Use of bevacizumab in a patient with Whipple's disease: managing diagnostic uncertainty.

A man in his 30s with intellectual disability presented with 1 month of diarrhoea, weight loss and dyspnoea. Investigations were hampered due to significant anxiety. Laboratory tests detected microcytic anaemia and hypoalbuminaemia. CT demonstrated a fat-containing infiltrate in the mediastinum, mesentery and axillae, and pulmonary ground-glass infiltrates. Biopsy of the axilla showed cystic lymphatic malformations involving adipose tissue and lymph nodes, leading to a provisional diagnosis of generalised lymphatic anomaly. Over the subsequent 4 months, the patient's respiratory status deteriorated, leading to type 1 respiratory failure necessitating intubation. After multidisciplinary discussion, a decision was made to trial bevacizumab, an anti-VEGF agent, with subsequent improvement in respiratory status. While intubated, gastroscopy was performed; duodenal biopsies revealed pathognomonic changes of Whipple's disease, confirmed on PCR of duodenal and axillae biopsies. This was deemed the most likely unifying diagnosis; antibiotic treatment was commenced, bevacizumab was ceased, and the patient has remained well after 18 months.

Underutilisation of gastric emptying studies and underrecognition of gastroparesis in people with diabetes treated in a hospital setting.

Delayed gastric emptying occurs in up to 30% of patients with long-standing diabetes and causes significant morbidity. We performed a retrospective cohort study of 341 patients who had participated in a gastric emptying study from 2018 to 2021 in a large teaching hospital. Given the expected prevalence of gastroparesis in people with diabetes, there were fewer studies than anticipated, which could lead to gastroparesis underrecognition.

Thioetherification of Aryl Halides with Thioacetates.

A palladium-catalyzed cross-coupling of thioacetates and aryl halides is described herein. Using a catalyst screening kit, tBuBrettPhos Pd G3 was found to be a unique catalyst for this reaction, affording the desired thioarene products in high yields under mild reaction conditions. The thioacetate starting materials are readily available, allowing for quick access to these more lab friendly reagents. Reactions described herein range from the late-stage coupling of complex thioacetates to the first report of a mild set of conditions for thiomethylation of aryl halides.

Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.

Should Sequential Bilateral Total Knee Arthroplasty Be Limited to Patients Younger than 80? A Two-Arm Propensity Matched Study.

Despite multiple studies, there remains a debate on the safety of bilateral total knee arthroplasty (BTKA) in the average age patient, with a paucity of data on the outcome of BTKA in an elderly population. This study included 89 patients aged 80 years and older undergoing sequential BTKA over 14 years were identified in a prospectively collected database. Two matched comparison groups were created: patients under 80 undergoing sequential BTKA and patients over 80 undergoing unilateral TKA (UTKA). An analysis of complications, mortality, revision, and patient-reported outcome measures was performed. Mean age of the elderly cohorts was similar: 82.6 for BTKA and 82.9 for UTKA. The average age BTKA cohort had a mean age of 69.1. Complication rates were higher in bilateral cohorts, more so in the elderly BTKA cohort. Pulmonary embolism (PE) was observed in bilateral cohorts only. In these patients, history of PE and ischemic heart disease was a strong predictive factor for developing a major complication. There was no difference in revision rates and infection rates between the three cohorts, and no difference in patient survivorship between the two elderly cohorts. Through the combination of low revision and high survivorship rates and comparable clinical outcomes, this article demonstrates that simultaneous BTKA is an appropriate option to consider for an elderly patient, with proper patient selection and perioperative management. The demonstrated risk groups show that emphasis on patient selection should be focused on medical history rather than chronological age.

A Media Biopsy: Examining the Quality of Cancer Reporting in Australia, 1997 and 2017.

This article investigates the quality of cancer reporting from a time of prosperity to a time of austerity for the press. Australia is a useful case study because of its concentrated press media market that has experienced a decline in the number of newsroom reporters from the 20th to the 21st century. We undertake a content analysis of news stories published in 1997 and 2017 about cancer treatments and cancer medical research. Using keyword searching techniques of the news database Factiva, 633 news reports about cancer were detected. Of these, 120 stories met the research criteria. Each story was assessed across eight variables using a coding tool, the Media Quality Index (MQI). The study finds 2017 stories had lower scores (equating to less quality) across all eight variables compared to the 1997 cohort. Of statistical significance, 2017 stories were less likely to quantify the benefits of a proposed intervention, while stories discussing medical research were less comprehensive about research findings. The 2017 stories were less likely to discuss side effects or the potential for harm, and were more sensational, with incongruent headlines compared to content. The empirical evidence pointing to a deterioration in mainstream media reporting about cancer has implications for broader health literacy. It may foster unrealistic patient expectations about clinical practice and treatment options, with public policy implications such as overutilization of health services. The study serves as a reminder to medical practitioners that health communication directly with patients is vital as media reporting alone cannot reliably inform patients about their cancer diagnosis and treatment.

