Outcomes of patients with myelofibrosis treated with compassionate use pacritinib: a sponsor-independent international study.

Myelofibrosis (MF) is a chronic yet progressive myeloid neoplasm in which only a minority of patients undergo curative therapy, hematopoietic stem cell transplantation. Ruxolitinib, a JAK1/2 inhibitor, is the lone therapy approved for MF, offering a clear symptom and spleen benefit at the expense of treatment-related cytopenias. Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. Due to an FDA-mandated full clinical hold, the randomized phase 3 PERSIST trials were abruptly stopped and PAC was immediately discontinued for all patients. Thirty-three patients benefitting from PAC on clinical trial prior to the hold were allowed to resume therapy on an individual, compassionate-use basis. This study reports the detailed outcomes of 19 of these PAC retreatment patients with a median follow-up of 8 months. Despite a median platelet count of 49 × 109/L at restart of PAC, no significant change in hematologic profile was observed. Grade 3/4 adverse events of epistaxis (n = 1), asymptomatic QT prolongation (n = 1), and bradycardia (n = 1) occurred in three patients within the first 3 months of retreatment. One death due to catheter-associated sepsis occurred. The median time to discontinuation of PAC therapy on compassionate use for all 33 patients was 12.2 (95% CI 8.3-NR) months. PAC retreatment was associated with modest improvement in splenomegaly without progressive myelosuppression and supports the continued development of this agent for the treatment of MF second line to ruxolitinib or in the setting of treatment-limiting thrombocytopenia.

Musculoskeletal complaints in military recruits during their basic training.

INTRODUCTION: Overuse injuries often start with a musculoskeletal complaint, which can progress over time to an injury. Little or no information is known about the development and severity of overuse injuries in military recruits. This study describes the musculoskeletal complaints in Dutch military recruits during their basic training and examines potential predictive factors for dropout due to injury. METHODS: In this prospective cohort study, Dutch military recruits reported complaints of the lower body weekly using a Numeric Rating Scale (NRS) pain score chart during their basic training. Number, location and severity of complaints during each of the first 12 weeks of basic training were analysed. RESULTS: Of the 930 recruits, 61% reported an NRS pain score of 3 or higher and 34% reported an NRS pain score of 5 or higher at least once. Complaints were mostly reported in the foot and ankle region and least reported in the upper leg region. Injury dropouts (11%) showed significantly higher proportions of complaints and higher maximal pain scores throughout most weeks of basic training. The maximal NRS pain score of the first two weeks was the strongest predictor of dropping out due to injury. CONCLUSIONS: Recruits who drop out due to injury report more severe complaints throughout basic training. Focusing on musculoskeletal complaints in the first phase of training seems helpful to identify recruits who are at risk of developing an injury.

A Paleolithic-type diet results in iodine deficiency: a 2-year randomized trial in postmenopausal obese women.

BACKGROUND/OBJECTIVES: Different diets are used for weight loss. A Paleolithic-type diet (PD) has beneficial metabolic effects, but two of the largest iodine sources, table salt and dairy products, are excluded. The objectives of this study were to compare 24-h urinary iodine concentration (24-UIC) in subjects on PD with 24-UIC in subjects on a diet according to the Nordic Nutrition Recommendations (NNR) and to study if PD results in a higher risk of developing iodine deficiency (ID), than NNR diet. SUBJECTS/METHODS: A 2-year prospective randomized trial in a tertiary referral center where healthy postmenopausal overweight or obese women were randomized to either PD (n=35) or NNR diet (n=35). Dietary iodine intake, 24-UIC, 24-h urinary iodine excretion (24-UIE), free thyroxin (FT4), free triiodothyronine (FT3) and thyrotropin (TSH) were measured at baseline, 6 and 24 months. Completeness of urine sampling was monitored by para-aminobenzoic acid and salt intake by urinary sodium. RESULTS: At baseline, median 24-UIC (71.0 µg/l) and 24-UIE (134.0 µg/d) were similar in the PD and NNR groups. After 6 months, 24-UIC had decreased to 36.0 µg/l (P=0.001) and 24-UIE to 77.0 µg/d (P=0.001) in the PD group; in the NNR group, levels were unaltered. FT4, TSH and FT3 were similar in both groups, except for FT3 at 6 months being lower in PD than in NNR group. CONCLUSIONS: A PD results in a higher risk of developing ID, than a diet according to the NNR. Therefore, we suggest iodine supplementation should be considered when on a PD.

Physical workload on upper extremities in various operations during machine milking.

