of reliable, definitive cortical support (15 cases, 88.2%) on 3D CT. A negative lateral position on fluoroscopy (seven cases), regardless of the combination in the AP view, was likely to predict the final loss of cortical support (six cases, 85.7%) on 3D CT; a positive/neutral lateral position (21 cases) was only associated with loss of support in four cases (19.1%) (p < 0.05). CONCLUSIONS: A lateral negative position of the anterior cortex on fluoroscopy for unstable pertrochanteric fractures may be highly predictive of post-operative final loss of the anteromedial cortical buttress, which should be avoided during operation.

Neuroticism Magnifies the Detrimental Association between Social Media Addiction Symptoms and Wellbeing in Women, but Not in Men: a three-Way Moderation Model.

Addiction symptoms in relation to the use of social networking sites (SNS) can be associated with reduced wellbeing. However, the mechanisms that can control this association have not been fully characterized, despite their relevance to effective treatment of individuals presenting SNS addiction symptoms. In this study we hypothesize that sex and neuroticism, which are important determinants of how people evaluate and respond to addiction symptoms, moderate this association. To examine these assertions, we employed hierarchical linear and logistic regression techniques to analyze data collected with a cross-sectional survey of 215 Israeli college students who use SNS. Results lend support to the hypothesized negative association between SNS addiction symptoms and wellbeing (as well as potentially being at-risk for low mood/ mild depression), and the ideas that (1) this association is augmented by neuroticism, and (2) that the augmentation is stronger for women than for men. They demonstrated that the sexes may differ in their SNS addiction-wellbeing associations: while men had similar addiction symptoms -wellbeing associations across neuroticism levels, women with high levels of neuroticism presented much steeper associations compared to women with low neuroticism. This provides an interesting account of possible "telescoping effect", the idea that addicted women present a more severe clinical profile compared to men, in the case of technology-"addictions".