Healthy knee KT1000 measurements of anterior tibial translation have significant variation.

PURPOSE: The most commonly used arthrometer for measuring and reporting anterior tibial translation after anterior cruciate ligament reconstruction is the KT1000. Reports on its consistency and reproducibility vary in the literature, but it remains the "gold standard". The purpose of this study was to assess agreement of KT1000 measurements in a daily clinical setting. METHODS: A retrospective analysis of anterior knee translation in the healthy knee of 770 patients over a 17-year time period was performed. In this cohort, a total of 24 investigators performed 1890 measurement sets at 89 Newtons (N), 134N and at maximum manual force (MMax) level. To assess the inter- and intra-observer agreement, the intraclass-correlation coefficient (ICC) was calculated. The "investigator effect" was a difference between two examiners in the same patient and the "device effect'' a difference within one examiner in the same patient. Minimally important difference (MID) was calculated as 0.5 of the standard deviation. RESULTS: Thirteen investigators were female, performing 1099 measurements and 11 were male, performing 791 measurements. ICC ranged between 0.558 and 0.644. At the MMax level, male investigators had a higher mm reading than female investigators (p < 0.001). Increased experience did not correlate with a higher ICC. MID ranged between 0.85 and 1.65 mm. CONCLUSION: This study investigated the KT1000 arthrometer in a clinical setting with a large number of investigators. This device delivers moderate agreement of results. Both the device and investigator effect are present. The MMax level has shown the lowest agreement and a dependency on the investigator gender. LEVEL OF EVIDENCE: Level III diagnostic study.

Advanced Age Is Not a Barrier to Total Knee Arthroplasty: A Detailed Analysis of Outcomes and Complications in an Elderly Cohort Compared With Average Age Total Knee Arthroplasty Patients.

BACKGROUND: Life expectancy and higher complication rates have made the routine use of total knee arthroplasty (TKA) in elderly patients disputed by some authors. The purpose of this study was to assess patient and implant survivorship, complication and revision rates, and patient-reported outcomes (PROMS) in a cohort of patients aged above 80 years undergoing TKA. A comparison with a propensity matched cohort of patients of average age within our database for TKA was performed. METHODS: A retrospective review of prospectively collected data identified 644 patients over the age of 80 years undergoing a TKA within a 14-year period. After calculating the average age of all TKA patients within the reviewed database, a cohort deemed average age was created within 1 standard deviation of the average age and matched using the following criteria: gender, surgeon, diagnosis, procedure type, and year. The primary outcomes were survivorship of the implant and the patient. The secondary outcomes were complications, transfusion rates, discharge destination, and PROMS. RESULTS: The revision rate was low for both groups (P = .051). Implant survivorship at 10 years was similar (P = .07). Mortality rate was higher in the elderly (P < .001). General complication rate was higher in the elderly (P = .031). Surgical complications rates were similar (P = .702). The PROMS at final follow-up were 4% lower in the elderly (P < .001). CONCLUSION: TKA in the elderly is a safe procedure. With measures minimizing the perioperative complications and blood loss, the outcome can be expected to be similar to patients of average age. The projected implant and patient survivorship in the elderly cohort is long enough to suggest that TKA in the elderly could have a high impact on remaining quality of life. Level III retrospective study.

Metastatic sigmoid colon adenocarcinoma and tumour-related sarcoid reaction.

The association between malignancy and tumour-related sarcoid reaction is well documented, characterised by non-caseating granulomatous disease in haematological and solid malignancies. Its occurrence in colon cancer is rare and of unclear clinical significance. Herein, we present a case report of a 32-year-old woman diagnosed with concurrent metastatic sigmoid colon adenocarcinoma and pulmonary granulomatous disease suggestive of a tumour-related sarcoid reaction.

Two Endosomal NHX-Type Na+/H+ Antiporters are Involved in Auxin-Mediated Development in Arabidopsis thaliana.