The aim of the study was to quantify the workload on the upper extremity for fundamental work tasks during machine milking. Eleven milkers working in a loose-housing system with a milking parlour participated in the study. Muscle activity for the biceps and the forearm flexors, as well as positions and movements of the wrists were simultaneously measured by electromyography and electrogoniometry while video-recording the work. The milking work was broken up in three main tasks "Drying (the cow's udder)", "Pre-milking (the first milk)" and "Attaching (the milking unit to the udder)" and three supplementary tasks. All three main tasks show high muscle load values and almost no time for rest. The highest load values for the biceps and flexor muscles were found during the tasks "Attaching, holding the milking unit" and "Drying", respectively. For 10% of the recording time, the milkers held active hands in 42 degrees dorsal flexion during the milking tasks "Pre-milking" and "Attaching" and in deviated positions exceeding 50% of their maximum values during "Attaching" and "Drying". The high muscle loads in combination with extreme positions and movements of the hand and forearm might contribute to the development of injuries among milkers. The result from the study aims to form a basis for technical improvements of the milking equipment to decrease the risk for arm wrist and hand disorders.

Wrist positions and movements as possible risk factors during machine milking.

High prevalence of hand and wrist symptoms has been found in females working with machine milking. Therefore the aim of this study was to quantify the positions and movements of the wrist during machine milking, and to compare tethering and loose-housing systems with respect to this. Biaxial electrogoniometers and data loggers were used for recording flexion and deviation angles of both the right and left wrists in 11 healthy milkers. For each individual 25 min of representative work was recorded in each system. High values of dorsiflexion and radial deviation were found, which might induce an increased risk of carpal tunnel syndrome. Moreover, the velocity and repetitiveness were close to those values described in repetitive work with a high risk of elbow and hand disorders in the fish-processing industry and giro-form data entry work. According to our findings, the load on the upper extremities has increased with respect to dorsiflexed hand position and repetitiveness when milking in the modern loose-housing milking system. This is probably due to the change of the working position and/or the higher productivity (number of cows that milked per time unit) in the loose-housing system as compared to the old-fashioned tethering system. These negative effects on wrist positions and movements should be considered when building new milking systems.

Riding instructors, their musculoskeletal health and working conditions.

UNLABELLED: The aim of this study was to gain a deeper understanding of riding instructors' working conditions, work load, and frequency of musculoskeletal problems and to identify potential risk factors for the development of musculoskeletal problems. A questionnaire was mailed to 800 instructors in Sweden containing questions on their work environment, work tasks, work load, and musculoskeletal symptoms. The Borg CR-10 scale was used to estimate the work load, and the Standardized Nordic Questionnaire was used to analyze the occurrence of musculoskeletal symptoms. Perceived symptoms were most frequently reported to be in the shoulders (60%), lower back (56%), and neck (52%) during the past 12 months; 91% of the riding instructors had experienced symptoms from at least one of nine anatomical areas during the past 12 months and 55% in the seven days prior to answering the questionnaire. Removal of manure from the stable was considered to be the task involving the heaviest work, and 14.5% had suffered an injury at work during the past year. The risk of developing musculoskeletal problems was 50% less for those who did physical exercise at least two hours a week besides riding (OR = 0.47, CI 0.25-0.89). CONCLUSIONS: The prevalence of symptoms was high, considering the low median age (33 years). Reducing workload, guarding against injury, and performing other exercises besides riding could be important measures for the prevention of musculoskeletal symptoms in this particular group of workers.

Gender difference in prevalence of upper extremity musculoskeletal symptoms among Swedish pig farmers.

There have been very few epidemiological studies dealing with pig farmers' musculoskeletal health. The aim of this study was to carry out a cross-section postal questionnaire survey dealing with musculoskeletal symptoms among female and male pig farmers in large-scale production. The participation rate overall was 70% (288/410). Over 10% of the questionnaires had missing gender data. Three different questionnaires were used: the general standardized Nordic questionnaire for the analysis of musculoskeletal symptoms; a questionnaire dealing with occurrence of numbness, reduced muscle strength, etc., in the wrists and hands; and occupational factors were screened by a special questionnaire. The results showed that musculoskeletal morbidity is high among pig farmers. The women had significantly more problems than the men with respect to the upper extremities. Symptoms in the wrists and hands such as numbness, reduced muscle strength, aching fingers and wrists, and tendency to drop things were significantly more common among the women than the men. Occupational factors dealing with, for example, the size of the pig farm, were not related to the occurrence of symptoms. Occupational factors of importance for the development of disorders, particularly among women pig farmers, should be given priority in ergonomic interventions.

Protoplast formation and cell wall regeneration in Clostridium perfringens.

A protocol was developed for the efficient production and regeneration of Clostridium perfringens protoplasts. Cell wall regeneration frequencies of up to 5% were obtained.

Milking is a high-risk job for young females.

The prevalence of and the impact of selected factors on self-reported musculoskeletal complaints in Swedish female milkers with special reference to symptoms in the upper extremities were investigated using data from mail-in surveys. An agricultural study group was formed of three subgroups: 161 active milkers, 108 non-milkers and 62 ex-milkers, women who had been milkers earlier but were no longer doing that kind of work. In the course of the analysis these subgroups were compared with each other and also, separately or in combinations, with a non-agricultural population consisting of 166 nursing assistants. Problems in the upper extremities were significantly more common in the agricultural group than in the non-agricultural group. Milkers ran a higher risk of developing symptoms in the wrists and hands than non-milking women. Symptoms such as numbness, coldness in the wrists and white fingers were more common in all agricultural subgroups than in the non-agricultural group. Numbness and white fingers were related to vibration exposure in the ex-milker and the non-milker groups but not in the milker group. Psychosocial factors such as occupational well-being were not related to the occurrence of symptoms. Milking in a modernized barn gave fewer problems in elbows than milking in a traditional barn. Milkers who had received ergonomic instruction on how to work in order to reduce muscle stress had fewer problems in the elbow region than those who had received no such information.

Pronator syndrome: a retrospective study of median nerve entrapment at the elbow in female machine milkers.

Pronator syndrome (median nerve entrapment at the elbow) is a rare condition, but it is more common among women than men. A long-term retrospective follow-up study evaluating the outcome of surgical release of the median nerve for female machine milkers has never been carried out before, nor has a long-term study of non-treated female milkers with pronator syndrome. In the present study, two groups of machine milkers (surgical and non-surgical) were compared. The clinical examination focused on two parameters: focal tenderness and individual muscle strength. The results showed that the surgical group had no focal tenderness on palpation over the median nerve at the elbow and no selective weakness in the muscles examined, as compared to what was found before surgery. In the non-surgical group, focal tenderness was found in 12 out of 14, and 10 out of 14 showed the same weakness as in an earlier examination. While this study has limitations in sample size, surgical release of the median nerve at the elbow level, in cases of pronator syndrome, appears to provide an immediate as well as long-term return to normal strength of FPL and FDP II, along with a significant improvement in subjective status. In the non-surgical group, spontaneous improvement of the strength of FPL and FDP II was found in only four out of the 14 cases.

Upper extremity nerve involvement in Swedish female machine milkers.

Entrapment of the median nerve in the proximal forearm, the so-called pronator syndrome, is considered a rather rare condition but it is four times more common in women than in men. In this study, 23 of 30 female machine milkers with symptoms in the forearm and hand were clinically diagnosed as having the pronator syndrome. The diagnosis of median nerve involvement was based on the clinical history and on physical examination by a hand surgeon. All 23 milkers complained of aching in the volar part of the forearm and had a sensation of numbness, tingling, and decreased muscle strength in their hands, mostly in the hands which usually were statically loaded with heavy equipment. Objectively, all had an experience of tenderness over the pronator teres muscle. Furthermore, they showed reduced muscle strength, especially in the following muscles: pronator teres (PT), flexor carpi radialis (FCR), flexor pollicis longus (FPL), and flexor digitorum profundus II (FDP II). To validate the manual muscle testing, Mannerfeldt's intrinsicmeter was used to quantify the clinically observed weakness. Eight of the 23 milkers with pronator syndrome were surgically released from neuropathy and were almost symptom-free at follow-up after six months. One patient had a slight sensation of numbness and had to be given surgical carpal tunnel release later on. The external exposure of the arm during the application of the milking cluster probably causes muscle and fascial tensions that induce compression of the nerve. Further studies are needed to establish the level of the internal exposure.

The Natural Course of Musculoskeletal Symptoms and Clinical Findings in Upper Extremities of Female Milkers.

To explore milkers' state of health with regard to symptoms in the wrists and hands, a study of 80 female milkers was carried out 12 months after a Nordic questionnaire study of these subjects. Of these 80, 41 had reported pain and discomfort in the wrists and hands at the time of the questionnaire study, whereas the remaining 39 had had no such symptoms. To determine the sensitivity and specificity of the Nordic questionnaire, the follow-up study included examination by an unbiased clinician. The occurrence of symptoms in the wrists and hands during the preceding 12 months was found to have been rather stable-30 of the 41 milkers still reported pain, aching, and discomfort, and eight new cases were recorded. On clinical examination, symptoms including numbness, tingling, and coldness in the forearms and hands were reported by 51 of the 80 milkers, 14 of whom had clinical symptoms and signs indicating median nerve entrapment. Peritendinitis was diagnosed in four subjects and a ganglion cyst in one. The findings in the remaining group did not meet diagnostic criteria. All subjects with wrist and hand symptoms were still at work a year after the initial study. The sensitivity of the Nordic questionnaire when it came to identifying subjects with clinical findings was found to be unsatisfactory. The actual incidence of wrist and hand disorders may be underestimated if the Nordic questionnaire is used as the only instrument in epidemiologic screenings.