In Arabidopsis thaliana, the endosomal-localized Na+/H+ antiporters NHX5 and NHX6 regulate ion and pH homeostasis and are important for plant growth and development. However, the mechanism by which these endosomal NHXs function in plant development is not well understood. Auxin modulates plant growth and development through the formation of concentration gradients in plant tissue to control cell division and expansion. Here, we identified a role for NHX5 and NHX6 in the establishment and maintenance of auxin gradients in embryo and root tissues. We observed developmental impairment and abnormal cell division in embryo and root tissues in the double knockout nhx5 nhx6, consistent with these tissues showing high expression of NHX5 and NHX6. Through confocal microscopy imaging with the DR5::GFP auxin reporter, we identify defects in the perception, accumulation and redistribution of auxin in nhx5 nhx6 cells. Furthermore, we find that the steady-state levels of the PIN-FORMED (PIN) auxin efflux carriers PIN1 and PIN2 are reduced in nhx5 nhx6 root cells. Our results demonstrate that NHX5 and NHX6 function in auxin-mediated plant development by maintaining PIN abundance at the plasma membrane, and provide new insight into the regulation of plant development by endosomal NHX antiporters.

Tofacitinib for the Treatment of Severe Alopecia Areata in Adults and Adolescents.

Alopecia areata (AA) is an autoimmune disease affecting people of all ages. There is currently no cure for AA, and a highly efficacious therapy for severe AA has been elusive. Recently, scientific advances have identified the Janus kinase pathway as a target for treatment. Both Janus kinase inhibitors approved by the US Food and Drug Administration, tofacitinib and ruxolitinib, have shown promise in open-label clinical trials. This review summarizes the results of long-term use of tofacitinib in severe AA.

Exercise training improves heart rate variability after methamphetamine dependency.

PURPOSE: Heart rate variability (HRV) reflects a healthy autonomic nervous system and is increased with physical training. Methamphetamine dependence (MD) causes autonomic dysfunction and diminished HRV. We compared recently abstinent methamphetamine-dependent participants with age-matched, drug-free controls (DF) and also investigated whether HRV can be improved with exercise training in the methamphetamine-dependent participants. METHODS: In 50 participants (MD = 28; DF = 22), resting heart rate (HR; R-R intervals) was recorded over 5 min while seated using a monitor affixed to a chest strap. Previously reported time domain (SDNN, RMSSD, pNN50) and frequency domain (LFnu, HFnu, LF/HF) parameters of HRV were calculated with customized software. MD were randomized to thrice-weekly exercise training (ME = 14) or equal attention without training (MC = 14) over 8 wk. Groups were compared using paired and unpaired t-tests. Statistical significance was set at P ≤ 0.05. RESULTS: Participant characteristics were matched between groups (mean ± SD): age = 33 ± 6 yr; body mass = 82.7 ± 12 kg, body mass index = 26.8 ± 4.1 kg·min. Compared with DF, the MD group had significantly higher resting HR (P < 0.05), LFnu, and LF/HF (P < 0.001) as well as lower SDNN, RMSSD, pNN50, and HFnu (all P < 0.001). At randomization, HRV indices were similar between ME and MC groups. However, after training, the ME group significantly (all P < 0.001) increased SDNN (+14.7 ± 2.0 ms, +34%), RMSSD (+19.6 ± 4.2 ms, +63%), pNN50 (+22.6% ± 2.7%, +173%), HFnu (+14.2 ± 1.9, +60%), and decreased HR (-5.2 ± 1.1 bpm, -7%), LFnu (-9.6 ± 1.5, -16%), and LF/HF (-0.7 ± 0.3, -19%). These measures did not change from baseline in the MC group. CONCLUSIONS: HRV, based on several conventional indices, was diminished in recently abstinent, methamphetamine-dependent individuals. Moreover, physical training yielded a marked increase in HRV, representing increased vagal modulation or improved autonomic balance.

A prospective patient-centred evaluation of urethroplasty for anterior urethral stricture using a validated patient-reported outcome measure.

BACKGROUND: Studies of interventions for urethral stricture have inferred patient benefit from clinician-driven outcomes or questionnaires lacking scientifically robust evidence of their measurement properties for men with this disease. OBJECTIVE: To evaluate urethral reconstruction from the patients' perspective using a validated patient-reported outcome measure (PROM). DESIGN, SETTING, AND PARTICIPANTS: Forty-six men with anterior urethral stricture at four UK urology centres completed the PROM before (baseline) and 2 yr after urethroplasty. INTERVENTION: A psychometrically robust PROM for men with urethral stricture disease. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Lower urinary tract symptoms (LUTS), health status, and treatment satisfaction were measured, and paired t and Wilcoxon matched-pairs tests were used for comparative analysis. RESULTS AND LIMITATIONS: Thirty-eight men underwent urethroplasty for bulbar stricture and eight for penile stricture. The median (range) follow-up was 25 (20-30) mo. Total LUTS scores (0 = least symptomatic, 24 = most symptomatic) improved from a median of 12 at baseline to 4 at 2 yr (mean [95% confidence interval (CI)] of differences 6.6 [4.2-9.1], p < 0.0001). A total of 33 men (72%) felt their urinary symptoms interfered less with their overall quality of life, 8 (17%) reported no change, and 5 (11%) were worse 2 yr after urethroplasty. Overall, 40 men (87%) remained "satisfied" or "very satisfied" with the outcome of their operation. Health status visual analogue scale scores (100 = best imaginable health, 0 = worst) 2 yr after urethroplasty improved from a mean of 69 at baseline to 79 (mean [95% CI] of differences 10 [2-18], p = 0.018). Health state index scores (1 = full health, 0 = dead) improved from 0.79 at baseline to 0.89 at 2 yr (mean [95% CI] of differences 0.10 [0.02-0.18), p = 0.012]). CONCLUSIONS: This is the first study to prospectively evaluate urethral reconstruction using a validated PROM. Men reported continued relief from symptoms with related improvements in overall health status 2 yr after urethroplasty. These data can be used as a provisional reference point against which urethral surgeons can benchmark their performance.

Defining a patient-reported outcome measure for urethral stricture surgery.

BACKGROUND: A systematic literature review did not identify a formally validated patient-reported outcome measure (PROM) for urethral stricture surgery. OBJECTIVE: Devise a PROM for urethral stricture surgery and evaluate its psychometric properties in a pilot study to determine suitability for wider implementation. DESIGN, SETTING, AND PARTICIPANTS: Constructs were identified from existing condition-specific and health-related quality of life (HRQoL) instruments. Men scheduled for urethroplasty were prospectively enrolled at five centres. INTERVENTION: Participants self-completed the draft PROM before and 6 mo after surgery. MEASUREMENTS: Question sets underwent psychometric assessment targeting criterion and content validity, test-retest reliability, internal consistency, acceptability, and responsiveness. RESULTS AND LIMITATIONS: A total of 85 men completed the preoperative PROM, with 49 also completing the postoperative PROM at a median of 146 d; and 31 the preoperative PROM twice at a median interval of 22 d for test-retest analysis. Expert opinion and patient feedback supported content validity. Excellent correlation between voiding symptom scores and maximum flow rate (r = -0.75), supported by parallel improvements in EQ-5D visual analogue and time trade-off scores, established criterion validity. Test-retest intraclass correlation coefficients ranged from 0.83 to 0.91 for the total voiding score and 0.93 for the construct overall; Cronbach's α was 0.80, ranging from 0.76 to 0.80 with any one item deleted. Item-total correlations ranged from 0.44 to 0.63. These values surpassed our predefined thresholds for item inclusion. Significant improvements in condition-specific and HRQoL components following urethroplasty demonstrated responsiveness to change (p < 0.0001). Wider implementation and review of the PROM will be required to establish generalisability across different disease states and for more complex interventions. CONCLUSIONS: This pilot study has defined a succinct, practical, and psychometrically robust PROM designed specifically to quantify changes in voiding symptoms and HRQoL following urethral stricture surgery.

A solution to the high-riding nipple-areola complex.

There are limited techniques described in the literature on how to lower the nipple-areola complex following surgery to the breast. We present a case of successful correction of a high-riding nipple using a Z-plasty technique with an 8-year follow-up in a breast reconstruction patient. The technique described may also be applicable to cases of high-riding nipples following aesthetic breast surgery such as reduction mammaplasty.

Retroesophageal internal jugular-to-internal jugular vein bypass for venous occlusion in a patient with complex hemodialysis access.

This report describes a right-hand dominant, self-dialyzing patient whose left brachiocephalic autogenous access was previously rescued for left brachiocephalic vein thrombosis with a bypass to the right internal jugular vein (IJV). After 1 year, the left IJV thrombosed, resulting in painful edema and venous dilatation. A retroesophageal IJV-IJV bypass was created, preserving the left brachiocephalic autogenous access.

Insertion and removal of intrauterine devices.

The intrauterine device (IUD) is an effective contraceptive for many women. The copper-releasing IUD can be used for 10 years before replacement and is a good choice for women who cannot, or choose not to, use hormone-releasing contraceptives. However, some women experience an increase in menstrual blood loss and dysmenorrhea. The progestin-releasing IUD can be used for five years. It may reduce menorrhagia and dysmenorrhea, although some women have increased spotting and bleeding during the first months after insertion. The ideal candidates for IUD use are parous women in stable, monogamous relationships. Pregnancy, unexplained vaginal bleeding, and a lifestyle placing the woman at risk for sexually transmitted diseases are contraindications to IUD use. Insertion of the IUD can take place at any time during the menstrual cycle provided the woman is not pregnant. Before insertion, a bimanual examination and a sounding of the uterus are necessary to determine the uterus position and the depth of the uterine cavity. The IUD is inserted into the uterus according to individual protocols, with the threads cut at a length to allow the patient to check the device's position. Expulsion may occur with both types of IUDs.